Iron is an essential nutrient best known for its necessity in forming hemoglobin, the protein in red blood cells that transports oxygen from the lungs to distant tissues. It also plays important roles in cell maintenance and growth. 

Healthy levels of iron are important to fuel and nourish the normal cells in our bodies, but iron can fuel and nourish cancer cells as well. A flurry of studies in recent years have contributed data, piece by piece, to the complex puzzle of how cancer cells use iron and how iron levels in the body may impact cancer risk. 

Studying iron-rich tumors has told researchers a lot about the underlying biology of cancer cells, the immune cells that accompany them, and the stroma that surrounds them. Ironing out the intricacies will be a complicated challenge, fraught with many wrinkles, but it may eventually lead to fresh new therapies for patients. 

Excess Iron and Cancer Risk 

Because our bodies cannot synthesize iron, we get iron entirely from our diet and supplements. Dietary intake, as well as genetic conditions that can affect how the body absorbs and processes iron, can dictate whether we have too much or too little, which can, in turn, impact overall health. 

So, if iron can help cancer cells grow, does having too much iron in your bloodstream affect your risk of cancer? 

While the answer isn’t clear cut, some data points to “yes.” One common measurement of healthy iron levels is the amount of an iron storage protein called ferritin circulating in the plasma. Clinical practice has established a range of ferritin levels typically considered “normal,” and ferritin concentrations outside of these ranges may indicate a medical issue that needs to be addressed. 

In a study published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research (AACR), researchers looked at measurements of serum ferritin in over 1 million individuals who received care at a large health system in Israel. They examined the correlation between high ferritin levels—those exceeding three times the upper limit of the reference range—and the risk of developing cancer. 

Individuals with elevated ferritin were nearly twice as likely to be diagnosed with cancer as those with ferritin levels below the reference range. The risk was especially high for hematologic malignancies (5.4-fold risk), pancreatic cancer (2.7-fold risk), hepatobiliary cancers (6.4-fold risk), and gastrointestinal malignancies other than colorectal cancer (5.1-fold risk). Conversely, cancers of the breast, male reproductive system, thyroid, brain, and skin were not associated with ferritin levels. 

Other researchers investigated whether modulating iron levels could aggravate cases of myelodysplastic syndrome (MDS), a cancer in which the bone marrow makes blood cells that do not mature into healthy blood cells. Some patients with MDS require regular blood transfusions because their red blood cells do not work properly, and regular blood transfusions can put patients at risk of excess iron. 

In a mouse model of MDS, researchers overexpressed the iron export protein ferroportin to induce iron overload and found that this worsened several MDS disease characteristics, including more reactive oxygen species and DNA damage and increased numbers of immature myeloid blasts. 

Conversely, when the researchers blocked ferroportin with the drug vamifeport, mice with MDS had improved anemia, longer survival, and a lower proportion of immature myeloid blasts than mice that did not receive vamifeport. The researchers suggested that these data may highlight the importance of maintaining healthy iron levels in patients with MDS and may position iron restriction as a potential therapeutic option to help reduce disease severity. 

How Cancer Cells Use Iron 

At the cellular level, what makes excess iron so lucrative for the development and progression of cancer? 

So far, researchers know that too much iron can produce free radicals and reactive oxygen species that can damage DNA, potentially leading to cancer-causing mutations. Iron plays a critical role in the formation of nucleotides that are used to replicate DNA, and it can also activate the cancer driver protein HIF2α. 

In a recent article in Cancer Discovery, a journal of the AACR, researchers identified an additional mechanism by which iron might promote cancer by helping to elongate telomeres, protective DNA sequences at the ends of chromosomes that can help determine how long a cell survives and how many times it replicates its DNA. To ensure the cell can continue dividing, many cancer cells have mechanisms to elongate their telomeres, including activation of the enzyme telomerase. 

Using human colorectal cancer samples, researchers found that iron levels positively correlated with activity of hTERT, a key subunit of telomerase. They observed that iron can activate the iron-sensing protein pirin, which can in turn boost hTERT expression. Further, the researchers identified a small molecule inhibitor of pirin, SP2509, that can block iron-mediated hTERT reactivation. Treatment with SP2509 decreased growth in several cell lines and mouse xenograft models. 

Iron is also a crucial component for some types of cellular metabolism, so the ability to process large amounts of iron may help cells grow faster. At the 2024 AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research, Joseph Mancias, MD, PhD, an assistant professor of radiation oncology at Dana-Farber Cancer Institute, explained how pancreatic cancer cells accomplish this feat. 

Pancreatic cancer cells commonly utilize a process called autophagy, in which cells degrade and recycle intracellular structures. In the course of studying how the cancer relies on autophagy, and perhaps how to target it, Mancias and colleagues identified a protein called NCOA4 that is upregulated during autophagy in pancreatic cancer cells. They showed that NCOA4 can bind to the iron storage protein ferritin and bring it into pockets called autophagosomes, where ferritin is degraded to release free iron. In mouse models, knocking out NCOA4 delayed tumor formation and improved survival. 

Mancias expressed hope that the seemingly crucial function of ferritinophagy in pancreatic cancer cells could make it a promising drug target. “[Ferritinophagy] may be one of the most important cell autonomous aspects of autophagy in pancreatic cancer, and it might be worth targeting,” he said. 

How Cancer-supporting Cells Use Iron 

Cancer cells are not the only cells that can use iron to spur tumor growth. Cancer-associated fibroblasts (CAFs) are a well-characterized component of the tumor microenvironment that can fuel cancer growth and survival in a multitude of ways. 

In a recent study, researchers identified a subset of iron-rich CAFs that use their abundant iron to reprogram gene expression so they can drive immune suppression in prostate cancer. These “FerroCAFs” accumulate iron by degrading heme, the iron-containing component of hemoglobin in the blood. The high iron levels activate a genetic reprogramming enzyme called KDM6B, which loosens chromatin and boosts expression of myeloid cell-associated cytokines. The cytokines attract immune-suppressive myeloid cells to the tumor, helping to dampen the antitumor immune response. 

Some tumor-promoting immune cells also use iron themselves. Similar to the FerroCAFs, researchers identified an iron-rich population of tumor-associated macrophages (TAMs), another cell type known to contribute to the immune-suppressive microenvironment of many tumor types. 

Macrophages can engulf and degrade pathogens as well as infected or damaged cells. This includes red blood cells that have escaped circulation, which can happen when vascular-rich tumors hemorrhage. The researchers showed that TAMs exposed to heme had a unique transcriptional profile with enhanced immune-suppressive capabilities. Inside these iron-rich TAMs (iTAMs), heme can bind to and inactivate the transcriptional repressor Bach1. This allows for the expression of genes like HMOX1, which helps degrade heme to release free iron for the cell to use, and endothelin receptor B (EDNRB). 

The researchers characterized EDNRB as a biomarker of iTAMs in mouse sarcoma models and patient samples of synovial sarcoma and melanoma, and also as a driver of iTAMs’ tumor-promoting functions. When they knocked out EDNRB in mouse macrophages, it decreased fibrosarcoma growth and blood vessel infiltration in mice. While more work will be necessary to identify how EDNRB stimulates tumorigenic activity in iTAMs, it may present a viable therapeutic target for further exploration. 

Leveraging the Vulnerabilities of Iron-loving Cells 

The complex interactions between iron, tumor cells, and the tumor microenvironment will necessitate further research to determine how researchers might best intervene. Nevertheless, a few possible strategies are emerging. 

An abundance of iron-related gene signatures among cells in the ovarian cancer tumor microenvironment spurred some researchers to test how iron chelation might affect ovarian cancer progression. In a study published in Cancer Discovery, researchers treated ovarian cancer mouse models with the iron chelator deferiprone (Ferriprox) and observed that the drug decreased tumor growth, the spread of cancer, and the presence of peritoneal micrometastases. Mice that received deferiprone survived a median of 25% longer than untreated mice, a margin that rose to 50% when deferiprone was combined with cisplatin. 

Researchers are also investigating how they can use cancer cells’ thirst for iron against them. In recent years, scientists have learned a great deal about a type of iron-dependent cell death called ferroptosis, in which iron oxidizes lipids in the cell, leading to cell death. Often, ferroptosis is precipitated by the genetic, environmental, or pharmacological failure of normal antioxidant mechanisms, leaving the cell unable to undo the oxidative stress caused by the accumulation of iron. 

Various research has shown that some cancer cells may protect themselves from ferroptosis by boosting the incorporation of oxidation-resistant lipids, such as oleic acid, into their cell membranes. A few existing therapies, including antiestrogen and antiandrogen hormone therapies for breast and prostate cancer, respectively, can promote ferroptosis by blocking oleic acid incorporation. Other cell signaling mechanisms, including T cell-secreted interferon gamma, can promote the incorporation of pro-ferroptotic lipids into the cell membrane. 

As researchers learn more about ferroptosis and how to induce it, the knowledge may provide an additional tool in the growing toolkit of ways researchers can leverage the weaknesses of iron-loving cancer tumors. With iron chelators such as deferiprone already approved for other indications, and several more strategies on the horizon, this field may provide hope for new interventions in coming years.

The American Association for Cancer Research (AACR) has members in 142 countries and territories around the world, many in countries that have different resource capacities than nations like the United States. While this can include low- and middle-income countries, it also applies to more economically developed countries that are still in the midst of building or improving upon the systems in place to support researchers. So, what does it mean for cancer researchers in those countries to be a member of the AACR?

“As a community, AACR sets the standards for scientific work in our field,” said Roger Chammas, MD, PhD, professor of oncology and chair in at the Center for Translational Research in Oncology at the Instituto do Câncer do Estado de São Paulo in Brazil. “AACR stays ahead of the emerging trends in cancer research, publishing discoveries across its various scholarly journals and sharing them through meetings, specialized conferences, and educational workshops, all while emphasizing the importance of professional mentorship.”

For Sok Ching Cheong, PhD, AACR is more than a professional organization. “It’s a gateway to the latest in cancer research and a platform for global collaboration,” said the chief scientific officer at Cancer Research Malaysia.

To expand global collaborations further and support its mission to eradicate cancer worldwide, AACR recently announced that it is waiving membership dues for current and future members living in certain countries/territories that meet a newly defined set of criteria evaluating available support for cancer research. To achieve this, AACR first developed a proprietary formula that went beyond income-level data to also examine the funding available for individuals to conduct cancer research and the support they receive for professional development. This new economic classification model now incorporates information from the World Bank and the Human Development Index as well as regional- and national-level research and development funding health expenditure data.

“As the world’s first and largest cancer research organization, AACR is proud to say that almost a third of our more than 58,000 members reside in countries and territories outside the United States. We are deeply committed to serving our members across the globe and taking into account the lived experiences of cancer researchers and the funding sources they have available,” said AACR Chief Executive Officer Margaret Foti, PhD, MD (hc). “The new classification system will allow for a more inclusive membership, and one that better reflects the unique circumstances of cancer research capacities in different countries and territories around the world.”

Under this new model, countries/territories are now separated into one of two categories: “high cancer research capacity” and “building cancer research capacity.” More than 170 countries fall into the latter category where AACR membership dues are now eliminated. China is the only country that moved from the lower research capacity level to the higher capacity level, but membership fees there will remain the same for the upcoming year.

Members of AACR receive numerous benefits including substantially reduced registration rates for the AACR Annual Meeting, sponsorship privileges for abstracts for presentation at the AACR Annual Meeting, access to summer training workshops, funding and award opportunities, a complimentary digital subscription to an AACR journal of choice. discounted publication charges for articles published in the journals, and much more.

“By offering access to high-quality information, education, and unique programs, AACR’s innovative policy of providing free membership to researchers from low- and middle-income countries fosters a sense of belonging,” Chammas said. “This initiative will strengthen global ties, fostering connections and enhancing collaboration between researchers from countries with advanced research capacity with those from the Global South, accelerating capacity building worldwide.”

From the other side of the world, Cheong said that this initiative will not only help address global cancer-related challenges, but also those unique to each country. Ultimately, she said it will “enhance our collective efforts in cancer prevention, detection, and treatment.”

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If you are interested in becoming an AACR member, learn more about the application process. If you are a current member located in one of the “building cancer research capacity” countries/territories, learn more about the changes and the membership renewal process.

As we head into the holiday season, Cancer Research Catalyst has tantalizing teasers in the form of science stocking stuffers straight from our November edition of Editors’ Picks. This month, the editors of the 10 American Association for Cancer Research (AACR) journals selected studies covering the immune-boosting benefits of dietary restriction, novel therapies like nanovaccines and p53-targeting peptides, and health disparities in specific communities, including chronic conditions in LGBTQ+ cancer survivors and cervical cancer in Native American women. 

Read the abstracts below or follow the links to the full articles, which are freely available for a limited time.  

JOURNAL: BLOOD CANCER DISCOVERY 

Multiple Myeloma Risk and Outcomes Are Associated with Pathogenic Germline Variants in DNA Repair Genes 

First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. PGVs were identified in 8.6% of the Discovery cohort and 11.5% of the Replication cohort, with a notable presence of high- or moderate-penetrance PGVs (associated with autosomal dominant cancer predisposition) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR = 3.9, FDR < 0.01) and BRCA2 (OR = 7.0, FDR < 0.001) were significantly enriched in patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem-cell transplantation (P < 0.01). 

Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. 

A related commentary was published in the November issue. 

JOURNAL: CANCER DISCOVERY 

T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study 

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non–small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. 

Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. 

A related commentary was published in the November issue. This issue also had a special collection of articles from Chinese researchers. Learn more about this collection. 

JOURNAL: CANCER EPIDEMIOLOGY, BIOMARKRS & PREVENTION 

Chronic Health Conditions, Disability, and Physical and Cognitive Limitations among LGBTQ+ Cancer Survivors 

Background: Cancer survivors are at high risk for chronic health conditions and physical and cognitive limitations. However, few studies have explored these outcomes among Lesbian, Gay, Bisexual, Transgender, Queer, Plus (LGBTQ+) survivors. 

Methods: We used pooled, weighted Behavioral Risk Factor Surveillance System data from 23 states that completed two specific modules at least once from 2020 to 2022. We calculated age-adjusted prevalence for heart disease, asthma, chronic obstructive pulmonary disease, depressive disorders, myocardial infarction, kidney disease, stroke, diabetes, hearing disability, vision disability, cognitive limitations, and difficulty walking, dressing, and running errands in LGBTQ+, lesbian, gay, or bisexual, transgender or gender nonconforming (TGNC), and non-LGBTQ+ cancer survivors. Four multivariable logistic regression models controlling for different factors were run for each outcome. 

Results: Of 40,990 cancer survivors, 1,715 were LGBTQ+. LGBTQ+ survivors had significantly higher age-adjusted prevalence of all outcomes. The prevalence of all outcomes was the highest among TGNC survivors, except for depressive disorders and cognitive limitations. LGBTQ+ survivors had higher odds of reporting asthma [adjusted OR (aOR): 1.5; 95% confidence interval (CI), 1.2–1.9], depressive disorders (aOR: 1.9; 95% CI, 1.6–2.4), kidney disease (aOR: 1.5; 95% CI, 1.1–2.1), stroke (aOR: 1.7; 95% CI, 1.3–2.3), diabetes (aOR: 1.3; 95% CI, 1.0–1.6), vision disability (aOR: 1.6; 95% CI, 1.2–2.2), cognitive limitations (aOR: 2.3; 95% CI, 1.8–2.9), difficulty walking (aOR: 1.7; 95% CI, 1.3–2.0), dressing (aOR: 2.0; 95% CI, 1.5–2.7), and running errands (aOR: 1.6; 95% CI, 1.3–2.1). In TGNC models, TGNC cancer survivors had increased odds of most outcomes in comparison to cisgender survivors. 

Conclusions: LGBTQ+ cancer survivors have an elevated burden of all chronic health conditions, disabilities, and limitations assessed. TGNC cancer survivors experience even higher burden of the same outcomes. 

Impact: Findings highlight substantial disparities regarding the health of LGBTQ+ cancer survivors. 

A related commentary was published in the November issue. This study was also covered as part of a blog post on LGBTQ+ cancer survivors. 

JOURNAL: CANCER IMMUNOLOGY RESEARCH 

A Single-Cell Analysis of the NK-Cell Landscape Reveals That Dietary Restriction Boosts NK-Cell Antitumor Immunity via Eomesodermin 

Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cells, dietary restriction also plays an extrinsic role in restricting tumor growth by regulating immune cells. NK cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether dietary restriction can assist NK cells in controlling tumor growth. In this study, we demonstrate that dietary restriction effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by dietary restriction was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that dietary restriction enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, dietary restriction activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. First, dietary restriction promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, dietary restriction enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that dietary restriction therapy enhances tumor immunity through nontumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation. 

This story was featured on the cover of the November issue. 

JOURNAL: CANCER PREVENTION RESEARCH 

Viewing Native American Cervical Cancer Disparities through the Lens of the Vaginal Microbiome: A Pilot Study 

Vaginal dysbiosis is implicated in persistent human papillomavirus (HPV) infection and cervical cancer. Yet, there is a paucity of data on the vaginal microbiome in Native American communities. Here, we aimed to elucidate the relationships between microbiome, HPV, sociodemographic, and behavioral risk factors to better understand an increased cervical cancer risk in Native American women. In this pilot study, we recruited 31 participants (16 Native American and 15 non-Native women) in Northern Arizona and examined vaginal microbiota composition, HPV status, and immune mediators. We also assessed individuals’ sociodemographic information and physical, mental, sexual, and reproductive health. Overall, microbiota profiles were dominated by common Lactobacillus species (associated with vaginal health) or a mixture of bacterial vaginosis–associated bacteria. Only 44% of Native women exhibited Lactobacillus dominance, compared with 58% of non-Native women. Women with vaginal dysbiosis also had elevated vaginal pH and were more frequently infected with high-risk HPV. Furthermore, we observed associations of multiple people in a household, lower level of education, and high parity with vaginal dysbiosis and abundance of specific bacterial species. Finally, women with dysbiotic microbiota presented with elevated vaginal levels of proinflammatory cytokines. Altogether, these findings indicate an interplay between HPV, vaginal microbiota, and host defense, which may play a role in the cervical cancer disparity among Native American women. Future longitudinal studies are needed to determine the mechanistic role of vaginal microbiota in HPV persistence in the context of social determinants of health toward the long-term goal of reducing health disparities between non-Hispanic White and Native American populations. 

Prevention Relevance: Cervical cancer disproportionally affects Native American women. Sociodemographic and behavioral factors might contribute to this disparity via alteration of vaginal microbiota. Here, we show the association between these factors and vaginal dysbiosis and immune activation, which can be implicated in high-risk HPV infection among Native American and other racial/ethnic populations. 

This story was featured on the cover of the November issue. 

JOURNAL: CANCER RESEARCH 

Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1 

Most patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR). Consequently, a portion of these patients develop AR-independent neuroendocrine (NE) prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the progression to NEPC suggests a model of lineage plasticity whereby AR-dependent luminal-like tumors progress toward an AR-independent NEPC state. Genetic analysis of human NEPC identified frequent loss of RB1 and TP53, and the loss of both genes in experimental models mediates the transition to a NE lineage. Transcriptomics studies have shown that lineage transcription factors ASCL1 and NEUROD1 are present in NEPC. In this study, we modeled the progression of prostate adenocarcinoma to NEPC by establishing prostate organoids and subsequently generating subcutaneous allograft tumors from genetically engineered mouse models harboring Cre-induced loss of Rb1 and Trp53 with Myc overexpression (RPM). These tumors were heterogeneous and displayed adenocarcinoma, squamous, and NE features. ASCL1 and NEUROD1 were expressed within NE-defined regions, with ASCL1 being predominant. Genetic loss of Ascl1 in this model did not decrease tumor incidence, growth, or metastasis; however, there was a notable decrease in NE identity and an increase in basal-like identity. This study provides an in vivo model to study progression to NEPC and establishes the requirement for ASCL1 in driving NE differentiation in prostate cancer. 

Significance: Modeling lineage transitions in prostate cancer and testing dependencies of lineage transcription factors have therapeutic implications, given the emergence of treatment-resistant, aggressive forms of neuroendocrine prostate cancer. 

A related commentary was published in the November 1 issue. 

JOURNAL: CANCER RESEARCH 

Precise In Situ Delivery of a Photo-Enhanceable Inflammasome-Activating Nanovaccine Activates Anticancer Immunity 

A variety of state-of-the-art nanovaccines combined with immunotherapies have recently been developed to treat malignant tumors, showing promising results. However, immunosuppression in the tumor microenvironment (TME) restrains cytotoxic T-cell infiltration and limits the efficacy of immunotherapies in solid tumors. Therefore, tactics for enhancing antigen cross-presentation and reshaping the TME need to be explored to enhance the activity of nanovaccines. Here, we developed photo-enhanceable inflammasome-activating nanovaccines (PIN) to achieve precise in situ delivery of a tumor antigen and a hydrophobic small molecule activating the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain–containing protein 3 inflammasome (NLRP3) pathway. Near-infrared light irradiation promoted PIN accumulation in tumor sites through photo-triggered charge reversal of the nanocarrier. Systematic PIN administration facilitated intratumoral NLRP3 inflammasome activation and antigen cross-presentation in antigen-presenting cells upon light irradiation at tumor sites. Furthermore, PIN treatment triggered immune responses by promoting the production of proinflammatory cytokines and activating antitumor immunity without significant systematic toxicity. Importantly, the PIN enhanced the efficacy of immune checkpoint blockade and supported the establishment of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Collectively, this study reports a safe and efficient photoresponsive system for codelivery of antigens and immune modulators into tumor tissues, with promising therapeutic potential. 

Significance: The development of a photoresponsive nanovaccine with spatiotemporal controllability enables robust tumor microenvironment modulation and enhances the efficacy of immune checkpoint blockade, providing an effective immunotherapeutic strategy for cancer treatment. 

A related commentary was published in the November 15 issue. 

JOURNAL: CLINICAL CANCER RESEARCH 

A Phase II Study of Atezolizumab, Pertuzumab, and High-Dose Trastuzumab for Central Nervous System Metastases in Patients with HER2-Positive Breast Cancer 

Purpose: Patients with HER2-positive breast cancer brain metastases have few effective systemic therapy options. In a prior study, pertuzumab with high-dose trastuzumab demonstrated a high clinical benefit rate (CBR) in the central nervous system (CNS) in patients with brain metastases. The current trial evaluated whether the addition of atezolizumab to this regimen would produce further improvements in CNS response. 

Patients and Methods: This was a single-arm, multicenter, phase II trial of atezolizumab, pertuzumab, and high-dose trastuzumab for patients with HER2-positive breast cancer brain metastases. Participants received atezolizumab 1,200 mg i.v. every 3 weeks, pertuzumab (loading dosage 840 mg i.v., then 420 mg i.v. every 3 weeks), and high-dose trastuzumab (6 mg/kg i.v. weekly for 24 weeks, then 6 mg/kg i.v. every 3 weeks). The primary endpoint was CNS overall response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria. Key secondary endpoints included CBR, overall survival, and safety and tolerability of the combination. 

Results: Among 19 enrolled participants, two had a confirmed intracranial partial response for a CNS overall response rate of 10.5% (90% confidence interval, 1.9%–29.6%). The study did not meet the prespecified efficacy threshold and was terminated early. The CBR was 42.1% at 18 weeks and 31.6% at 24 weeks. Seven patients (36.8%) required a dose delay or hold, and the most frequent any-grade adverse events were diarrhea (26.3%) and fatigue (26.3%). 

Conclusions: The addition of atezolizumab to pertuzumab plus high-dose trastuzumab does not result in improved CNS responses in patients with HER2-positive breast cancer brain metastases. 

JOURNAL: CLINICAL CANCER RESEARCH 

A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6–Targeting Antibody–Drug Conjugate, in Patients with Small Cell Lung Cancer 

Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. 

Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks during dose escalation (0.3–2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by IHC) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. 

Results: As of August 2022, 99 patients received ABBV-011 monotherapy [dose escalation, n = 36; Japanese dose evaluation, n = 3; dose expansion, n = 60 (1 mg/kg, n = 40)]; the median age was 63 years (range, 41–79 years). Also, 32%, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. The most common treatment-emergent adverse events were fatigue (50%), nausea (42%), and thrombocytopenia (41%). The most common hepatic treatment-emergent adverse events were increased aspartate aminotransferase (22%), increased γ-glutamyltransferase (21%), and hyperbilirubinemia (17%); two patients experienced veno-occlusive liver disease. The objective response rate was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n = 40), the objective response rate was 25%; the median response duration was 4.2 months (95% confidence interval, 2.6–6.7); and the median progression-free survival was 3.5 months (95% confidence interval, 1.5–4.2). 

Conclusions: ABBV-011 1.0 mg/kg every 3 weeks monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation. 

JOURNAL: MOLECULAR CANCER RESEARCH 

GRAIL1 Stabilizes Misfolded Mutant p53 through a Ubiquitin Ligase-Independent, Chaperone Regulatory Function 

Frequent (>70%) TP53 mutations often promote its protein stabilization, driving esophageal adenocarcinoma (EAC) development linked to poor survival and therapy resistance. We previously reported that during Barrett’s esophagus progression to EAC, an isoform switch occurs in the E3 ubiquitin ligase RNF128 (aka GRAIL—gene related to anergy in lymphocytes), enriching isoform 1 (hereby GRAIL1) and stabilizing the mutant p53 protein. Consequently, GRAIL1 knockdown degrades mutant p53. But, how GRAIL1 stabilizes the mutant p53 protein remains unclear. In search for a mechanism, here, we performed biochemical and cell biology studies to identify that GRAIL has a binding domain (315-PMCKCDILKA-325) for heat shock protein 40/DNAJ. This interaction can influence DNAJ chaperone activity to modulate misfolded mutant p53 stability. As predicted, either the overexpression of a GRAIL fragment (Frag-J) encompassing the DNAJ binding domain or a cell-permeable peptide (Pep-J) encoding the above 10 amino acids can bind and inhibit DNAJ-Hsp70 co-chaperone activity, thus degrading misfolded mutant p53. Consequently, either Frag-J or Pep-J can reduce the survival of mutant p53 containing dysplastic Barrett’s esophagus and EAC cells and inhibit the growth of patient-derived organoids of dysplastic Barrett’s esophagus in 3D cultures. The misfolded mutant p53 targeting and growth inhibitory effects of Pep-J are comparable with simvastatin, a cholesterol-lowering drug that can degrade misfolded mutant p53 also via inhibiting DNAJA1, although by a distinct mechanism. 

Implications: We identified a novel ubiquitin ligase-independent, chaperone-regulating domain in GRAIL and further synthesized a first-in-class novel misfolded mutant p53 degrading peptide having future translational potential. 

This story was featured on the cover of the November issue. 

JOURNAL: MOLECULAR CANCER THERAPEUTICS 

Dual A_2A/A_2B Adenosine Receptor Antagonist M1069 Counteracts Immunosuppressive Mechanisms of Adenosine and Reduces Tumor Growth In Vivo

While A_2A adenosine receptor (AR) was considered as a major contributor to adenosine-mediated immunosuppression, A_2B, having the lowest affinity to adenosine, has also emerged as a potential contributor to tumor promotion. Therefore, in adenosine-rich tumor microenvironment (TME), where A_2B could be complementary and/or compensatory to A_2A, simultaneous targeting of A_2A and A_2B ARs can provide higher potential for cancer immunotherapy. We developed M1069—a highly selective dual antagonist of the A_2A and A_2B AR. In assays with primary human and murine immune cells, M1069 rescued IL2 production from T cells (A_2A dependent) and inhibited VEGF production by myeloid cells (A_2B dependent) in adenosine-high settings. M1069 also demonstrated superior suppression of the secretion of protumorigenic cytokines CXCL1, CXCL5, and rescue of IL12 secretion from adenosine-differentiated dendritic cells compared to an A_2A-selective antagonist (A_2Ai). In a one-way mixed lymphocyte reaction (MLR) assay, adenosine-differentiated human and murine dendritic cells treated with M1069 demonstrated superior T-cell stimulatory activity compared to dendritic cells differentiated in presence of A_2Ai. In vivo, M1069 decreased tumor growth as a monotherapy and enhanced antitumor activity of bintrafusp alfa (BA) or cisplatin in syngeneic adenosine^hi/CD73^hi 4T1 breast tumor model, but not in the CD73 knockout 4T1 tumor model or in adenosine^low/CD73^low MC38 murine colon carcinoma model. In summary, our dual A_2A/A_2B AR antagonist M1069 may counteract immune-suppressive mechanisms of high concentrations of adenosine in vitro and in vivo and enhance the antitumor activity of other agents, including BA and cisplatin. 

This story was featured on the cover of the November issue. 

JOURNAL: CANCER RESEARCH COMMUNICATIONS 

Health Disparities among Patients with Cancer Who Received Molecular Testing for Biomarker-Directed Therapy 

Health disparities present a barrier to successful oncology treatment. The potential for precision oncology to reduce health disparities has not previously been analyzed. We performed a retrospective analysis of 12,627 patients from six major cancer centers whose tumors underwent molecular testing at Caris Life Sciences between 2010 and 2020. Kaplan–Meier and Cox regression were used to describe and analyze overall survival. The molecular and demographic features of the cohort were analyzed by χ² and ANOVA tests. Black patients composed 25% of the cohort and White patients 63%. Among this molecularly-tested cohort, there were minimal outcome differences based on race, geographic location, or poverty level. When analyzing the interaction of age, race, and sex, racial-based disparities were noted primarily for young non-White women in the study cohort but were more pronounced for men and women of all ages in the broader patient population within the Surveillance, Epidemiology, and End Results database. Mutations in five genes—APC, EGFR, STK11, TP53, and KRAS—were found to affect overall survival among our cohort, and their prevalence varied by race in specific tumor types. Real-world outcomes data in mutation-defined cohorts also provided additional context to previously reported therapeutic response trends. Our study shows that patients who undergo molecular testing display reduced racial health disparities compared with the general population, whereas persistent racial disparities are influenced by age and sex. Genomic-driven racial disparities should be examined at a tumor lineage-specific level. Increased access to molecular testing for all eligible patients may play a role in improving health equity. 

Significance: This study is the largest of its kind to analyze health disparities and genomic features among a diverse multiinstitutional cohort of patients who underwent molecular testing. Continuing to increase awareness of and access to molecular testing approaches may help to reduce cancer health disparities and improve outcomes for all patients. 

By Members of the American Association for Cancer Research Associate Member Council Kristin Altwegg, PhD, Heather Beasley, PhD, Katie M. Campbell, PhD, and past member, Bianca Islam, MD, PhD, MSc 

During the National Cancer Institute (NCI) Director’s Address and Fireside Chat at the American Association for Cancer Research (AACR) Annual Meeting 2024, Kimryn Rathmell, MD, PhD, inspired many in the audience—including members of the AACR Associate Member Council (AMC)—with her vision and objectives for cancer research and patient care.

Wanting to learn more about her career trajectory and lessons for the next generation of cancer researchers, past and present AACR AMC members had the opportunity to sit down with Rathmell to address questions about resiliency in a scientific career, mentorship, women in leadership roles, communicating science, the age of artificial intelligence, and more.  

“And then sometimes things in life come along and really rock your world” 

Kristin Altwegg: I had the opportunity to take the Becoming a Resilient Scientist series through the National Institutes of Health (NIH) Office of Intramural Training and Education, and the AACR AMC recently shared an article on “Resilience as an Early-Career Researcher.” How has resilience played a role in the steps that you have taken and the decisions that you have made over the course of your career? 

Kimryn Rathmell: I would like to read your article. I think that might be enlightening for me as well. I’m not sure that this career is particularly different from others in terms of how much resiliency helps, but it certainly does help. One example I remember as an undergraduate was of learning how to stand up for what it was that I wanted to do with my career. This was not a career path that was something everybody thought I should do. Being willing to say, “No, I think I can,” actually gives you a career—that’s step one.   

I look at experiences that I had later in graduate school. Actually, I was a medical student first, and then had to decide that I was on this path and going to pause, earn a PhD, and create the career of a physician-scientist. As you all know, this comes with some built-in challenges around the fact that science is hard. That’s why it takes a long time to learn how to do it. Experiments fail, hypotheses turn out to be incorrect, which is why we test them. And in science we thrive on rigor, which means that we invite criticism. 

That’s not always fun, but it helps us learn how to be as rigorous as we can be. We learn how to handle the rejection of papers and grants and other things that we try to get approved. In the middle of all of that training period, life goes on. I had my first child while in graduate school, and I was learning to decide “is this doable” and “how am I going to navigate the expense of an additional person in my house,” as well as being a parent and a student and advancing a scientific career. Each of those things helps you measure how sturdy you are. And then sometimes difficulties in life come along and really rock your world and things pause. My father died by suicide when I was a fellow and I had to navigate my family through a very difficult experience and make decisions about what was possible. 

That probably influenced me a lot as an early-career faculty member because I was coming out of that and was very much “head down, focus on my science, blinders on,” and maybe that was good. I didn’t take on a lot of extra things early on. That was the easiest thing for me to do. But I want to add that I think resiliency is more than a personal core strength, it also comes from the people around you, your network and community are a great source of resiliency, especially when your own inner reserve might be weaker. I’m looking forward to reading your paper because I think we all need to understand where we gain our resiliency.  

“We are surrounded by superstars and sometimes forget that we are also superstars” 

Kristin Altwegg: The Becoming a Resilient Scientist series has a lecture on impostor fears. In both the early and later stages of your career—and in becoming the director of NCI—have you ever encountered impostor fears and, if so, how did you get through them? If you have students or mentees in similar situations, how do you support them? 

Kimryn Rathmell: Yeah, I think it’s pretty natural. We work in a very high-level arena and we are surrounded by superstars and sometimes forget that we are also superstars. So, it’s easy to look around at all of these people, as if this is an elite sport that we’ve all chosen to do. And you’re in there—I like basketball analogies—passing the ball and maybe you’re not scoring points yet, but that doesn’t mean you’re not playing right along with the superstars. I have felt impostor syndrome in that space at almost every step of the way.  

One of my most notable experiences that I can point to was when I was elected as the president of the American Society for Clinical Investigation. Okay, it’s a big deal. And I went to my first meeting as the incoming president. I had just been elected and there was definitely a sense of impostor syndrome going into that. So much so that for a black-tie event, I had planned to wear something that somehow I thought no one would really notice me. Like black, and simple, and out of the way because I just wanted to get through it.

And then, someone told me something about how big of a deal it was and asked, did I really feel it? And so, at the last minute, I packed this big, gold dress that I’d never worn before. And it had an effect on me—I felt like I had just had cataract surgery. Like I suddenly could see them and me in a different way because my impostor syndrome was definitely holding me back. And I thought to myself I’m going to own this thing. It was transformational, and it was a lot about that dress. 

“Mentorship is more than teaching about science, it’s more than telling people to think bigger than where they are” 

Heather Beasley: Switching a little bit from resiliency more so to mentorship, we want to talk a little bit about some of your earliest mentors that really have shaped you. Like yourself, I had my first baby in grad school, and mentorship is extremely important. How did these mentors shape your decision to be a physician-scientist, and were there mentors that helped you transition to your leadership role as the NCI director?  

Kimryn Rathmell: A lot of people had small and large roles in helping me find the way. In terms of becoming a physician-scientist, I have to point to my PhD advisor, Gilbert Chu, MD, PhD, at Stanford. And it wasn’t subtle. I was a med student working in his lab and he said, “You should get a PhD. You should be a physician-scientist. This is the only way. You love asking and answering questions. You love the connections.” But it wasn’t that easy for me. I mean, it took years of him saying that over and over again for me to say, “Okay, I think I can actually do that!” So, it wasn’t just once, and he was fairly persistent about it. 

I mentioned that I had my first child in grad school. When I told him that, he was thrilled. He said, “That is great!” And this is back in the day when there was no maternity leave for grad students. We just worked it out and I had an appropriate amount of time in which I just disappeared from the lab because he was supportive. And that’s just one example. He was supportive of me and the other people in the lab throughout. So, mentorship is more than teaching about science, it’s more than telling people to think bigger than where they are. And it goes all the way to helping them develop as people through the years that you’re working with them. So, I have to give him props for me being here at all.  

And then more recently, the easiest person to point to is Ned Sharpless, MD, who was an NCI director before me, who also came from UNC-Chapel Hill. I had spent 12 years there. And Ned was starting his lab about a year before I started my lab. So, Ned has been a peer mentor for me for a long time. He was in the lab down the hall. He knew all this stuff about what you do with graduate students, where you get things done in core facilities, and how you write letters for people. I’ve had all those conversations with Ned. Ned was a very easy person to turn to and say, is this a good idea? What did you like? What didn’t you like? And then I actually met with him about every week for my first two months as NCI director. This place had lots of acronyms and structures that were unfamiliar. And you walk into a brand-new place and it’s all really different. Having a guide was essential. 

“Women in leadership roles … it’s about speaking up and feeling confident in our own skin … and being recognized on a purely merit-based system” 

Heather Beasley: As women leaders supporting one another, I want to talk about some of the challenges that you faced and that you might face, to give the AACR Associate Members something to think about with respect to navigating these decisions that we all have to make, both professionally and personally. 

Kimryn Rathmell: It’s important that people look out for each other. In a long-ago era there was a sense that women necessarily didn’t do that for each other. I’ve never had that experience, but I know that’s experienced by many. I think in the current era, there are enough women out there who know what we all need in terms of respect and recognition and to be a part of the team—that there is a lot of camaraderie out there. There’s a real sense of people working to lift each other up, which the field needs, and I think is a newer way things are working.  

It’s also recognizing that seeing women in these kinds of leadership roles is not just about addressing childcare and maternity leave. It is about a lot more than that. It’s about overcoming imposter syndrome, it’s about recognizing when that’s happening and helping people move through that and recognize their own strengths and capabilities. It’s about overcoming some of the challenges that we have from our upbringing. It’s about speaking up and feeling confident in our own skin and recognizing where cultural norms are getting in the way of people doing the work and being recognized in a purely merit-based system.  

We all want to be recognized for the work that we’re doing and for what we’re contributing to the fight against cancer. And that gets in the way when a lot of us are the first woman. I really don’t like being referred to as the first woman. Now I’m the second woman in this job, so that’s a lot easier. Being recognized as the first woman kind of sounds like maybe you only got it because you’re a woman. I’d rather win an award or have a prize or be recognized because what I did moved the needle and it was viewed as important! 

“Talking to advocates … I find that to be one of the most rewarding things that I do now” 

Bianca Islam: Just over the past decade, I think we’ve seen communication reaching far nationally and internationally through the use of social media. As a group, we think of communication in four roles: press/media, patients and patient advocates, policymakers, and underserved communities. Just from watching you, we know that you have experience in communicating with all these groups at different points of your career. Of these four groups, which group would you say has been the most challenging to talk to, and how have you worked to improve that? 

Kimryn Rathmell: I think all of those are important—and all of those are difficult. It’s good that you identify these categories of communication because it helps when it comes to improving things. I would put scientific communication as maybe the easiest one. Maybe that’s because we get the most training on that and because we learn a lot about that, we do a lot of that, we’re used to the modes of communication. I find all the others to be somewhat harder. The media is hard because your quotes may go out in print but can be misunderstood without any editing or context. 

It’s a different feeling of visibility and vulnerability when talking in that venue, because it feels somehow more, maybe it’s because it’s reaching a different audience. I certainly hope that the papers I write that go into journals are read by lots of people in the scientific community. But if you say something on a podcast, I don’t really know who those people in the audience are. And you don’t know how your words will resonate. That’s a different stress level. 

It’s important to spend time thinking about and learning how to say something depending on who you are talking to. I thought that I might mention talking to advocates in this conversation. I find that to be one of the most rewarding things that I do now, but I thought that was very challenging early on, partly because I’m more of a basic scientist. I could lean into my physician experience and talk patient and clinical matters and that resonates.

But if I really want to talk, if I really want to connect in a way that’s even more meaningful with advocacy groups, I need to convince them that the science that I’m doing is important and help them understand what it is and how it all fits in. Those conversations can be harder because the language is not always there. But pushing through those difficult conversations to the place where you can actually connect can be even more powerful. Those conversations are super important and it’s worth having the hard part. 

“Having advocates who are in the peer review space makes you write a grant in a little bit of a different way” 

Bianca Islam: That makes a lot of sense, and it actually leads into some follow-up questions. As scientists, our bread and butter is to get grants and funding, and a lot of foundations and organizations are including patients and patient advocates in the decision-making process for awarding grants. I’m aware that the Veterans Affairs system, and some foundation grants include patient advocates, but I’m not sure about the NIH. On a broader scale, how are we going to help early-career scientists navigate this path? How do we introduce someone who may not be a physician, how do they get access to advocates, and what kind of training could be provided by mentors to help facilitate that?  

Kimryn Rathmell: I think it’s just creating those opportunities and being willing to have some discomfort in conducting some of those conversations. Having advocates who are in the peer review space makes you write a grant in a little bit of a different way—and that’s good. I tell this story often, but we had a patient advocate come to our laboratory retreat and it really was transformative. It changed the whole tenor of the conversations of the students and postdocs once we had someone from outside our world, but who was very interested and engaged, wanting to understand what they were doing.  

“We’re all scientists, and we’re all learning, and we’re all here to make a difference” 

Katie Campbell: One of the things that I love was that you focused on asking yourself “is this what I want to be doing,” especially as an undergraduate. As we interact with more trainees, their assumption is that they’re supposed to go into academia, but academia is not the traditional route anymore. It might be traditional in that it’s a long historic route for a PhD scientist, but it’s not the customary route anymore. Can you talk a little bit more about the diversification in the workforce, not just in the people sense, but also the training. How do we support trainees across these areas? 

Kimryn Rathmell: First, we’re all scientists, and we’re all learning, and we’re all here to make a difference. That’s why people go into these fields. So, the workforce has changed. It used to be that the dominant path where people would move through the system was to transition into academic jobs. I don’t think there are actually fewer academic jobs than before, but I also don’t think that as an industry, academia has grown as much as the private sector. And so, the balance is now quite different. 

I think that has changed some of the ways that we approach training, that it’s good for people to be open to what they want to do and helping them figure that out. You know, it’s not always obvious. I say that I was sure I was going to be a physician-scientist. I’m not sure that I knew. It evolved with time and with some experimentation and testing what I liked and what I didn’t. I look for my folks in the lab to have that same opportunity. It’s wonderful that there are a variety of ways that people can try teaching, for example.  

Most universities have—I know Vanderbilt has one—a program where you can spend some time working at a primarily teaching college. That is one route. I’ve had a couple of students love doing that. Others love the drug development part of it, or some other aspect that really lends itself well to the industry sector. Others have gone to government and others have gone to academic labs. We should appreciate the wide array of opportunities that are out there. And just be honest about what path people are ready for, what path they’re really setting themselves up to follow. 

“But in terms of informatics … it’s really moving into an essential skill that people have to have some knowledge of to be able to do the work that we do” 

Katie Campbell: And one final question and kind of building upon this is—we’re comfortable teaching what we know, right? And while you go to a lab for training in a particular thing, AI and ChatGPT have transformed the way that we think about how we can do science and really accelerated that. How do you support trainees who want to do something different than you (it’s not different from how our parents raised us in a certain way)? As we prepare to be mentors in this field, how do we better prepare to be mentors and trainees as we transition into the age of AI? 

Kimryn Rathmell: I think your analogy is great about parenting—it’s about looking at where people’s talents lie. We’re also in an era where collaboration is the norm. And so, we can help to find those kinds of opportunities for people. For example, I still can’t really do computational biology even today, but in the earlier days of my laboratory, we needed to move into that space. This is when we had gene arrays, before RNA-seq was cool, but even that was hard.

We had a partnership where a student went and stayed with another lab for two weeks, learned those skills, and then we collaborated with them for years. That student is actually now the director of clinical bioinformatics at Memorial Sloan Kettering. So, the informatics stuck for her. But in terms of informatics, use of AI, and the quantitative aspects of cancer research, it’s really becoming an essential skill that people must have some knowledge of to be able to do the work that we do. 

A special collection in the November 2024 issue of Cancer Discovery, “New Horizons for Cancer Research: Innovative Ideas by Leading Chinese Researchers,” was motivated by a simple philosophy—that good ideas don’t have geographic boundaries. 

“Cancer researchers in China, who now represent the largest cancer research workforce in the world, are making incredible strides against cancer,” said Robert Kruger, PhD, senior executive editor of Cancer Discovery, a journal of the American Association for Cancer Research (AACR), and editorial director for the AACR journals. “Given Cancer Discovery’s longstanding reputation of showcasing major advances in cancer research, we felt it important for the journal to magnify the pioneering ideas that Chinese researchers are exploring to our readers across the globe.” 

Earlier this year, the journal issued a call for commentaries on BioArt, a social media account popular with Chinese researchers. As part of the initiative, Cancer Discovery’s executive editor, Elizabeth McKenna, PhD, participated in a live social media discussion to answer researchers’ questions about the journal and the types of commentaries it was seeking. 

“We were particularly interested in commentaries exploring new and thought-provoking ideas on emerging topics,” said McKenna. “We are excited to amplify the voices of Chinese thought leaders to new audiences and promote the exchange of ideas through the pages of Cancer Discovery. Too often, Western and Eastern research communities are siloed, so we hope this collection will help bridge these communities and foster new conversations and research approaches.” 

In the end, nine commentaries were selected, covering topics such as using machine learning to improve cancer risk prediction, integrating traditional Chinese medicine with Western medicine, developing new ways to target p53, and exploring the non-H. pylori microbiome in gastric cancer, among others. Keep reading to learn about some of the commentaries, and be sure to check out the full collection here. 

A Call for Innovative Translational and Clinical Research to Address China’s Unique Cancer Landscape 

Government initiatives have accelerated cancer research in China in recent years, but more focus is needed on research that addresses China’s particular cancer landscape, wrote Nan Sun, PhD; Jie He, MD, PhD; and colleagues in the first commentary of the collection. 

The authors argued that China has features of both developed and developing countries, and this distinction has led to a unique set of cancers in the country, including higher rates of thyroid cancer, nasopharynx cancer, liver and intrahepatic bile duct cancers, lung cancer, esophageal cancer, and gastric cancer, compared with the global average. 

Clinical research in China, however, has largely focused on other cancer types. “In other words, there remains a significant disparity between the clinical demands in China and the recent remarkable advancements in cancer research within the country,” the authors explained. 

To mitigate this discrepancy, Sun, He, and colleagues called for increased financial incentives from the government to promote cooperation between the pharmaceutical industry and basic researchers, as well as stronger intellectual property laws to encourage the development of first-in-class therapeutics. With this support, researchers should work toward developing and testing drugs specific to the cancer types prevalent in China, the authors continued, utilizing tools such as artificial intelligence to expedite drug discovery and databases to facilitate data sharing and collaboration. 

Advancing Cancer Prevention Through an AI-based Integration of Traditional and Western Medicine 

The multifaceted nature of cancer development complicates prevention and early detection efforts, said Shao Li, MD, PhD, and colleagues in another commentary. They posited that a deeper understanding of the various levels of tumor development—molecular to organismal—and how they interact and evolve with time is required to improve cancer prevention and detection, particularly in China, where fewer than 30% of breast, colorectal, and lung cancers are detected early. 

To this end, the authors proposed using artificial intelligence (AI) to integrate traditional Chinese medicine (TCM) with modern Western medicine. The holistic nature of TCM, which is rooted in understanding whole body changes, “aligns with the current shift in Western medicine from reductionism to systematism, offering new perspectives for cancer prevention research and providing a valuable complement to Western medical practices,” they noted. 

Li and colleagues suggested that AI could analyze large multimodal data sets collected from patients who received either TCM or Western medicine to identify bodily changes and molecular markers associated with cancer and then integrate these to formulate accurate risk prediction models. Further, analyzing the effects of various herbal remedies and Western medicines through self-reported use of traditional medicine, electronic medical records, and other sources could identify potential strategies for cancer interception. 

“The development of AI technology empowers us to deepen our understanding of cancer development and translate related data and insights from traditional medicine into actionable strategies in cancer prevention,” the authors summarized. 

Early Cancer Detection Through Comprehensive Mapping of Dynamic Tumorigenesis 

The third commentary of the series continued the theme of improving cancer risk prediction, with Chen Wu, MD, PhD, and colleagues noting the need for spatial mapping of cell populations and their interactions as normal tissue evolves to precancer and then to cancer.  

“Such advancements will enable the identification of potential molecular targets for early detection, thereby enhancing our ability to build prediction models for identifying high-risk individuals,” the authors wrote.  

They explained that a cancer evolution map will require a prospective cohort of healthy individuals who are followed over time with detailed documentation of demographics, lifestyle, medical history, and psychological factors. They suggested that researchers utilize spatiotemporal multiomics technologies to study multifaceted changes to the tissue during cancer development and that they periodically collect blood and urine samples to track genetic features, metabolic markers, and environmental exposures. Additionally, the authors recommended that the research be conducted by an interdisciplinary team of epidemiologists, clinicians, cancer biologists, and data scientists. 

The analysis and validation of these large data sets will benefit from machine learning approaches and cutting-edge model systems such as organ-on-a-chip and advanced organoids, Wu and colleagues noted. 

Building an Organ-wide Macroscopic View of Cancer Hallmarks 

While a tumor may form in a particular tissue, it exists within the context of the whole body. Suling Liu, PhD; Zhihua Liu, PhD; Shengtao Zhou, MD; and their colleagues argued that crosstalk between different organs could influence cancer progression, presenting opportunities for therapeutic intervention. 

Crosstalk between organs may occur through extracellular vesicles, metabolites, hormones, or hematopoietic cells, which can be released from one organ to another to deliver signals that promote tumorigenic processes at the receiving site. These signals may even influence response to treatment and cancer-related complications, including cachexia, the authors explained.  

One example of such influence is the impact of gut bacteria on cancers outside the gastrointestinal tract due, in part, to the release of metabolites. The release of the metabolite indole-3-acetic acid by gut bacteria, for instance, is associated with greater likelihood of chemotherapy response in patients with pancreatic cancer.  

While any of the mediators of organ crosstalk are potentially actionable, the authors suggested that “microbiota and related metabolites are optimal to be targeted as they are easy to identify and to be functionally characterized, and most importantly, could be readily modulated.” However, they noted that additional preclinical and clinical studies are needed to test the efficacy and safety of targeting organ crosstalk mediators for cancer treatment. 

Tobias Janowitz, MD, PhD, from Cold Spring Harbor Laboratory, opened up about his close personal experience with cancer cachexia at the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research. Shortly after beginning his research into the condition, he watched his late mother wither away from it. 

He recalled a particularly poignant observation she made days before her death: “My body is used up.” 

Cachexia is characterized by the significant, rapid weight loss and deterioration of muscle tissue that accompany many cancer diagnoses. Often, Janowitz explained, cachexia can be as dangerous as the cancer itself. Unfortunately, cachexia is remarkably common among patients with pancreatic cancer, a disease with a 12.8% five-year relative survival rate. 

“A thing I often tell the fellows is that if the patient doesn’t have weight loss, then they don’t have pancreas cancer,” said conference co-chair Peter J. Allen, MD, of Duke University. 

But a session at this year’s meeting cast the subject in a more hopeful light, complete with new insights into the mechanisms underlying pancreatic cancer cachexia and new treatment modalities that are inching closer to the clinic. 

What Is Cachexia? 

If the body is designed to fight back against disease, why does it waste away when confronted with cancer? It makes sense from an evolutionary perspective, explained Teresa A. Zimmers, PhD, of the Oregon Health & Science University Knight Cancer Institute. When mammals don’t feel well, we typically become lethargic and uninterested in food or other things that bring us pleasure. This, Zimmers said, is an evolutionary adaptation to protect ourselves from predation and prevent the spread of contagion to others. 

Often, the body reacts before we’re consciously aware of the problem. Unexplained weight loss is a common symptom that leads to a diagnosis of pancreatic cancer; in fact, individuals presenting to the clinic with unexplained weight loss are around three times more likely to be diagnosed with pancreatic cancer than the general population. 

But weight loss isn’t the only complication of cachexia. The condition also involves the wasting of muscle and adipose tissue, which can also precede a diagnosis of pancreatic cancer by months to years. Cardiac muscle can also be affected, leading to impaired heart function. Other studies have shown systemic disruptions to the immune system in patients with cachexia, which can stymie responses to immunotherapies such as immune checkpoint inhibitors. 

At the molecular level, Zimmers is particularly interested in the role of the inflammatory cytokine interleukin-6 (IL-6) in driving cancer cachexia through a variety of cellular signaling pathways. She and her colleagues performed a phase II clinical trial testing the standard-of-care chemotherapies nab-paclitaxel and gemcitabine, with and without the IL-6-targeting antibody tocilizumab, as a first-line treatment in patients with advanced pancreatic cancer. Although the addition of tocilizumab did not impact progression or survival, it did significantly decrease the amount of skeletal muscle lost. 

A Full-body Disease 

How can so many independent processes be coordinated to form the complex phenotype of cachexia? Janowitz wasn’t surprised to learn that the brain was involved. 

“Cachexia, in no small part, is a behavioral condition,” Janowitz said. “I would like to submit that behavior is mostly orchestrated by the brain, and so it makes sense to look in the brain for the mechanisms that drive cachexia.” 

The upregulated IL-6 signaling observed in cachexia can influence brain function by suppressing activity in areas related to pleasure seeking and hormone sensing, Janowitz explained. He and his colleagues showed that delivery of an IL-6-blocking antibody into the brains of cachectic mice could reverse full-body symptoms of cachexia, including weight loss and decreased food intake. 

In behavioral experiments, mice with cachexia were less persistent in tasks related to food and water foraging. Using a fluorescent reporter that responds to dopamine, the researchers showed that cachectic mice experienced less dopamine release upon earning a reward than did mice without cachexia. 

“I really think that cancer neuroscience in the broader sense … the connectivity of the central nervous system, through the endocrine system and the inflammatory system, with the tumor … is an area where a lot can be discovered,” Janowitz said. 

Janowitz and colleagues also showed that mice with cachexia had an unusual response to metabolic stress. Instead of undergoing ketogenesis to produce energy during starvation, cachectic mice produced a massive inflammatory response that could contribute to immune suppression. 

New Treatments Offer Hope 

Andrew E. Hendifar, MD, MPH, of Cedars-Sinai Medical Center, began his presentation with a rare message of hope for the field. “Usually when I give a talk on clinical trials in cancer cachexia, I talk about why the trials are negative,” he said. “Today, fortunately, is going to be a different type of talk.” 

Hendifar explained that interventions for cancer cachexia are incredibly limited, with only dietary counseling, progesterone analogs, and short-term corticosteroid treatment being recommended by consensus guidelines. Further, clinical trials to test new interventions face design challenges in terms of disease scope, the confounding effects of different cancer treatments, and an optimal endpoint to demonstrate that an intervention “works.” It is partially for this reason, he argued, that clinically meaningful improvements have been difficult to demonstrate. 

Nevertheless, he discussed three recent trials moving the needle forward. The MENAC clinical trial tested a multipronged approach to treat cachexia in patients with lung or pancreatic cancer. The intervention consisted of nutritional counseling, exercise, ibuprofen, and omega-3 fatty acid supplements on top of standard cancer therapy. While patients who received the intervention did not gain weight during the trial, they lost significantly less weight than patients receiving cancer treatment alone. 

Since ibuprofen has shown hints of efficacy against cachexia, another trial tested a stronger nonsteroidal anti-inflammatory drug (NSAID), ketorolac, in patients with pancreatic cancer and cachexia. Preliminary results showed that a five-day course of ketorolac could increase body mass and steps per day in some patients. 

But the most notable news came in the form of a study published the day before the meeting began. In a phase II clinical trial, researchers found that a drug targeting the protein GDF15 could induce weight gain in patients with cachexia—the first time in quite a while that such a benchmark has been reached, Hendifar said. 

GDF15 is a cellular stress response protein that is secreted by some fat, muscle, tumor, and immune cells in a variety of physiological stress conditions, including cancer, pregnancy, and tissue injury. Preliminary data showed that GDF15 levels are high in patients with pancreatic cancer and cachexia, and the investigational GDF15-targeting antibody ponsegromab may help stabilize their weight.

Among patients with lung, colorectal, or pancreatic cancer cachexia and high levels of GDF15, increasing doses of ponsegromab increased placebo-adjusted changes in body mass, up to a median of 3 kg at the highest dose level. Patients receiving the highest dose of ponsegromab also noted improvements in patient-reported symptom scores and non-sedentary physical activity. 

“To conclude, 2024 has been very kind for the therapeutic development in cancer cachexia,” Hendifar said. “I’m really pleased to be able to present some positive data for the first time in a while.” 

Despite decades of research into gastric cancer, commonly known as stomach cancer, it still claims many lives around the world and its causes are proving more complex than we once thought. Fortunately, new discoveries suggest the gastric microbiome—a diverse community of stomach bacteria—may hold the key to combating this deadly disease. 

A recent commentary published in the American Association for Cancer Research (AACR) journal Cancer Discovery  highlights this potential paradigm shift underway in our understanding of gastric cancer. 

For decades, Heliobacter pylori (H. pylori) has been the primary suspect in gastric cancer research, and for good reason. It’s one of the few bacteria definitively linked to cancer, as it can trigger a cascade of changes in the stomach lining that can lead to tumor formation. However, recent data are changing our understanding of this complex disease and prompting researchers to reconsider H. pylori’s exclusive causal role. Such new insights could potentially open the door to better prevention, earlier detection, and more effective treatments. 

H. pylori and a Delicate Ecosystem 

H. pylori, which the World Health Organization has classified as a class 1 carcinogen since 1994, infects the stomach lining and can cause chronic inflammation, ulcers, and over time, cancer. In light of this knowledge, identifying and treating H. pylori infections has been a major focus of gastric cancer prevention. 

But here’s the catch: most people with H. pylori don’t get cancer. This has puzzled researchers for years. What’s protecting some people while others go on to develop tumors?  

Rather than being the result of a single “bad” species of bacteria, mounting evidence suggests that gastric cancer may arise from a microbial imbalance—a condition known as dysbiosis. Dysbiosis occurs when the natural balance of bacteria in the stomach is disrupted. Think of the gastric microbiome as a delicate ecosystem. When it’s in balance, the bacteria coexist harmoniously, maintaining stomach health. But when H. pylori or other harmful bacteria overgrow, they upset this balance, setting off a chain reaction of harmful changes. 

A 2018 study revealed that as stomach tissue progresses toward cancer, its microbial community changes dramatically. Notably, bacteria like Streptococcus anginosus (S. anginosus), typically found in the mouth, became more prevalent—not particularly surprising given the physical connection between saliva and the stomach. Strikingly, these oral bacteria often persisted in the stomach even a year after treatment cleared H. pylori, and their persistence was linked to inflammation, tissue damage, and precancerous changes. 

Even stronger evidence has emerged over the past couple years with direct demonstrations of the gastric cancer-promoting roles of S. anginosus as well as Fusobacterium nucleatum and Prevotella melaninogenica. Furthermore, S. anginosus appeared to synergize with H. pylori, the two seemingly working together to amplify inflammation and accelerate tumor growth. 

This points to the broader and more complex polymicrobial reality of gastric cancer, and it’s likely that networks of microbes work in tandem to flip the switches necessary to drive each step of stomach tumor development. 

New Approaches for Prevention and Early Detection 

These findings open the door to new diagnostic tools. Current screening methods focus primarily on H. pylori, but this approach has limited predictive value since most H. pylori-positive individuals do not develop gastric cancer. 

The discovery of other cancer-promoting bacteria offers a promising alternative. Identifying other microbes, particularly those more abundant in advanced stages of gastric precancerous progression, could offer a more reliable way to diagnose developing gastric cancer. This approach could leverage microbial biomarkers to identify high-risk individuals earlier and more accurately. 

Already, one study hinted at the potential value of analyzing the bacteria in the saliva of patients: Changes in specific bacterial species were linked to different stages of progression, and in the future could provide important biomarkers for early detection in the clinic. Beyond saliva, gastric fluids and fecal samples may also hold promise. Collectively, these efforts could pave the way for population-wide screening programs, helping to identify high-risk individuals for follow-up endoscopy, especially in regions where gastric cancer rates are high, and access to health care is limited. 

If we know certain bacteria are linked to cancer, could we stop the disease by targeting those microbes? It’s a promising idea. Current prevention strategies often rely on antibiotics to eliminate H. pylori. But what if we could go further by using probiotics or prebiotics to restore a healthy microbial balance in the stomach? 

Efforts in the realm of personalized medicine—aimed at tailoring treatments and prevention strategies based on an individual’s unique microbiome—could also make a difference.  

A Global Perspective: Why It Matters Now 

Gastric cancer is the fifth most common cancer worldwide, but its burden isn’t evenly distributed, as East Asia accounts for nearly half of all cases. In China alone, there are an estimated 300,000 new cases of gastric cancer annually, a stark contrast with the estimated 27,000 new cases that will occur in the United States in 2024. Interestingly, more than 500 million people in China—over one-third of the population—carry H. pylori. Yet, only a small percentage of them will go on to develop gastric cancer.  

Expanding screening programs to include microbial biomarkers could revolutionize how we identify and manage gastric cancer risk. By incorporating a wider spectrum of gastric microbiome biomarkers—that reflect additional bacteria linked to tumor progression or dysbiosis patterns—we could more accurately pinpoint individuals at high risk. This would enable earlier interventions, potentially preventing cancer from developing or catching it at a more treatable stage, ultimately saving lives. 

As the deadliest cancer in the United States, lung cancer is expected to account for approximately 125,070 deaths in 2024 alone. Fortunately, researchers continue to make strides in developing and testing therapeutics, and these efforts have led to 11 new approvals by the U.S. Food and Drug Administration (FDA) for lung cancer so far this year. 

Among the new approvals were several for therapies targeting the epidermal growth factor receptor (EGFR), a cell surface protein that promotes cell division and is mutated in about 20% to 50% of non-small cell lung cancers (NSCLC), the most common type of lung cancer. EGFR mutations, including the prevalent exon 19 deletion and exon 21 L858R substitution, put the protein into overdrive and cause dysregulated cell division and cancer development.  

The first-generation EGFR inhibitors were approved in the early 2000s for patients with late-stage NSCLC. However, most patients’ tumors eventually became resistant to these inhibitors, so second- and third-generation EGFR inhibitors were developed to overcome some of the common mechanisms of resistance, as summarized in a previous blog post. 

In recent years, researchers and regulatory agencies have expanded the reach of EGFR inhibitors, making them available to additional patients including those with early-stage or newly diagnosed lung cancers.  

Osimertinib for Early-stage NSCLC 

Osimertinib (Tagrisso) is a third-generation EGFR inhibitor that targets common EGFR mutants as well as T790M, an acquired EGFR mutation that confers resistance to earlier-generation EGFR inhibitors. Originally approved for metastatic NSCLC, the therapeutic has been available to patients with nonmetastatic EGFR-mutated NSCLC since 2020—first as adjuvant therapy for patients with resectable stage 1, 2, or 3 tumors and more recently for patients with stage 3 tumors that cannot be surgically removed. 

The expanded indications for osimertinib have benefited many patients with early-stage disease, including Daniel West, who received adjuvant osimertinib to treat his stage 2B NSCLC. West, whose cancer is now in remission, shared his story in the American Association for Cancer Research (AACR) Cancer Disparities Progress Report 2024. 

Inhibition of a Less Common EGFR Mutant in Lung Cancers 

Most FDA-approved EGFR inhibitors target EGFR with the exon 19 deletion or exon 21 L858R mutations, but approximately 9% of EGFR mutations occur in exon 20. For many years, patients whose NSCLC harbored this less common EGFR mutation were not eligible for EGFR inhibitor therapy. That changed in 2021, when two EGFR inhibitors, amivantamab (Rybrevant) and mobocertinib (Exkivity), received approval to treat locally advanced or metastatic tumors with EGFR exon 20 mutations after progression on chemotherapy.  

Unlike most approved EGFR inhibitors, which are small molecule inhibitors or monoclonal antibodies, amivantamab is a bispecific antibody that works by simultaneously binding and blocking the activity of EGFR and the MET protein. Since MET activation is one way cancer cells circumvent EGFR inhibition, the combined block is meant to delay or prevent treatment resistance. 

New Combinations for Treatment of Advanced NSCLC 

Researchers have also made advances in delaying treatment resistance or improving responses by combining EGFR inhibitors with other therapeutics. This has led to the approval of several new combinations for the treatment of locally advanced or metastatic NSCLC, including in the first-line setting. 

This includes a regimen combining the EGFR inhibitor erlotinib (Tarceva) with the angiogenesis inhibitor ramucirumab (Cyramza) for newly diagnosed NSCLCs harboring exon 19 deletion or exon 21 L858R EGFR mutations. Ramucirumab inhibits the vascular endothelial growth factor receptor 2 (VEGFR2), whose activity has been shown to drive resistance to EGFR inhibition; by inhibiting both proteins, the combination suppresses this resistance mechanism. 

Combinations involving amivantamab have also been approved to treat locally advanced or metastatic NSCLC. One approved regimen combines amivantamab with another EGFR inhibitor, lazertinib (Lazcluze), for newly diagnosed tumors with the exon 19 deletion or exon 21 L858R mutations. The combined inhibition of EGFR (intracellularly by lazertinib and extracellularly by amivantamab) and MET (by amivantamab) is intended to overcome MET-dependent treatment resistance. Two other recent approvals greenlit amivantamab in combination with chemotherapy for either newly diagnosed NSCLC harboring exon 20 insertion mutations or NSCLC with exon 19 deletion or exon 21 L858R mutations that progressed after prior EGFR inhibition.  

In addition, the FDA approved osimertinib in combination with platinum-based chemotherapy as first-line therapy for certain locally advanced or metastatic tumors. The approval was based on clinical trial results that showed greater outcomes with the combination than with osimertinib alone. 

Together, these advances illustrate how cancer research is driving progress and making effective treatments available to even more patients. As researchers continue to uncover new insights into EGFR-driven cancers and their resistance mechanisms, we will hopefully see improved outcomes and longer survival for all patients with EGFR-mutated lung cancer. 

In 1977, Sir Richard Peto, FRS, FAACR, postulated that larger animals with longer lifespans should develop cancer more readily than their smaller, shorter-lived companions. Since cancer is driven largely by errors in DNA replication, animals with more cells and more time to accumulate mutations should also develop more cancer, he argued. 

He observed, however, that this does not appear to be the case. Why, then, do most elephants, whales, and bears get less cancer than humans? 

The finding became known as “Peto’s paradox,” a challenge to comparative oncologists to learn more about cancer in vertebrates and understand why cancer incidence doesn’t correlate directly with mass and longevity. Researchers speculated that perhaps understanding the evolutionary processes that prevent cancer in other animals could help us learn how to prevent or treat it in humans. 

Work on that front has produced some intriguing findings. In 2015, for instance, researchers found that elephants have 19 extra copies of the tumor suppressor gene TP53 to help them ward off cancer. 

But there’s more to cancer risk than genetics, explained Zachary Compton, PhD, a postdoctoral fellow in the University of Arizona Cancer Center’s NCI T32 fellowship program and first author of a recent study in Cancer Discovery, a journal of the American Association for Cancer Research (AACR). “Evolution has all of these crazy stochastic ways it can deal with the same problem,” Compton said. “You don’t expect there to be just one way of handling cancer across the diversity of life.” 

In the study, Compton and colleagues analyzed cancer incidence in nearly 300 vertebrate species to identify characteristics associated with cancer prevalence in animals. In addition to finding more species with incredibly high or low cancer rates to study further, the researchers demonstrated a smidge of support for Peto’s original hypothesis and hinted at an explanation for the apparent paradox. 

The Pressures of Natural Selection 

Compton is particularly interested in the evolutionary underpinnings of cancer. The constraints of natural selection suggest that cancer would be selected against during the evolutionary development of a species. 

“Somatic dysfunction is going to decrease the fitness of an individual,” Compton said. “If you have to pump energy into cells that are not working correctly … you would expect natural selection to prune that.” 

But traits like body mass, longevity, and gestation time are also subject to selection pressure, Compton explained. With all of these traits intertwined, it can be difficult to tease apart the push and pull of different selective advantages and how they may drive or suppress cancer. 

Such an endeavor requires a large sample size, for starters. Compton and colleagues collected 16,049 necropsy records from 292 different animal species at 99 animal care institutions in the United States and London. The records were derived from institutions bound by accreditation requirements to perform a necropsy on every animal that dies in their care, whether from known causes or simply old age. 

“All of these deceased animals have had a really thorough investigation by a veterinary pathologist to determine … not only what they died from but what they died with,” Compton explained. 

The researchers assessed whether neoplasia (uncontrolled cell growth) was present and in what tissue, and they developed a terminology dictionary based on the neoplasia descriptions to predict whether neoplasms were benign or malignant. Across all species, each of which had a minimum of 20 necropsy records, the median neoplasia prevalence was 4.89%, and the median malignancy prevalence was 3.2%. 

Further, Compton and colleagues evaluated the associations between evolutionary traits—including maximum lifespan, adult body mass, basal metabolic rate, gestation length, litter size, time to sexual maturity, and growth rate—and the prevalence of neoplasia and malignancy.  

Larger body mass was significantly associated with a higher prevalence of neoplasia; for every tenfold increase in body mass, the risk of neoplasia increased by 2.1%. Other factors associated with malignancy and/or neoplasia included increased maximum longevity, larger litter size in mammals, and, in a subset analysis of 15 species, somatic mutation rate, or the rate at which new mutations occur in the body.  

Longer gestation time was significantly associated with a lower prevalence of both neoplasia (5.3% decrease in neoplasia risk per tenfold increase in months of gestation) and malignancy (5.65% decrease in malignancy risk per tenfold increase in months of gestation). Compton speculated that for a large animal to develop rapidly in the womb (or an egg), they must possess mechanisms to suspend natural growth restriction programs—mechanisms that could potentially be exploited later to form cancer. 

Because both longevity and gestation time are generally associated with body mass, the researchers performed additional analyses in which they normalized data based on these factors. Body mass was more strongly associated with neoplasia and malignancy prevalence when accounting for gestation time, and vice versa. 

Compton and colleagues also addressed the notion that animals in captivity may live longer than nature intended and thus be more susceptible to cancer. In this study, the vast majority of species typically developed tumors within their natural lifespan, and age at death only correlated with higher rates of malignancy in amphibians. 

“We not only controlled for natural lifespan, but we discovered that we didn’t need to control for it,” Compton said. “The rates [of neoplasia] we were seeing weren’t because animals live longer in zoos.” 

Species ‘Leaderboards’ for Future Research 

A component of the study that Compton found particularly exciting was the identification of animals with unusually high or low levels of neoplasia prevalence—a “leaderboard” of species for other researchers to explore. He hopes that animals particularly resistant to neoplasia or malignancy can provide clues to cancer prevention mechanisms that can be repurposed in humans. Similarly, species with abundant cancer may point to genetic, viral, or environmental causes that we can model to study analogous cancer drivers in humans. 

Overall, the median prevalence of neoplasia and malignancy varied among taxonomic orders, from 12% and 7%, respectively, in mammals to 1.2% and 0%, respectively, in amphibians. Still, there were outliers in each group. 

“It’s not like all of the large mammals have low cancer … or a certain group of amphibians or reptiles,” Compton said. “There are representative species from all of these clades that seem to be very good at preventing cancer.” 

Mammals with exceptionally low levels of neoplasia included the Nubian ibex, the tammar wallaby, and several species of bats. Many species of birds appeared particularly resistant to neoplasia, including the black-footed penguin and common songbirds like finches and starlings. Lizards such as the plumed basilisk and the chameleon forest dragon, plus a handful of snakes, also had no neoplasia detected. 

On the other end of the leaderboard, ferrets and opossums had the highest risks of neoplasia—63% and 56%, respectively. Rounding out the top 10 list for neoplasia prevalence were the Dominican mountain chicken frog, jaguar, four-toed hedgehog, Asian elephant, pygmy sugar glider, milk snake, common mouse, and chimpanzee. 

Where Do Humans Stack Up? 

According to federal statistics, approximately 39.3% of Americans will be diagnosed with cancer during their lifetime, but Compton warned that we may not know the exact prevalence of malignancy in humans. Most natural human deaths do not warrant autopsies, and there is currently no robust way to estimate benign neoplasia at the population level. 

But Compton hopes that the data from this study may help researchers better understand and model cancer development and cancer suppression mechanisms that may be translatable to humans. Then, perhaps, we can decrease our own species’ cancer incidence rate or make the disease less deadly. 

This study, Compton emphasized, demonstrated that the breakthrough findings about p53 in elephants was merely a starting point for comparative oncologists. “There is so much that nature has to teach us about cancer risk and what controls it,” he said. 

Research consistently points to the chronic disparities that exist for some populations in accessing cancer care. The crucial next step that follows identifying these gaps is developing intervention programs to close them.  

Evidence-based interventions—whether it be education initiatives, tobacco cessation programs, public service announcements (PSAs), or something similar—have helped more people from racial and ethnic minoritized groups and medically underserved populations get screened for cancer, address preventable risk factors like smoking, participate in medical research, and more. But even with this progress, additional intervention programs are needed to continue to address cancer health disparities. 

For the past 17 years, the American Association for Cancer Research (AACR) Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved has facilitated the exchange of innovative ideas with presentations on the latest research devoted to this field. At this year’s meeting, held September 21-24, more than 450 abstracts were presented, including intervention programs that have demonstrated results in helping address issues such as food insecurity, quitting vaping, screening and clinical trial awareness, and quality of life during survivorship. 

Cancer Research Catalyst spoke with the researchers behind a few of these interventions, who shared the progress they are making in addressing disparities and their vision for the future of these programs.  

Food Farmacy: From the Farm to the Hospital  

If they build it, will they come? Those within the Harris Health System wondered that as they dreamed of a field of fresh produce in the area surrounding Lyndon B. Johnson (LBJ) Hospital in Houston, Texas. This area is considered a food desert by the U.S. Department of Agriculture, meaning many residents lack access to healthy food options. So, they built a nearby farm to kick start a farm-to-hospital nutritional program that supplies access to tomatoes, green beans, lettuce, squash, and other produce in addition to more healthy food options secured outside of the farm.  

The farm has resulted in a number of interventions, including one for cancer patients led by Hilary Y. Ma, MD, the center medical director of the MD Anderson Cancer Center Oncology Program at LBJ Hospital. As part of the program, a two-question screener is used for all cancer patients to identify those who lack access to healthy foods. If they are identified as food insecure, clinicians can refer them to the Food Farmacy, which is located around the corner from the medication pharmacy within the hospital, where they can pick up 30 pounds of healthy food. Patients are also provided with other resources detailing how to eat healthier, including 1:1 nutrition counseling. Each referral is good for three redemptions, and referrals can be refilled by physicians.  

At the meeting, Ma shared results from the first year of the program. In total, 3,254 of the 9,809 patients screened were positive for food insecurity and 88.9% of them were referred to the Food Farmacy. Of those, 50.7% redeemed their referrals, many of whom provided positive feedback. One said, “I always struggle to get food in the house because it’s hard to make ends meet because I’m on social security and so it helps me a lot.” Another said, “I love the bananas and the carrots. Oh, the chicken, too. Oh, and they give you also dry beans.” 

Both patients and clinicians noted the ease of the program’s structure, in terms of the ability for clinicians to refer patients with one click within the electronic medical record and then for patients to pick up the food right on site. Ma said that the next step is to evaluate this intervention’s impact on clinical outcomes, both specific to cancer and more general health such as weight management, as well as explore options to expand the program. 

“It’s about scalability and sustainability,” Ma said. “Not every health care system, especially a safety net system, has the resources to build something like this or have a farm near the campus of the hospital. We have built relationships with community organizations and even with private investment to be the initial key ingredients for further growth.” 

Kick Vaping: By Latinos for Latinos 

When Rafael Orfin and his colleagues searched for vaping cessation interventions specifically geared toward Latinos, they came up empty. 

“We couldn’t find any that were even in Spanish,” said the senior human subject research specialist at the University of Rochester Medical Center. “We wanted to fill in the gap when it came to cessation services available that were created for and by Latinos.” 

Kick Vaping is a text messaging intervention for Latinos between the ages of 18 and 25 that features four different storylines—each with 212 preplanned text messages—disseminated over the course of 12 weeks. The storylines are built around language and gender, with one for English speakers and then ones for those who speak Spanish depending on if they identify as male, female, or nonbinary. For each group, the storylines are told in four consecutive phases. The first is pre-quit, which lasts for 15 days with 55 messages. Then three messages are sent over the course of the day someone decides to quit. Next is the post-quit intensive phase, which has the highest volume of messages (87 over 28 days) considering this is the time people often need the most support. Finally, the post-quit maintenance period lasts seven weeks with 67 messages.  

These messages were further supplemented with automated responses triggered by keywords (such as crave/antojo or stress/estrés) as well as specific messages sent over 11 days if someone admitted to relapsing. Plus, participants could also engage via text with members of the research team. 

“We’d have a genuine conversation and just kind of lay out their motivations, their anxieties, their barriers,” Orfin said. “Folks really loved that component, and I think it helped a lot … having a genuine person that cared about you on the other end of the messages.” 

In a pilot program with 40 participants, Orfin said they retained 90% of study participants who then completed a follow-up assessment after three months. When asked how much this program helped them quit vaping, choosing from four options—“not at all,” “a little,” “somewhat,” and “a lot”— 86.1% of the participants responded with “a lot.”  Further, self-efficacy scores for avoiding vaping significantly increased at the three-month mark and 88.9% reported being satisfied with the program. 

The next step is to assess the efficacy of the intervention in a randomized controlled trial, with a long-term vision of disseminating this program throughout the Latino community, not just in the United States but across Latin and South America.  

Active Living After Cancer and Project CHURCH: Adaptation Equates to Participation  

The Active Living After Cancer (ALAC) program was originally adapted from a group program that encouraged physical activity in healthy but sedentary adults. Over the past 11 years, the intervention has reached over 2,000 cancer survivors and has continued to be tweaked to better serve those in medically underserved communities around Texas, according to Karen M. Basen-Engquist, PhD, MPH, a professor in the Department of Health Disparities Research at The University of Texas MD Anderson Cancer Center.  

“We recognized the need for cancer survivors to have access to programs to help them improve their quality of life through physical activity out in the community,” Basen-Engquist said. “And we’re working to tailor it now to different communities and test it in different settings.” 

One of the latest adaptations has been a partnership with Project CHURCH, an acronym for creating a higher understanding of cancer research and community health, which was created to reach African American cancer survivors and cancer patients—oftentimes at their church.  

“We find the African American community trusts the program more because it goes through the church,” explained Stacy Mitchell, program manager of the ALAC Research Project at the University of Texas MD Anderson Cancer Center. “They’re starting a class with people they’ve probably known for years. Plus, the pastor, who they trust, is going to talk about how it’s important to increase your physical activity and function to reduce cancer recurrence.” 

Mitchell said the ALAC team also works with the pastor or health ministry liaison to make any adaptations that the church feels is necessary. For example, in addition to workouts, the 12-session program includes cognitive and behavioral components such as meditation or cooking demonstrations to help learn about nutrition. But not every church is comfortable with meditation, so that can be replaced with a prayer or a spirituality discussion with a church leader.  

Ultimately, Mitchell and her colleagues found that the retention rate of African American participants was higher when ALAC worked through the Project CHURCH partnership compared to its partnership through another institution not associated with the church. In the Project CHURCH cohort, 95% stayed until the completion of the 12 sessions, compared to 85% in the other cohort.  

Part of the program also encouraged participants to be more active in their leisure time, such as parking a greater distance from the entrance to a grocery store to walk further. Weekly physical activity through actions like this were measured by the Godin Leisure-time Exercise Questionnaire. Those in the Project CHURCH cohort increased their scores by 38.8 units from before the program compared to an increase of 12.5 units in the other cohort.  

This is only one example of the types of adaptations that Mitchell and her colleagues are making to expand the reach of the ALAC program, with other versions dedicated to Hispanic communities as well as virtual classes for people who may not be able to attend in person. 

“Once a patient finishes treatment, we always get the ‘what’s next,’” Mitchell said. “We just like to let them know Active Living After Cancer is what’s next.” 

Colorectal Cancer Education: Boosting Screening and Clinical Trial Awareness  

Michelle Moseley, MA, CHES, and her colleagues within the Office of Community Engagement at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center want to eventually deliver colorectal cancer education year-round, but to start, they developed a series of educational initiatives that they felt addressed a key area of need in their community. 

“Colorectal cancer is one of the most commonly diagnosed cancers, and in our catchment area, colorectal cancer screening has been underutilized in some of the populations that we’re working with,” Moseley explained. “Clinical trials awareness, education, and participation has been low, as well, [and] we know that awareness and education play a role.” 

The Office of Community Engagement arranged educational sessions with community groups such as the Chinese Community Health Resource Center, Mujeres Unidas, Shanti Project, Chinese Newcomers Service Center, and Vietnamese American Nail Association. These sessions could be in person or virtual and often involved a PowerPoint-like presentation as well as video vignettes featuring colorectal cancer survivors who shared their stories about the benefits of screening and catching the disease early. 

While each session could include some tailored information specific to the ethnic or racial group they were engaging with, the programs largely focused on providing an overview of colorectal cancer and clearing up common misconceptions. That included explaining the location and function of the colon and rectum, providing visual aids for how screening through colonoscopies and fecal immunohistochemical tests (FIT) work, and digging into the importance of clinical trials and the role they played in bringing common treatments—such as allergy pills, pain medications, or X-rays—to patients to alleviate concerns related to participating in research. Moseley and her colleagues also shared this information at community events, like festivals or health fairs, via handouts and time spent networking with attendees.  

The sessions, which were conducted between the fall of 2019 and May 2024, were assessed via pre- and post-engagement surveys. From a total of 772 completed surveys, knowledge improved about colorectal cancer by 14% (76% before vs. 91% after) and about clinical trials by 7% (83% vs. 90%). Further, respondents either strongly agreed or agreed that they now understood the importance of people of color participating in clinical trials (78%) and would seek out clinical trial information (69%), search for clinical trials (59%), or talk to a health care provider about clinical trials (75%). Nearly one half (48%) also said they would join a clinical trial while 70% said they would talk to family/friends about joining one. As for screening, 92% indicated they would get screened and 89% said they would talk with family/friends about colorectal cancer. 

Moseley said they are also evaluating how to improve the programs in the future, which may involve creating shorter educational materials, adding information about blood-based screening tests, and including more testimonials from patients and clinical trial participants. They are also working on a year-round awareness campaign with multiple components, including attendance at health-related events not directly connected to cancer, posters in public transportation vehicles and waiting areas, and radio PSAs.  

“We would ultimately like to have an impact on saving lives,” Moseley said. “We’d like to be able to prevent colorectal cancer by having people engage in regular screening and … we would like to be able to have trials that people can actually enroll in on the spot when we’re providing the education.”