New Discoveries and Honors

Matthew G. Vander Heiden, MD, PhD, former Damon Runyon Innovator and current mentor, says he gets a lot of questions from his cancer patients about how their diet might impact disease progression. Often, these patients have heard the hypothesis that an aggressively calorie-restricted diet or the low-carbohydrate, high-fat ketogenic diet may slow tumor growth. The logic for these diets is that cancer cells require high levels of glucose to fuel their rapid proliferation, so depriving them of sugar might throw a wrench in the works. However, as Damon Runyon Fellow Evan C. Lien, PhD, a postdoc in Dr. Vander Heiden’s lab at MIT, put it: “A lot of the advice out there isn’t necessarily based on very good science.”

Like a leaky gas pipe in an apartment building, failure to repair DNA damage can have disastrous consequences, including the introduction of cancer-causing mutations. This is why our cells have complex mechanisms for recognizing and repairing broken DNA strands before too much damage has been done. In a big-picture sense, we know how DNA repair works: proteins responsible for sensing damage activate a cascade of other proteins, depending on the nature and location of the problem. But a granular understanding of this process, including which genes are involved, continues to elude scientists.

Prostate cancer is among the most common cancers in American men, accounting for one in five new cancer diagnoses. Hormone therapy is currently the standard of care for patients with metastatic disease, but nearly all patients develop resistance to this treatment eventually. Extensive effort has therefore been directed toward the search for new drug targets, illuminating the biological underpinnings of the disease. Given a tumor sample from a patient with prostate cancer, researchers can now identify millions of genetic and molecular features, from single DNA mutations to RNA transcription errors to mutant protein complexes.

Epidermal growth factor receptor (EGFR) is a protein on the surface of cells that receives signals telling the cell to grow. Mutations in the EGFR gene are known to drive a number of cancers, including non-small cell lung cancer. For patients with common EGFR mutations, known as “classical mutations,” EGFR inhibitor treatments are available and effective. But such targeted therapies have not been developed for patients with atypical mutations, often leaving chemotherapy as the only treatment option.

We are delighted to announce that Damon Runyon-HHMI Fellow Tyler Starr, PhD, of Fred Hutchinson Cancer Research Center, has been named a 2021 STAT Wunderkind. This award, granted annually to “the best early-career researchers in health and medicine in North America,” recognizes Tyler’s exceptional promise in the study of viruses and our immune systems.

Breast cancer is the most common cancer diagnosed in women worldwide, and an estrogen receptor known as ERα plays a critical role in more than 70% of these cancers. In healthy cells, when bound to estrogen, ERα activates a signaling pathway that controls cell growth, proliferation, and survival. In breast cancer, an abnormal variant of ERα sends this pathway into overdrive. For patients with ERα-positive breast cancer, estrogen-blocking hormone therapies like tamoxifen can prolong survival. Up to half of these patients will acquire resistance, however, creating an urgent need for novel treatment strategies targeting ERα.

Myeloproliferative neoplasms (MPNs) are cancers that arise when a mutated blood stem cell begins to produce too many red blood cells, white blood cells, or platelets. A number of mutations can drive MPNs, and studies have demonstrated that different mutations result in different clinical outcomes. For example, between the two most commonly mutated genes, JAK2 and CALR, JAK2-mutated MPNs tend to be the more aggressive cancers.

As cancer cells evolve in response to treatment or other environmental pressures, a patient may end up with a highly diverse population of cancer cells circulating throughout their body. In these cases, a single biopsy from the tissue where the cancer originated is not enough to fully understand the cancer’s genome or how best to target it. Liquid biopsies are thus increasingly used to study circulating tumor cells (CTCs) in the blood, with single-cell CTC sequencing emerging as the next step in unraveling the mysteries of disease progression and treatment response.

One way to determine how successfully a patient’s cancer treatment has eradicated the disease is to check the bloodstream for free-floating DNA originating from tumor cells, also known as circulating tumor DNA (ctDNA). The detection of ctDNA can serve as a powerful prognostic tool, allowing clinicians to assess the effectiveness of treatment and predict the likelihood of disease recurrence.

Researchers at Stanford University have discovered sugar-bound RNA strands protruding from the cell surface, challenging the long-held assumption that these two types of molecules are kept separate within the cell. These newfound “glycoRNAs,” identified by former Damon Runyon Fellow Ryan Flynn, MD, PhD, may serve an important role in immune signaling. A shock to biologists across disciplines, this finding has particular significance in the world of cancer research, as the development of effective immunotherapies hinges on our understanding of how the immune system is activated.

Immune checkpoint blockades are remarkably effective at exposing tumor cells to immune system attack, but only in the minority of patients with highly mutated tumors. While a high number of genetic mutations may seem like a bad thing, more mutations mean tumors produce more antigens, making them more recognizable to immune T-cells, and thus more susceptible to immunotherapy. In a groundbreaking report, Damon Runyon alumni Robert K. Bradley, PhD, and Omar Abdel-Wahab, MD, offer proof of concept that introducing errors in the short-lived RNA—rather than permanent DNA damage—still causes tumors to present antigens on their cell surface, stimulating immune response. The hope is that drugs that induce such RNA errors could be used in combination with checkpoint blockades to shrink therapy-resistant tumors.

Selection bias occurs when those chosen to participate in a study are not representative of the target population, limiting how much we can trust the study results. In order to quantify this selection bias, researchers have come up with a metric known as the diagnosis-to-treatment interval (DTI), which measures treatment urgency among trial participants. DTI, however, is not an ideal metric for selecting trial participants, as non-biological factors like access to medical care also influence the amount of time between diagnosis and treatment. Finding a biological basis for DTI would offer a more objective measure of clinical urgency, and thus be more useful in mitigating selection bias.

The American Society of Clinical Oncologists hosted their annual meeting this past weekend (June 4th-8th, 2021), giving oncology professionals from around the globe the chance to present cutting-edge research on new cancer therapies, ongoing clinical trials, and standards of patient care. Among the studies presented were those of several former and current Damon Runyon Clinical Investigators, whose research unites lab inquiry with clinical application.

One of the many ways tumor cells evade capture by the immune system is by presenting proteins on their surface that signal “don’t touch me” to immune T-cells. These proteins are called immune checkpoints. Therapies that block them—known as immune checkpoint blockades (ICB)—are remarkably effective, but they only work for a minority of cancer patients. In search of more widely beneficial immunotherapies, Damon Runyon Physician-Scientist Gabriel Griffin, MD, and colleagues at the Broad Institute of MIT and Harvard are investigating other mechanisms of immune system evasion to target in combination with ICB. Specifically, they have set out to find epigenetic regulators—proteins that turn genes “on” and “off”—that play a role in helping cancer cells avoid detection.

Prostate cancer (PCa), second only to skin cancer in prevalence among American men, has multiple subtypes defined by which key gene was mutated early in disease progression. Molecular analysis of PCa tumors has illuminated these subtype-defining genetic events, yet it remains unclear how these early alterations influence later genetic events and, eventually, result in different clinical outcomes. While molecular characterization often guides treatment decisions in breast and other cancers, more clarity is needed about these pathways for PCa subtyping to be clinically relevant. At Weill Cornell Medicine, Damon Runyon Clinical Investigator Chris Barbieri, MD, PhD, and colleagues are leading this charge.

Established by an Act of Congress in 1863, the National Academy of Sciences (NAS) is the body of distinguished researchers “charged with providing independent, objective advice to the nation on matters related to science and technology.” Election to membership is among the highest honors a scientist can receive. This year, three Damon Runyon alumni join the NAS ranks, bringing the total number of Damon Runyon alumni in NAS to 89.

By the time patients experience symptoms, their tumors contain a genetically diverse collection of cancer cells, each with an accumulation of mutations. If we could better understand the sequence of events that leads from a single mutation to a heterogeneous population of tumor cells, earlier detection and intervention might be possible. However, attempts to trace this evolution where it has already occurred (in model organisms, immortalized cell lines, or patient samples) face significant challenges.

The KRAS gene, responsible for encoding a protein that serves as an “on/off” switch for cell growth, is one of the most commonly mutated genes in cancer. The frequency and nature of its mutation differ across cancer types, however, with the highest occurrence of mutation found in cancers of the colorectum, pancreas, lung, and blood plasma.

The tumor, once an indistinct mass of heterogeneous cells, is gaining single-cell resolution. Until recently, even distinguishing between healthy cells and malignant cells within a tumor sample presented a challenge.

Nearly all human cancers, and particularly blood cancers, involve dysregulated gene expression – the wrong genes are switched on or the right ones are switched off. The molecule responsible for switching genes on and off is called a transcription factor. Identifying which transcription factor is misbehaving and how is often the key to developing effective cancer treatments.

A new study demonstrates the staying power of the immune response generated by a personalized cancer vaccine called NeoVax, which works by targeting specific proteins on each patient’s tumor cells to activate the body's immune system against the cancer.

Pancreatic cancer is one of the most difficult forms of cancer to treat effectively. Standard courses of chemotherapy drugs often come up short for patients, leading to a dismal 5-year relative survival rate of just 10%. And while the past few years’ transformative breakthroughs in immunotherapy have drastically improved the prognosis for many patients diagnosed with other forms of cancer, most pancreatic cancers have proved frustratingly resistant to immunotherapy alone.

This year, thirteen Damon Runyon alumni were chosen as American Association for the Advancement of Science (AAAS) Fellows in honor of their invaluable contributions to science and technology.