Seventy percent of cancer-related deaths are from cancer types with no available screening options, underscoring the importance of detecting cancer early when it is more easily treated. The American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10, kicked off its plenary program with a session on Discovery Science in Early Cancer Biology and Interception, which was chaired by Daniel De Carvalho, PhD, a professor at University of Toronto and researcher at the Princess Margaret Research Centre. 

“[Early cancer detection] is where we can have the biggest impact from cancer research on clinical care,” De Carvalho said. He noted that novel early detection approaches will depend on understanding the molecular changes that occur as cells evolve from normal to precancer to cancer. 

“We really need to understand early cancer biology and figure out ways to use this for cancer interception,” he said.  

Just in time for the newly declared National Cancer Prevention and Early Detection Month, the session featured four presentations that explored the early changes underpinning cancer development and efforts to target these for cancer treatment.  

What changes underlie clonal hematopoiesis? 

In the first presentation, Margaret Goodell, PhD, FAACR, a professor at Baylor College of Medicine, discussed mechanisms that may drive clonal hematopoiesis, a state characterized by the outgrowth of genetically distinct populations of hematopoietic stem cells. Clonal hematopoiesis commonly occurs with aging and increases an individual’s risk for several blood cancers. 

Understanding how clonal hematopoiesis develops is key to identifying novel approaches to prevent this premalignant condition from progressing to cancer, Goodell noted.  

In three separate vignettes, she shared distinct mechanisms underlying clonal hematopoiesis, including commonly occurring mutations in PPM1D, the gene that encodes the p53 suppressor protein WIP1. Goodell showed that these mutations inactivated DNA repair and cell death mechanisms and made cells more likely to proliferate with unresolved DNA damage, particularly after exposure to chemotherapy drugs. Consistent with these preclinical findings, blood samples from patients who had received chemotherapy were enriched for PPM1D-mutated cells.  

Chemotherapy exposure also increased the occurrence of mutations in the chromatin regulator SRCAP, the focus of Goodell’s second vignette. In contrast to PPM1D mutations, the commonly occurring SRCAP mutations increased DNA repair by upregulating the expression of DNA damage genes through histone alterations. Goodell noted that, although mutations in PPM1D and SRCAP had contrasting effects on DNA repair, they both provided survival advantages to hematopoietic stem cells—a phenomenon that might be explained by different environmental contexts. 

Finally, Goodell discussed mutations in DNMT3A, which she described as “the most important tumor suppressor in the hematopoietic system.” She explained that hematopoietic stem cells with DNMT3A mutations exhibit enhanced self-renewal and suggested that this may be due to the mutants’ epigenetic impacts.  

Goodell proposed that these mechanistic insights could lay the foundation for future cancer interception efforts. “In the long term,” she said, “we think there will be great opportunities for interventions if we can understand which mutations are particularly bad, in which contexts they arise, and how we can interfere with their functions.” 

Why does breast cancer risk increase with age? 

Most breast cancers are diagnosed in individuals 55 years of age or older, and research presented by Kornelia Polyak, MD, PhD, FAACR, a professor at Harvard Medical School and Dana-Farber Cancer Institute, shed light on the cancer-promoting changes that occur with aging.  

Using rat models, Polyak and colleagues discovered that aging was associated with dysregulated proliferation of mammary epithelial cells (from which most breast cancers arise), altered gene expression, changes to the proportion of certain immune cells, modified tissue states, and the decline of various cellular functions.  

Among the genes whose expression increased with aging was midkine (MDK), a growth factor that has been implicated in cancer and other diseases. Polyak shared data demonstrating that MDK was upregulated with aging in rat mammary tissue, as well as in plasma samples from older individuals and in human breast cancers. Additionally, individuals under the age of 55 whose normal breast tissue had higher levels of MDK were found to have a greater five-year risk of breast cancer, and young patients whose breast cancers had high levels of MDK had lower disease-free survival rates. 

Further experimentation revealed that MDK may impact breast cancer development by activating the tumor-promoting PI3K signaling pathway, repressing tumor suppressive pathways, and enhancing metabolic activity—consequences mediated by SREBF1, a regulator of cell metabolism. 

How does genome instability promote cancer? 

Don Cleveland, PhD, FAACR, a professor at the UC San Diego School of Medicine, shared mechanistic insights into chromothripsis (chromosome shattering) and its contributions to cancer development. He demonstrated that abnormal chromosomes accumulate in micronuclei, where they undergo chromothripsis through the action of the N4BP2 nuclease. Shattered chromosome fragments remain near one another due to tethering by the DNA repair protein TOPBP1, and this proximity facilitates aberrant ligation of the chromosome fragments into circular DNAs that amplify the expression of certain oncogenes and drive drug resistance.  

Separately, he proposed that Epstein-Barr virus (EBV) may promote cancer through a similar tethering action as shattered chromosome fragments. He showed that the viral protein EBNA1 becomes tethered to an EBV-like DNA sequence in chromosome 11, which leads to chromosome breakage and the separation of the MLL gene from the rest of chromosome 11. The MLL-containing DNA fragment enters micronuclei and undergoes chromothripsis, re-ligation, and amplification of MLL. This, in turn, inactivates the DNA repair protein ATM and may promote the formation of cancer. (MLL is a negative regulator of ATM.) 

Can genome instability be targeted for cancer treatment? 

The accumulation of DNA damage can lead to cancer and, if left unresolved, trigger cell death. For this reason, many researchers are exploring inhibiting DNA repair as a potential approach to treat cancer. Michael Kastan, MD, PhD, FAACR, a professor at Duke University and executive director of Duke Cancer Institute, demonstrated the potential of an investigational chemical inhibitor of the DNA repair proteins ATM and DNA-PK to sensitize cells to radiation.  

ATM and DNA-PK are signal transducers activated early in the response to DNA damage and regulate a multitude of downstream effector proteins that ultimately repair the damage or trigger cell death. 

Kastan explained that ATM and DNA-PK are logical targets because 1) they are important regulators of DNA repair, 2) their activity is not essential to the survival of cells, and 3) cells that lack either protein remain sensitive to radiation. 

He and colleagues identified XRD-0394, a novel dual inhibitor of ATM and DNA-PK, that could be delivered systemically. In preclinical models, XRD-0394 inhibited both proteins in a dose-dependent manner. Importantly, it led to cell death only in the presence of radiation, which allowed the drug to be delivered systemically without widespread toxicities.  

Based on these preclinical data, Kastan and colleagues initiated a phase I clinical trial to evaluate the safety and pharmacokinetics of the drug in patients. The drug has not led to any dose-limiting toxicities thus far, and patient tumor samples indicate that the drug successfully inhibits ATM in patients. Kastan plans to explore combining XRD-0394 with various other therapies, such as immune checkpoint inhibitors, PARP inhibitors, and cytotoxic drugs.  

“The great enemy of truth is very often not the lie—deliberate, contrived, and dishonest, but the myth—persistent, persuasive, and unrealistic.” When John F. Kennedy delivered that remark, he wasn’t referring to prostate cancer, but his lesson applies nonetheless.

It is a fact that the incidence of prostate cancer is 60% higher in Black men compared to white men in the United States. But a common myth that if you feel fine then you don’t need a prostate exam may prevent people from getting screened.

It is a fact that Black men are 2.2 times more likely to die from prostate cancer than white men. But belief in the myth that prostate cancer is an old man’s disease—even though Black men are diagnosed at younger ages compared to white men—may make one put off screening until it is too late.

In a poster at the American Association for Cancer Research (AACR) Annual Meeting 2024, Mallorie C. Jones, MA, project manager, Division of General Internal Medicine in the Perelman School of Medicine at the University of Pennsylvania, presented a study in which she and her colleagues aimed to dispel myths like these by turning to a trustworthy member of the community—a Black pastor from Philadelphia who survived his own battle with prostate cancer.

Mallorie C. Jones, MA, presenting her poster on using a culturally sensitive video to increase knowledge about prostate cancer among Black men at the AACR Annual Meeting 2024.

“Our study aimed to address these barriers by providing education from trustworthy and reliable sources in settings that were easily accessible to members of the community,” Jones explained in a press release.

They paired the pastor with a urologist over a video call and recorded their conversation to create a 10-minute educational resource that addresses both the facts and myths surrounding prostate cancer. Ultimately, the researchers found that 93% of those who watched the video said they would get screened. You can view a snippet from the video below.

Community Matters

To test the impact of the video, the researchers arranged 14 events between April and December 2023 within local Black communities at faith-based, union, and occupational spaces.

“We utilized a combination of indoor and outdoor events to maximize accessibility and visibility and collaborated with other specialties offering education, resources, or screenings whenever it was feasible,” Jones explained. “In addition to distributing the educational video and a survey, participants who completed the measures received giveaway items from the Philadelphia Flyers, the University of Pennsylvania, a $10 gift card, and the option to get a PSA screening by a licensed phlebotomist on-site.”

At these events, 619 men aged 40 and above agreed to watch the video and take part in the surveys. About half (47%) were Black men and the majority (98%) had at least a high school diploma. Of the 93% who said they would get screened after watching the video, Jones said they all did so on-site at the event. The phlebotomist drew a sample of their blood to test for amounts of the protein prostate-specific antigen—which is what PSA stands for—as high levels can be an indicator of prostate cancer.

Among those who didn’t get screened on-site, eight had a PSA screening recently and were not due for a retest. Another 10 participants said they had already scheduled or would schedule a screening with their own health care providers.

Raising Awareness

The participants were asked 10 questions pre- and post-video to assess their awareness about prostate cancer. After viewing the video, the researchers found an increase in knowledge for half of the questions, which touched on the following topics:

Prostate cancer is the most common cancer in men.

Black men are more likely to get and die from prostate cancer than any other men.

A familial connection with prostate cancer increases the chance of developing the disease.

The two main tests for prostate cancer are a PSA screening and a digital rectal exam, during which a gloved finger is placed in the rectum to feel the prostate.

Black men over 40-years-old are recommended to get tested for prostate cancer every year.

Of those, Jones said one of their most important findings was that awareness of Black men’s higher propensity to get and die from this disease rose from 74% to 97%. Further, 98% indicated the information provided by the video was useful, 97% found the information credible, and 94% believed this resource could help increase awareness about prostate cancer among Black men.

For four of the questions, however, awareness did not significantly increase. These questions focused on whether:

getting up to urinate at night was a sign of prostate cancer;

a high-fat diet could decrease chances of developing the disease;

just one of the screening methods would be enough; and

early screening would not be able to tell if someone has prostate cancer.

“The length of the video may impact the ability of the participants to retain the entirety of the information,” Jones said in a press release. “We plan to amend the video to contain a brief recap to reinforce all of the items that were asked about on the knowledge questionnaire, but with an emphasis on those that did not yield a statistically significant post-video result.”

In the future, once Jones and her colleagues optimize the video to maximize its effectiveness and have published the study, they hope to share it so it can be used as an educational resource. For instance, Jones said the video could be used by unions such as Local 22 of the International Association of Fire Fighters, which represents Philadelphia firefighters and paramedics, and the American Federation of Labor and Congress of Industrial Organizations (AFL-CIO), which represents more than 12.5 million working people.

They also would like to collaborate with community organizations that have greater access to Black men—such as local chapters of the National Association for the Advancement of Colored People (NAACP)—or those with perceived environmental and/or occupational predispositions to cancer. They intend to explore ways to make this type of information more accessible to Spanish-speaking individuals, as well.

“Not only may this culturally sensitive educational video be a valuable asset when educating diverse groups of men about prostate cancer and prostate cancer screening,” Jones said, “but this may also be a useful technique that can be applied to a variety of topics and populations.”

In 1796, Edward Jenner inoculated a young boy with cowpox to protect him from smallpox, an early example of vaccination. 

Fast forward 200+ years: smallpox has been eradicated, and the cowpox virus (now known as vaccinia virus) is being used to develop an entirely different type of vaccine—one that treats cancer. 

Unlike preventive vaccines, such as those that protect against COVID-19 and the flu, therapeutic cancer vaccines are designed to treat existing cancers by training the patient’s immune system to recognize and destroy cancer cells.  

At the American Association for Cancer Research (AACR) Annual Meeting 2024, researchers reported that a newly developed therapeutic cancer vaccine was effective in patients with head and neck squamous cell carcinoma (HNSCC). 

The new vaccine, TG4050, uses an engineered form of the vaccinia virus to deliver 30 personalized neoantigens (proteins unique to each patient’s tumor) into the patient to induce activation of an antitumor immune response.  

The researchers hypothesized that TG4050 could help reduce the high risk of disease recurrence in patients whose HNSCC has been surgically removed. 

“A therapeutic vaccine tailored to each patient’s unique tumor may lead to strong immune responses, which could eliminate any minimal residual disease that may eventually lead to disease relapse,” explained presenter Olivier Lantz, MD, PhD, a clinical immunologist and researcher at Institut Curie in Paris. 

During his presentation, Lantz shared data from an ongoing phase I clinical trial evaluating the safety and efficacy of TG4050. The trial includes 33 patients with stage 3 or 4 HPV-negative HNSCC who underwent surgery and other standard-of-care treatments. Patients were randomly assigned to one of two arms: the 17 patients in Arm A received TG4050 immediately after standard-of-care treatment, while the 16 patients in Arm B were assigned to receive TG4050 only upon disease relapse.   

Lantz reported that none of the evaluable patients in Arm A experienced disease relapse after a median follow-up of 16.2 months. Three patients in Arm B experienced disease relapse—one after 6.2 months, another after 8.8 months, and a third after 18.5 months. 

Adverse events associated with TG4050 were mild to moderate, and the most common TG4050-related adverse event was a reaction at the injection site. 

“Our findings indicate that TG4050 is safe and promotes an immune response against several neoantigens in most patients,” Lantz said. 

He noted that most patients whose immune cells were evaluated after vaccination showed signs of activated neoantigen-specific T cells, the majority of which were not present prior to receiving TG4050. Further, the neoantigen-specific T cells had an effector memory phenotype, suggesting they may have antitumor activity.  

“We are really excited by these preliminary data, as well as by the body of evidence that is being built by the community in favor of neoantigen-based vaccines,” Lantz said. “Studies like ours are demonstrating the potential of individualized neoantigen-based therapeutic vaccines to be a part of tomorrow’s standard of care.” 

Three Years Later, A Pancreatic Cancer Vaccine Stays on Message 

Messenger RNA (mRNA) became a household term during the pandemic, but long before the first COVID-19 vaccines were approved, mRNA vaccines were being explored for cancer treatment.  

The idea: inject a patient with mRNA that encodes a protein unique to that patient’s tumor. Since these personalized neoantigens are not found in normal cells, the immune system recognizes them as foreign and mounts a response against any cell that expresses them. This allows the therapy to target cancer cells, while minimizing the effect on healthy cells. 

The downside of personalized neoantigen cancer vaccines, however, is that they must be custom-made for each patient, a process that can slow down treatment, explained presenter Vinod Balachandran, MD, a surgical oncologist and member of the David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center.  

To circumvent this issue, Balachandran and colleagues explored the use of an mRNA platform, which allows the vaccines to be manufactured relatively quickly. They developed an mRNA-based personalized cancer vaccine, autogene cevumeran, to target up to 20 unique neoantigens identified from each patient’s tumor and evaluated its potential against pancreatic cancer, a disease with a high risk of relapse and death. 

In his presentation, Balachandran reported three-year follow-up data from a phase I clinical trial that evaluated the postsurgical use of autogene cevumeran combined with immune checkpoint inhibition and chemotherapy for patients with resectable pancreatic cancer.  

This presentation built upon results reported at last year’s AACR Annual Meeting, which showed that patients who had vaccine-induced immune responses were less likely to experience disease recurrence during the first 18 months of follow-up compared with those who did not experience a response to the vaccine. 

This year, Balachandran reported that, after a median follow-up of three years, responding patients continued to have significantly longer median recurrence-free survival (not reached) compared with those who did not experience a vaccine-induced immune response (13.4 months).  

He also showed that the treatment led to the expansion of multiple CD8+ T cell clones, which, for most responding patients, persisted in the blood long term and remained responsive in ex vivo rechallenge experiments.  

“Our data indicate that autogene cevumeran can induce CD8+ T cells with significant longevity, substantial magnitude, and durable function,” summarized Balachandran. “The findings that individualized neoantigen-specific cancer vaccines can induce a robust immune response that correlates with delayed disease recurrence continues to support these vaccines as an encouraging therapeutic approach for pancreatic cancer.”  

New Horizons in the Search for Neoantigens 

A key step in developing personalized vaccines is finding the right neoantigens, a task that has been facilitated by recent advances in technologies. In a major symposium on Antigen Discovery and Validation for Cancer Vaccines, researchers shared some of the new approaches they are applying to identify neoantigens and evaluate their immunogenicity.  

These approaches included algorithms that combine next-generation sequencing, peptidomics, and various endogenous factors to predict neoantigen immunogenicity; assays to characterize how T cells respond to neoantigens; and the generation of large libraries of T-cell receptors that respond to diverse antigens. 

As this field continues to grow, what advances can we expect next? Read our interview with prominent cancer vaccine researcher Catherine J. Wu, MD, FAACR, to learn more about cancer vaccines and anticipated progress. 

Groundbreaking clinical developments begin with fundamental research at the lab bench. Bench research depends on technological advances to allow scientists to reconceptualize problems and find new solutions for patients. The full spectrum of cancer research encompasses all of these facets working together as a well-oiled machine. 

It’s a paradigm that the program chairs of the American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10 in San Diego, wanted at the foundation of the meeting. 

“[We made] a concerted effort to weave technology into the scientific program by pairing presentations on discoveries in basic science, translation, and clinical science with presentations on the tools that support and amplify those discoveries,” said Christina Curtis, PhD, the RZ Cao Professor of Medicine, Genetics, and Biomedical Data Science; director of Artificial Intelligence and Cancer Genomics; and director of Breast Cancer Translational Research at Stanford University, during the Opening Plenary session of the meeting. 

Curtis chaired the Program Committee and the Opening Plenary session with Keith T. Flaherty, MD, FAACR, director of Clinical Research at Mass General Cancer Center and a professor of medicine at Harvard Medical School. Together, the two have worked for a full year to direct the focus and scope of the meeting. As they welcomed attendees to the Opening Plenary session, they emphasized the importance of interdisciplinary approaches to complex problems, and how they designed the meeting program with that angle in mind. 

“We hoped to move beyond standard multidisciplinary sessions and instead create sessions that demonstrate how these different approaches inform one another—sessions that, for example, showcase clinical investigations, computational approaches, and a novel diagnostic, or sessions that highlight basic science advances whose clinical application is being informed by computational insights,” Flaherty said. 

The Opening Plenary acted as a poignant example of this intermingling of technology, laboratory discoveries, and clinical advances. In an expert reflection of the meeting theme—inspiring science, fueling progress, revolutionizing care—the four speakers shed light on how research on the tiniest elements of the human body can indeed inform gargantuan advances in clinical care. 

Mapping the Route from Molecules to Drugs 

Just as geographical atlases depict roads, businesses, and other points of interest and help represent the relationships between them, cell atlases provide a high-resolution map of how individual cells with distinct functions are distributed throughout a tumor, tissue, or organism. 

Aviv Regev, PhD, FAACR, head and executive vice president of Research and Early Development at Genentech, is head of the Human Cell Atlas project, which aims to map all of the cells in the body to better understand human development and disease. 

So far, the Human Cell Atlas has mapped several million cancer cells across a variety of tumor types, Regev said. Current challenges involve analyzing this vast library of data in ways that can benefit patients. 

Regev likened the data generated by older genomics methods to a fruit smoothie—information from multiple cell types blended together making individual origins indistinguishable. Tech advances in single-cell genomics have allowed researchers to look at tissue in a more granular manner, similar to examining each piece of fruit in great detail. 

Insights from skin cells have helped researchers study melanoma progression and develop possible treatment strategies—especially for tumors that respond poorly to immunotherapy. A combination of spatial analyses and single-cell RNA sequencing revealed that malignant cells comprising immune “cold” niches have a distinct gene expression signature that can predict immune cell exclusion. Regev and colleagues found that while tumors with more “cold” niches did not respond as well to immunotherapy as those with more “hot” niches, they were more likely to respond to inhibitors of the cyclin dependent kinases 4 and 6 (CDK4/6), suggesting a potential therapeutic vulnerability. 

Regev touched on some newer technologies that can facilitate the comprehensive mapping of tumors, including ways that artificial intelligence (AI) and machine learning can help recognize patterns in the data. She explained the “lab in a loop” system of discovery, in which vulnerabilities uncovered during high-throughput screening can inform new drugs to be tested in the clinic, which can, in turn, provide real-world data that may raise questions for new screens. 

AI can assist with many steps of this process, Regev said. She showed how machine learning could help streamline perturbation screens, for instance; instead of disrupting a single gene per cell, researchers may now be able to disrupt multiple genes in tandem, allowing the AI to look for patterns that can discern the effects of each perturbation. When such screens lead to potential drug targets, new machine learning algorithms can also help predict which putative compounds have the highest chance of turning into successful drugs. 

“Drug discovery and development, just like biology, only work when all components are tied together,” Regev said. “We rely on everyone and everything being connected together—the lab, the clinic, the data, and the algorithms—but when they are connected together, they have the potential to go after the big problems.” 

Robot Readers: AI in Histopathology 

Jakob Nikolas Kather, MD, a professor of clinical artificial intelligence at Technical University Dresden in Germany, was equally enthusiastic about the ways researchers are using new AI technologies to potentially enhance clinical care. 

“For artificial intelligence, we need a lot of data, and one type of data that we really like is routinely available data. When we treat our cancer patients in clinical routine, a lot of data is generated as a byproduct,” Kather said. 

While physicians can routinely assess genomic characteristics and expression of various proteins in patient tumors—markers that may help predict prognosis or direct treatment options—these tests require resources and infrastructure that aren’t available everywhere. Conversely, histopathology slides stained with hematoxylin and eosin (H&E) are cheaper and readily available. Can researchers infer complex biomarker information from a simple stained slide? 

Kather and colleagues have shown that they can feed histopathology slides into a deep learning model and train the model to recognize which tumors exhibit high microsatellite instability, a marker of eligibility for certain therapies. They have also trained AI models to predict the prognosis of patients with colorectal cancer and determine—without staining for PD-L1—if the tumor might respond to PD-1 or PD-L1 inhibitors. 

“The hope is that we can use these biomarkers on very inexpensive, routinely available H&E data,” Kather said. “Of course, to bring this to the clinic, we have to take many steps … but the technology is here, and now it’s basically our job to bring it … to our patients.” 

Kather touched on new types of machine learning offering potential fresh approaches to process data. These include multimodal models that incorporate basic H&E data with immunohistochemistry or genomic data, as well as foundation models that use a two-step approach to let the algorithm recognize broad patterns in data before telling it what it needs to differentiate. He also discussed how large language models—such as ChatGPT—are beginning to use insights from language processing to analyze images and electronic health records. 

“We’re living in very exciting times, and basically, our job is to take these new technologies and to translate them into new scientific insights and clinical usefulness for cancer patients,” Kather said. 

Going Global: Novel Insights into Target and Drug Discovery 

What happens when the insights gleaned from large data sets and AI highlight potential targets we don’t yet know how to drug? 

“The genetic methods point us to proteins and pathways that remain poorly characterized biochemically, that lack chemical tools and might even be considered historically undruggable,” said Benjamin Cravatt, PhD, a professor and the Norton B. Gilula Chair in Biology and Chemistry at the Scripps Research Institute. Cravatt emphasized the importance of finding new drug targets by mapping so-called “ligandability” across the proteome. 

Cravatt and colleagues designed a method called activity-based protein profiling to probe for all the places in the proteome that a potential drug structure might bind. Fluorescent probes are designed to mimic ligands that can target binding pockets of interest throughout the proteome. Protein lysates are incubated first with the probes, then with a putative drug compound, to assess which drugs might outcompete the probes in proteins of interest. 

This method was successfully used to identify compounds that can target serine hydrolases, a metabolic enzyme that is upregulated in a variety of cancer types. Cravatt showed that one such compound could block palmitoylation of NRAS in acute myeloid leukemia cells. 

In addition to targeting specific enzyme families, Cravatt explored how to perform larger-scale screening to identify potentially druggable sites across the proteome, including in proteins previously thought to be undruggable. For this, he and his colleagues assembled a library of compounds known to interact with cysteines, a common interaction site for drugs that bind covalently to proteins. The researchers incubated the library with proteins then added a cysteine-binding probe. Cysteines that did not take up the probe were assumed to have interacted with a drug compound. 

Using this method, Cravatt and colleagues identified a variety of putative targets. “We got our glimpses of the power of covalent chemistry to expand ligandable—if not druggable—space,” Cravatt said. “The proteins that harbored these cysteines, for the vast majority of them, this was their first evidence of interacting with small molecules.” 

They identified a cysteine binding site on the transcription factor FOXA1, a pioneer factor that helps other, cancer-driving transcription factors bind to chromatin and activate oncogenic gene programs. The researchers have designed a ligand for this difficult-to-drug protein and shown that the ligand disrupts the ability of FOXA1 to bind to its intended target sites. While they have not yet proven that their compound acts as an inhibitor, Cravatt expressed hope that they could use this data to design FOXA1 antagonists. 

Mowing the Glycan Lawn to Fight Cancer 

Proteins aren’t the only druggable targets in cancer cells. Carolyn Bertozzi, PhD, FAACR, the Baker Family Director of Stanford ChEM-H, the Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences, and professor, by courtesy, of Chemical and Systems Biology and of Radiology at Stanford University, has turned her sights to a relatively unconventional drug target: sugars. 

The cell surface is dotted with glycans—molecular scaffolds consisting of a protein, lipid, or RNA backbone complexed with various sugar tags. Sialoglycans, which contain the sugar moiety sialic acid, are commonly upregulated in tumors. 

“The well-manicured garden of a healthy cell’s sialoglycans turns into a tropical forest, where they are denser and presented on different kinds of scaffolds,” Bertozzi explained. 

Research has shown that sialic acid can activate an immune checkpoint-like signaling cascade in immune cells that dampens antitumor immune responses. This introduced sialoglycans as a promising drug target, but blocking their signaling proved to be more complex than blocking other immune checkpoints. The sialic acid receptors, called siglecs, form a broad family of proteins that cannot be targeted by a single antibody. 

Bertozzi and colleagues pivoted to targeting the sialoglycans instead. 

“The idea was to develop a therapeutic molecule that we analogized to a lawnmower, and this lawnmower would park on the surface of the targeted cancer cells and mow the lawn—and literally strip the sialic acids off of that cell, thereby depriving it of the ability to engage any member of the siglec receptor family,” Bertozzi said. 

Bertozzi and colleagues designed a cancer-targeted sialidase—an enzyme that cleaves sialic acid residues—using her Nobel Prize-winning bio-orthogonal chemistry approach. The researchers ligated the sialidases to the antibody trastuzumab (Herceptin)—which targets the growth factor receptor HER2, overexpressed in a variety of human cancers—at carefully curated locations that would not disrupt the activity of trastuzumab. In mouse models, these “T-sia” molecules inhibited the growth of HER2-positive breast cancer cell xenografts. 

“Attaching this sialidase to trastuzumab turns these tumors from cold to hot and provokes an immune reaction that actually is durable,” Bertozzi said. 

Bertozzi and colleagues are currently streamlining their T-sia prototype to translate it to the clinic, and they aim to launch clinical trials soon. She expressed hope that this method could be used to ligate sialidases to a variety of cancer-targeting antibodies for use in several cancer types.

Like Taylor Swift’s Eras Tour, Kimryn Rathmell, MD, PhD, began her tenure as the director of the National Cancer Institute (NCI) in December 2023 following a “Cruel Summer” that saw Congress pass legislation to raise the debt ceiling but cut funding for scientific research—among other things—and put a freeze on increases until after 2025. Despite that challenge, Rathmell is “…Ready for It,” taking a position she could only imagine in her “Wildest Dreams”; prepared to help other physician-scientists overcome obstacles she knows “All Too Well (Two Decades Version)”; excited to explore the “Blank Space[s]” that currently exist between different fields of research, science, and government bodies; and dedicated to achieving the NCI’s goal of helping patients with cancer “Long Live.”

But “Don’t Blame Me” for all of the Swift references. Rathmell herself kicked off her address at the American Association for Cancer Research (AACR) Annual Meeting 2024 on April 8th with an image of multiple colored boxes that she asked audiences if they recognized. Naturally, it was the backdrop of the Eras Tour poster with Swift’s images removed. Why? Well, Rathmell is from Nashville, so of course she is a fan. But she also believes cancer research is entering a new era that will require researchers to think a little differently. So, she wanted attendees to experience a talk that was a little different from what you might expect from the NCI director.

The Spaces In Between

To encourage attendees to think beyond the whole picture and see the “spaces in between,” she showed a Rorschach inkblot and a Magic Eye image created for the National Institutes of Health (NIH). The point was that magic can be found between the edges of two things that might not seem like they connect or even among areas we often overlook.

When it comes to cancer research, Rathmell mentioned how this applies to the new spaces artificial intelligence (AI) is opening for scientists,  the fact that researchers are uncovering the ways the microbiome influences our health, how genome scientists are now exploring the noncoding regions of the genome, and the new perspectives community-based participatory research can offer to scientists.

Rathmell said that breaking down barriers to work across various areas of science is what will define the next era of cancer research. She said the previous “traditional” era involved top-down research and care in which researchers focused on their own specialized work. Meanwhile, the “current” era from the past decade or so involved a horizontal approach with the rise of team science, interdisciplinary research, and new technology and data capabilities.

“Our next era…would be better defined as 360˚,” she explained. “Truly cross-sector collaborations, better engagement, not just sharing of our knowledge but including and learning from our knowledge to create something that is new,” she said.

“This is thinking in the spaces on steroids and is becoming the norm.”

This will include looking for ideas outside of a scientist’s normal research zone, whether that is from scientists in different fields, patients (especially those within underserved populations), or even government agencies not in health care. In fact, the reignited Cancer Moonshot, which President Biden announced in February 2022, included the formation of the Cancer Cabinet that brings together representatives from more than 20 government agencies such as the NCI and NIH as well as the Department of Energy, Department of Agriculture, Department of Labor, Environmental Protection Agency, the National Aeronautics and Space Administration, and others.

“The approach of putting everyone at the same table and really ensuring that all of government is working together—that’s actually a major culture shift and is working remarkably well,” Rathmell said. “And so that’s going to be a big part of how we move into really reaching every patient and being able to say that cancer is a different kind of disease.”

Reigniting the Cancer Moonshot

A commentary published in Cancer Discovery, a journal of the AACR, by Catharine G. Young, PhD, assistant director for Cancer Moonshot Policy, and Danielle M. Carnival, PhD, deputy assistant to the president for the Cancer Moonshot, detailed some of the progress the Cancer Moonshot has made in the past two years since President Biden’s announcement to reignite the mission he initially established as vice president in 2016.

Among the achievements are:

The Self-collection for HPV testing to Improve Cervical Cancer Prevention (SHIP) Trial, which was launched by the NCI Cervical Cancer “Last Mile” Initiative to test the effectiveness of self-screening methods for cervical cancer.

SmokeFreeNative, an initiative from NCI and the Indian Health Service that uses text messages to encourage American Indians and Alaska Natives to quit smoking while still recognizing the significance of traditional tobacco in their cultures.

The Advanced Research Projects Agency for Health (ARPA-H), which has already awarded more than $500 million to researchers for projects that include new ways to prevent cancer, visualize cancer cells during surgery, and treat cancer through the use of bacteria.

The Cancer Moonshot Scholars, an early-career program within the NCI that invests in growing the next generation of cancer researchers.

New reimbursement codes established by the Centers for Medicare and Medicaid Services for patient Principal Illness Navigation services to remove barriers that prevent some patients from receiving these services that can help them better understand their options.

During another session at the AACR Annual Meeting 2024, “The Cancer Moonshot: Opportunities to Fulfill the Vision of the National Cancer Plan,” Rathmell compared the original Cancer Moonshot funded under the 21st Century Cures Act as the launchpad and the reignited Cancer Moonshot to a rocket in which they take what they learned and focus on making a difference in patient care. The mandate delivered by President Biden is to reduce mortality from cancer by 50% by 2047 and to “end cancer as we know it.”

“The government can’t do this alone, academia can’t do this alone, and industry can’t do this alone,” Elizabeth M. Jaffee, MD, FAACR, deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and chair of the President’s Cancer Panel, said during the panel. “This is a time when we’ve made so much progress, so many discoveries. But we can’t stop funding now. This would be the worst time to stop funding this amazing progress that we’re seeing.”

What About the Budget?

Concerns over cancer research funding were expressed by multiple members of the panel, which also included AACR President Patricia M. LoRusso, DO, PhD (hc), FAACR, of the Yale Cancer Center and Bianca N. Islam, MD, PhD, of Case Western Reserve University School of Medicine. Plus, Rathmell fielded several questions about the NCI budget following her address.

Panelists at the “The Cancer Moonshot: Opportunities to Fulfill the Vision of the National Cancer Plan” during the AACR Annual Meeting 2024. From left to right: Roy S. Herbst, MD, PhD, NCI Director W. Kimryn Rathmell, MD, PhD, Elizabeth M. Jaffee, MD, FAACR, AACR President Patricia M. LoRusso, DO, PhD (hc), FAACR, and Bianca N. Islam, MD, PhD.

Ultimately, the NCI will be operating with $96 million less in 2024. While Congress granted an additional $120 million over what was in the NCI’s base budget for the previous fiscal year, 2023 marked the final year the NCI received funding—$216 million—for the Cancer Moonshot under the 21st Century Cures Act. For 2025, at most the budget can only increase by 1% under the debt ceiling legislation passed in June 2023, which Rathmell acknowledged won’t even cover general cost of living increases.

“I always thought if I were just the NCI director, I would fix it all, and it turns out it’s hard,” Rathmell said. For now, she expressed the importance of ensuring early-stage investigators can get R01 research grants. For the fiscal year 2024, NCI will fund the top 17% of R01 applications from early-stage investigators compared to 10% for more established and new researchers. “I really believe that we need our early-stage investigators getting on with their R01s and bringing their great ideas to life and we can’t have a period of time where that gap happens.”

Rathmell was also glad they were able to keep cancer centers whole, which should help support investigators at NCI-designated cancer centers but acknowledged it will still be a tight squeeze. “We’re essentially flat and it’s feeling like it’s less because it costs more to do everything every day,” she added.

For those concerned about the loss of funding, many of the panelists encouraged attendees to reach out to their legislators. For example, Islam mentioned how young researchers could become involved with the AACR’s Early-career Hill Day in which researchers visit the Capitol to lobby for government support.

“One of the things that I’ve learned during my time at the Hill with my colleagues is when you go into these offices, everyone is human,” Islam said. “And our stories make us human. So you need to learn how to share those personal stories.”

The National Cancer Plan

No matter the budget, Rathmell is dedicated to fulfilling the goals of the reignited Cancer Moonshot and the National Cancer Plan, which was devised under former NCI Director and current NIH Director Monica Bertagnolli, MD. In a commentary published in Cancer Discovery, Rathmell broke down her vision for the National Cancer Plan and provides examples of how the plan is achieving success.

During her address, she compared the plan to a machine. She separated the eight goals into two buckets. The health-centric goals—detect cancer early, deliver optimal care, develop effective treatments, and prevent cancer—were described as interlocking gears that drive improvement in patient outcomes. The empowering goals—maximize data utility, eliminate inequalities, optimize the workforce, and engage every person—act as the engine that ensures those gears are effective. Meanwhile, the fuel that powers all of this is discovery science.

NCI Director W. Kimryn Rathmell, MD, PhD, included this breakdown of the National Cancer Plan in Cancer Discovery.

Still, the message to come out of both Rathmell’s address and the panel was the need for greater collaboration to achieve the goals of this plan and the Cancer Moonshot.

“If we are going to end cancer as we know it, we need to realize that we need to unify our forces, our troops, our teams,” LoRusso said. “Partnerships working together tend to have a greater impact on discoveries than most individuals working alone.”