New Discoveries and Honors

A team of scientists at Yale University School of Medicine, led by former Damon Runyon Innovator Jason M. Sheltzer, PhD, recently cracked a century-old scientific mystery: the role of aneuploidy, or abnormal chromosome number, in driving cancer. As far back as the 19^th century, scientists looking under a microscope noticed that when cancer cells divide, the chromosomes sometimes split unequally, resulting in two aneuploid daughter cells.

Glioblastoma, the most common and aggressive form of brain cancer, is notoriously difficult to treat. Once arisen, the tumor rapidly invades healthy brain tissue, making removal by surgery nearly impossible and chemotherapy or radiation therapy success short-lived. Even immunotherapy drugs, increasingly relied upon when first lines of treatment fail, have proven ineffective, leaving glioblastoma patients with very few options. But this may change soon.

In 2018, the Foundation for the National Institutes of Health (FNIH) established the FNIH Trailblazer Prize for Clinician-Scientists to recognize “the outstanding contributions of early career clinician-scientists” whose research “translates basic scientific observations into new paradigm-shifting approaches for diagnosing, preventing, treating or curing disease.”

Chimeric antigen receptor (CAR) T therapy, in which a patient’s own immune T cells are genetically engineered to target and kill their tumor cells, have been the subject of intensive research efforts since the first patients were treated in 2011. Fueled by the promise of immune cells that can serve as a “living drug” against cancer, scientists are committed to making CAR T cells safe and effective for more patients.

Adenoid cystic carcinoma (ACC) is a rare but aggressive cancer that usually develops in the salivary glands and is often diagnosed in younger adults. Because of its rarity, ACC has received relatively little attention from cancer researchers, and as a result, there are no approved therapies for the disease.

Craniopharyngiomas are a rare type of brain tumor that arise near the pituitary gland and are very difficult to treat, whether surgically or with radiation therapy, without inflicting vision loss, memory loss, or hormone disruption. Even in cases when the tumor is successfully removed, craniopharyngiomas are notorious for coming back.

If you asked a hundred people to rate a hundred movies, you would generate enough data to be able to make some predictions. Someone who enjoyed Notting Hill would likely enjoy Pretty Woman, for instance; the new Guardians of the Galaxy movie will likely be a hit with longtime Marvel fans.

At the annual meeting of the American Association for Cancer Research, held this spring in Orlando, former Damon Runyon Clinical Investigator John V. Heymach, MD, PhD, started with the bad news.

In the context of cancer, “drug addiction” has a different meaning—counterintuitively, it’s when cancer cells, not patients, depend on continuous treatment for survival. This can happen if, after the drug target is inhibited, some compensatory signaling pathway is turned on that serves a similar function in the cancer cell. When drug treatment stops, the cell goes into “withdrawal” and this alternative pathway becomes overactive, so much so that it leads to cell death.

Due to their critical role in so many cellular functions, proteins that span the cell membrane are the target of more than half of all FDA-approved drugs. Some of these transmembrane proteins are single-pass, meaning they cross the membrane only once, while others are more complex, multipass proteins, meaning they cross the membrane in at least two places. Drugs targeting the latter are primarily small molecule inhibitors, named for their size relative to antibodies and other large proteins.

A major challenge in treating brain cancer is delivering drugs across the blood-brain barrier (BBB), the dense network of cells and blood vessels that prevents toxins and pathogens from entering the brain. Unfortunately, the BBB also bars entry to therapeutic molecules, leaving highly toxic radiation or chemotherapy treatment as the only recourse for many patients with brain cancer.

Cancer immunotherapies work by triggering the body’s immune response against tumors. Tumor cells can evade destruction by the immune system, however, by attracting helper T cells, the “peacekeepers” of the immune system.

Glioblastomas (GBMs) are the most common—and the most aggressive—type of cancer originating in the brain. Part of the reason these tumors are so hard to treat is that the cancer cells suppress the immune cells that enter their environment. Not only can they outcompete immune cells for critical nutrients, effectively starving the immune cells, but some GBMs can even adjust their metabolism to produce metabolites that directly inhibit immune cell activity.

P53, the most frequently mutated gene across all human cancers, is mutated in the majority of pancreatic cancers. But despite the overwhelming evidence that p53 mutations contribute to cancer progression, therapies targeting mutant p53 have had limited success, suggesting an incomplete understanding of the protein’s function. In order to understand what goes wrong when p53 mutates, researchers need a clearer picture of how normal p53 prevents tumor development in the first place.

Human papillomavirus (HPV) was first identified as a cancer driver in the 1970s, when a German doctor named Harald zur Hausen discovered that the virus causes about 75% of human cervical cancers. HPV has since been linked to several other types of human cancer, including head and neck cancer, as discovered by then-Damon Runyon Clinical Investigator Maura L. Gillison, MD, PhD, in 2000.

Cancer cells are often assumed to be “hypermetabolic,” meaning their energy-producing cycles run on overdrive to fuel the uncontrolled division and growth that defines a tumor. But new findings from former Damon Runyon Fellow Caroline R. Bartman, PhD, and her colleagues at Princeton University challenge this assumption, revealing how much we still have to learn about cancer metabolism.

The process of transcription, in which DNA is copied into RNA, is carried out by a complex cellular machinery that controls which genes are expressed as proteins. Researchers have observed certain organizational features of this machinery, such as the clumping of certain proteins into “condensates,” which function as a unit though unbound by a membrane.

Messenger RNA conveys instructions for how to build a protein in the form of codons—sequences of three nucleotides (A, C, G, or U) that correspond to a specific amino acid. The codons CGU, CGC, and CGA, for example, all correspond to the amino acid arginine. During the process of translation, ribosomes move along the messenger RNA, “reading” out the codons and building a chain of amino acids as translational RNAs (tRNAs) deliver them one by one.

Chimeric antigen receptor (CAR) T cell therapy, in which a patient’s own immune T cells are genetically engineered to target their cancer cells, is one of the most promising advances in cancer therapy of the past decade. Having demonstrated the effectiveness of CAR T cells against a range of blood cancers, researchers now seek to design CAR T cells that can remain active in the body for longer and more efficiently eliminate tumors, with the goal of reducing costs and bringing CAR T therapy to more patients.

Cell adhesion molecules (CAMs) are proteins found on the cell surface that facilitate interactions between cells. They are responsible for organizing and binding cells within tissue structures, creating circuits between neurons, and chaperoning immune cells to their destinations. Known as “cellular glue” and essential for organ function, CAMs are found throughout the body.

Small-cell lung cancer (SCLC), which accounts for about 15% of lung cancer diagnoses, is a relatively rare but aggressive disease. Most SCLC patients respond to chemotherapy at first, but nearly all experience disease recurrence, and at that point treatment options become scarce. Because SCLC is driven by mutations that knock out “tumor suppressor” genes, rather than activate cancer driver genes, it has been difficult to treat with targeted therapies.