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.

Chimeric antigen receptor T cell (CAR T cell) therapy, in which a patient's own immune cells are engineered to target their cancer, has changed the treatment landscape for many blood cancers. Despite promising early results, however, long-term follow-up has revealed that nearly half of patients treated with CAR T cells eventually experience cancer recurrence. Using a variety of techniques in cell lines and patient samples, Dr. Singh [Bakewell Foundation Clinical Investigator] aims to understand how interactions between engineered T cells and blood cancer cells in some cases lead to long-term remission, and in others to therapeutic failure. The broad goals of his lab are to understand the biological signals that cause these therapies to fail, and to use this knowledge to design next-generation immunotherapies that can cure more patients.

The microorganisms that live in the digestive tract, also known as the intestinal microbiome, have emerged as important factors in patients' response to cancer therapy. Studies have found that the intestinal microbiome can modulate the anti-tumor immune response to several types of therapy, including chimeric antigen receptor T cell (CAR T cell) therapy, in which a patient's own immune cells are genetically modified to target their cancer. CAR T therapy has led to unprecedented responses in patients with high-risk blood cancers such as leukemia and lymphoma. However, patients may experience disease relapse or CAR-mediated toxicities. Dr. Smith has found that responses to CAR T therapy are linked to alterations in and abundances of the intestinal microbiome. Her research will investigate how the intestinal microbiome mediates this impact on CAR T cells. Dr. Smith was previously a Damon Runyon Physician-Scientist, a complementary award program designed for clinicians interested in research to acquire the skills needed to become physician-scientists.

A key question in cancer biology is how genetic mutations, acquired over time, interact with environmental factors to affect emergence and progression of disease. This is particularly relevant in blood cancers because many people acquire genetic mutations in blood-forming stem cells in the bone marrow but only a small proportion go on to develop acute myeloid leukemia (AML). Dr. Swann [William Raveis Charitable Fund Fellow] is investigating whether inflammatory signals alter the behavior of stem cells that have already acquired an initial mutation, causing them to acquire features of cancer that will hasten the onset of AML. Specifically, Dr. Swann is interested in whether pre-cancerous stem cells change their gene expression in response to inflammation, which might allow them to outcompete normal cells in the bone marrow. He is utilizing cutting-edge techniques such as CRISPR editing of blood stem cells to investigate the molecular pathways responsible for these biological changes. This project has the potential to identify molecular pathways activated by inflammation that might promote AML development, offering new targets for therapeutic interventions. Dr. Swann received his VetMD (DVM) from the University of Cambridge and his DPhil (PhD) from the University of Oxford.

Before a gene can be expressed, a protein known as a splicing factor must remove non-coding regions (introns) from the RNA strand. Mutations in splicing factors, and specifically one called SF3B1, can lead to the development of certain blood cancers. Dr. Vallurupalli [David M. Livingston, MD, Physician-Scientist] will use genome editing technologies to generate and characterize SF3B1-mutant models in human adult blood stem cells. She will also screen for other genetic factors that may influence the outcome of SF3B1 mutations. Her goal is to identify previously unrecognized therapeutic targets for treating splicing factor-mutated blood cancers.

Up to 50% of patients with acute myeloid leukemia (AML) have a genetic alteration called DNA methylation, in which a carbon methyl group is added to the DNA molecule, typically turning the methylated gene "off." A mainstay of therapy is the use of hypomethylating agents, which prevent copying of these modifications during cell division, but this therapy is effective in only 20-30% of patients. Using chemical and genetic manipulation in mouse bone marrow, Dr. Viny [Damon Runyon-Doris Duke Clinical Investigator] aims to determine the effect of DNA methylation on the ability of specific regions of the genome to be accessible to proteins involved with gene expression and other regions to be inaccessible and "silenced." In a prospective phase II clinical trial, he will treat relapsed AML patients with dual hypomethylating agents. By studying these patients' genetic profiles, he aims to determine the genetic features that contribute to therapy response, paving the way for more effective interventions to be developed for patients with acute myeloid leukemia. Dr. Viny was previously a Damon Runyon Fellow.

Age is the greatest risk factor for developing cancer due to the continuous and life-long accumulation of DNA mutations. Although we have identified causes of childhood cancer, including the inheritance of cancer-predisposing genes, other major contributing factors have not yet been identified. Blood cancer is the most common cancer in children and sequencing data indicate that the first genetic mutations occur during fetal development. Dr. Wagenblast will use human blood stem cells and CRISPR/Cas9-mediated genome engineering to model leukemia evolution and identify biological processes that specifically contribute towards cancer development in children. The goal is to leverage this understanding to identify novel therapeutic targets against childhood blood cancer.

Certain cancers of the blood are treated by transplanting stem cells that can regenerate all kinds of blood cells from healthy donors. Even though this procedure has the potential to cure the cancer, common complications such as bloodstream infections or graft-versus-host disease (when the body rejects the donor cells) can lead to major side effects and even death. There is substantial evidence that these complications are linked to the microbes residing in the gut, collectively termed the gut microbiome, but the exact mechanism for this interaction is unknown. To address this knowledge gap, Dr. Wirbel will study how the genomes of gut microbes change over time in a large cohort of blood stem cell transplantation patients, using modern DNA sequencing techniques and developing novel analyses pipelines. He will then investigate whether the genes that are changing in microbial genomes might influence the human immune system and thereby contribute to these clinical complications.

Dr. Wirbel plans to develop a computational tool for the reference-free analysis of microbial genomes over time based on long-read sequencing. By comparing newly assembled genomes across different sampling time points, the tool will detect structural variation (deletion or insertions into the genome) in microbial genomes. Additionally, genomic inversions (“flipping” of the orientation of DNA) and genes associated with these changes will also be identified.

Dr. Zhang is studying a unique three-stranded nucleic acid structure, called an R-loop, to understand its role in cancer development and find ways to target and control its formation. R-loops consist of a DNA-RNA hybrid and a displaced strand of DNA. R-loops occur frequently in human genomes, and while they play an important role in blood cell differentiation and immune cell function, they can also interfere with DNA repair and promote genome instability, giving rise to leukemia. However, the dynamic nature of R-loop formation hampers the detection of this structure in a small cell sample. To address this challenge, Dr. Zhang is developing novel techniques to map R-loops in normal blood stem cells versus blood cancer cells at single-cell resolution. He also plans to investigate leukemia-specific R-loops in vitro and in vivo with CRISPR-based screening techniques. The goal of his research is to aid development of therapeutic interventions for R-loop-related gene expression dysregulation in cancer, especially leukemia. Dr. Zhang received his PhD from Ohio State University, Columbus, his MS from University of Edinburgh, Edinburgh, and his BS from Chongqing University, Chongqing.

Thalidomide derivatives are a mainstay of treatment in multiple myeloma, a cancer of white blood cells called plasma cells. However, around one in ten individuals treated with thalidomide derivatives for multiple myeloma will develop a blood clot, which can be life-threatening. It is critical to determine how to continue to use thalidomide derivatives to kill myeloma cells, while working to understand why these drugs increase the likelihood of clotting. Thalidomide derivatives work by degrading proteins important to myeloma cell growth; Dr. Zon hypothesizes that these drugs could similarly lead to the degradation of proteins that prevent blood clotting. She is comprehensively evaluating what factors promote blood clots patients with multiple myeloma, with the goal of developing more targeted medications to prevent blood clots and improve treatment outcomes in blood cancer patients.