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 focuses on how cells become cancerous when they have an abnormal number of chromosomes or broken parts of a chromosome. The centromere, which joins two arms of a chromosome, is essential for faithful chromosome segregation during cell division and genome stability. When chromosomes fail to be delivered correctly to each new cell, the abnormal chromosomes may form “neocentromeres” which have been discovered in developmental disorders and cancer. Dr. Li is developing tools to examine and manipulate these neocentromeres, which may lead to a better understanding of how cancer cells evolve and potentially novel anti-tumor strategies.

DNA methyltransferase enzymes, responsible for adding methyl groups to DNA strands, are critical for controlling gene expression. These enzymes are often disrupted in cancers, including acute myeloid leukemia (AML), but their regulation is not understood. One form of enzyme regulation, called allostery, involves a regulator molecule binding to an enzyme at a site other than its active site. Dr. Liau is pioneering approaches to explore allostery, specifically focusing on allosteric mechanisms that regulate DNA methyltransferase function. His research will shed light on the impact of cancer mutations on enzyme function and strategies to pharmacologically modulate their activity. The approaches developed will be broadly expanded to study other enzymes disrupted in cancer and leveraged with synthetic chemistry to enable therapeutics discovery.

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.

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.

Cancer survivors are at a higher risk of developing blood cancers than the general population due to the toxic effects of cancer treatments. Therapy-related blood cancers are often resistant to existing drugs and therefore extremely challenging to treat. Contrary to previous thought, recent studies show that the mutations causing these blood cancers can be identified in patients' blood many years before they receive therapy. Dr. Papaemmanuil has discovered that the existing mutations alone are not sufficient to cause therapy-related cancer but require the acquisition of additional mutations that affect large segments of the DNA, or "allelic imbalances." She will pursue further studies to screen patients and understand the mechanisms of therapy-related blood cancers. These findings will inform clinical strategies of early detection and targeted intervention to better treat this aggressive disease.

Kinase proteins, which regulate the activity of other proteins, are a major class of cancer therapy targets, with over 65 FDA-approved drugs targeted against them. However, tumors can evolve resistance to kinase-targeting therapies, and it remains difficult to predict whether a specific tumor will resist a particular kinase-targeting drug. Dr. Singh will use protein structural models and biophysical predictions to analyze how kinase mutations cause cancers to resist therapy. As these computationally intensive calculations could require decades on a single desktop computer, he will use a computing platform called Folding@home, which harnesses idle computer time donated by citizen scientists around the world to run the calculations. By developing new algorithms to predict whether a known mutation will resist a kinase-targeting drug, Dr. Singh hopes to advance precision oncology to allow clinicians to predict a treatment's chance of success given a patient's tumor profile. While his work primarily focuses on resistance to the drug crizotinib, used to treat non-small-cell lung carcinomas, his approaches can be extrapolated to other tumors and cancer targets. Dr. Singh received his BA and his PhD in computational and molecular biophysics from Washington University in St. Louis.

Molecular dynamics (MD) simulations are computational microscopes that model and capture atomically detailed protein motions. To analyze MD simulations, Dr. Singh will construct Markov State Models, network representations of a protein's conformational landscape, and couple them with information theoretic measures of communication between mutated residues and drug binding sites. Alchemical Free Energy calculations will predict the impact of mutation on a drug's binding energy using artificial "alchemical" intermediates to measure the energetic cost of mutating a residue.