Blood stem cells, which give rise to various blood cells in the body, acquire mutations with increasing frequency as we age. In the absence of blood cancer development, this state is called clonal hematopoiesis. Up to a quarter of individuals over 60 years old will have recurrent mutations detected in their blood. Recent studies suggest that those with clonal hematopoiesis have an increased risk of developing heart disease and blood cancer, as well as increased levels of inflammatory cytokines – signaling molecules released by immune cells to promote inflammation. Dr. Kim will dissect the mechanisms underlying increased inflammation, which could provide insight into various inflammatory conditions associated with clonal hematopoiesis and potentially elucidate how clonal hematopoiesis progresses into blood cancer.

Cancer cells rely on efficient uptake, conversion, and exchange of nutrients and vitamins to support their rapid growth and survival. The molecular transport channels that allow passage of nutrients between the different cellular compartments are critical for the survival of cancer cells and are thus promising as potential drug targets. However, drug discovery efforts are hampered by a lack of basic understanding of these channels' identities, functions, and regulation inside cancer cells. Dr. Kory's research aims to identify transporters central to cancer cell nutrient supply and detoxification pathways and determine their role in the emergence, survival, and aggressiveness of cancer. Her research is relevant to all cancers, but particularly pediatric, blood, and breast cancers.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Intensive chemotherapy cures only a subset of patients, and immunotherapy has had limited success in AML. One novel approach is chimeric antigen receptor (CAR) T cell therapy, which involves genetically engineering a patient's own immune cells to target cancer cells. The difficulty with this approach is that the majority of available targets present on AML cells also reside on many normal cells. Based on emerging data demonstrating overexpression of the gene CD70 in AML cells compared to normal tissues, Dr. Leick [The Mark Foundation for Cancer Research Physician-Scientist] and his colleagues have recently optimized a CD70-targeted CAR T therapy and demonstrated its efficacy in AML. Despite the superiority of this CAR over prior versions, however, it is less effective against AML cells that present a low amount of the antigen. Dr. Leick is now working to improve this CAR through genetic modification and/or a dual targeting approach. His work has the potential to generate a safe, highly potent, optimized strategy for treating this leukemia.

Dr. Li’s research aims to uncover a missing link between repeated DNA sequences, genomic instability, and viruses. While abnormal expansion of “repeats” has been found at unstable genomic regions, known as fragile sites, that are implicated in cancer growth, the mechanisms and consequences of this genomic instability remain poorly understood. Dr. Li recently discovered a cluster of Epstein Barr Virus (EBV)-like repeat sequences in the genome that breaks when bound by abnormally high levels of EBV antigens. These findings illustrate how a chromosome can be broken in long-term EBV infection, which can threaten genome stability and trigger cancer development. Dr. Li aims to leverage this discovery to advance our understanding of how broken repeats threaten genome integrity for clinical screening of individuals susceptible to EBV-associated diseases, and for the prevention and treatment of disease in these individuals. This research could also lead to the discovery of other virus-like repeats and the potential biological function of these virus-like repeats in our genome.  

Sex differences are markedly evident in many types of cancer, and one of the major contributors to sex-biased differences lies in the sex chromosomes. In contrast to the traditional view that Y chromosome-encoded proteins only function in male reproductive organs, recent evidence suggests that select Y chromosome-encoded proteins are also expressed in male non-reproductive tissues. Furthermore, dysregulation of the Y chromosome-encoded proteins has been implicated in cancers in non-reproductive organs. Upon closer examination, this subgroup of Y chromosome proteins each has corresponding proteins on the X chromosome. Dr. Liu will study the function of the Y chromosome-encoded proteins and whether and how protein sequence differences from their X chromosome-encoded counterparts lead to functional distinctions in cancer development.

In addition to acute illness, viruses can cause cancers. While our understanding of cellular immunity against viruses that have DNA-based genomes is robust, we know less about how cells protect themselves against RNA-based viruses such as hepatitis C, a leading cause of liver cancer. Because many cellular defenses against viruses are known to be shared between mammals and bacteria, Dr. Mendoza [HHMI Fellow] is looking for new cellular defenses against RNA viruses in bacteria and will investigate how these defenses work. The resulting discovery of anti-viral defenses will broaden our understanding of how cells protect themselves against RNA viruses, which will improve our capacity to support patients' immune systems when infected with cancer-causing RNA viruses. Dr. Mendoza received their PhD from the University of California, San Francisco, and their BS from the University of Miami.

Chimeric antigen receptor (CAR) T cells are a type of immunotherapy that uses genetically engineered T cells from patients to treat cancer. While a one-time treatment has the potential to generate long-term protection from relapse, CAR T cells often fail due to poor persistence. Dr. Mi recently studied samples from patients with durable remissions of leukemia and found that rare persistent CAR T cells share a distinct set of molecular and cellular features. She will now define the properties of persistent CAR T cells across multiple blood cancers, trace their T cell origins and evolutionary dynamics using novel technologies, and experimentally evaluate her findings in preclinical models. These studies could illuminate how CAR T cells change over time in patients and help guide development of future cellular therapies with more durable effects for patients with different types of cancers.

Human cells compact their vast genomes into the small confines of the nucleus by wrapping their DNA into a highly complex structure called chromatin. Packaging DNA into chromatin, however, affects all nucleic acid-transacting machines (e.g., transcription factors) that need to access the genomic information stored in the DNA. NuRD is a large multi-subunit protein complex that plays a major role in making chromatin either accessible or inaccessible. Dysregulation of NuRD and aberrant targeting of the complex can result in the emergence of several types of cancers, including breast, liver, lung, blood, and prostate cancers. Dr. Osorio Valeriano’s [Philip O'Bryan Montgomery, Jr., MD, Fellow] work will reveal mechanistic aspects of NuRD-mediated chromatin regulation and pave the way for the development of novel therapeutic approaches that target cancers more effectively. Dr. Osorio Valeriano received his PhD from Philipps University and his MSc and BSc from the National Autonomous University of Mexico.

Leukemia is a cancer of the immune system and is a major cause of death from cancer in children and young adults. Chimeric antigen receptor (CAR) T cell therapy, which involves genetic engineering of a cancer patient’s own immune system cells to fight cancer, has demonstrated curative potential. Despite excellent initial responses to treatment, however, leukemia recurs in up to half of pediatric leukemia patients after CAR T treatment. A major cause of treatment failure is that CAR T cells do not attach to cancer cells as strongly as natural T cells do to their targets, and this limits their ability to find and kill cancer cells. Dr. Pauerstein’s research is attempting to improve CAR T cell sensitivity to cancer cells using synthetic cell adhesion molecules, a type of molecular glue between two cells. Engineering adhesion into CAR T cells should build a synthetic immune synapse that can help improve cell-based treatments for leukemia and eventually other cancers.  Dr. Pauerstein received his MD, PhD from Stanford University, Stanford and his BA from Rice University, Houston.

It has been long recognized that B-cell malignancies such as follicular lymphoma (FL) are dependent on interactions with nearby non-malignant cells for survival. However, this dependency has yet to be exploited therapeutically. Dr. Shanmugam aims to define the pro-tumorigenic growth factors in the environment around malignant B cells in FL and elucidate the mechanisms of how these growth factors promote FL cell survival and proliferation. This knowledge will enable the development of new treatments that block these interactions and new laboratory models of follicular lymphoma.