Blood Cancers

Current Projects
Nathan Singh, MD

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.

Project title: "Tailored cellular engineering to overcome costimulation-driven CAR T cell dysfunction"
Institution: Washington University
Named Award: Bakewell Foundation Clinical Investigator
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): John F. DiPersio, MD, PhD
Cancer Type: Blood
Research Area: Immunotherapy
Melody Smith, MD

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.

Project title: "Regulatory mechanisms of the intestinal microbiome on chimeric antigen receptor T cells"
Institution: Stanford University
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Robert S. Negrin, MD
Cancer Type: Blood
Research Area: Immunotherapy
James Swann, VetMB, DPhil

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.


Project title: "Emergency myelopoiesis pathways as common drivers of clonal dominance and disease progression in acute myeloid leukemia"
Institution: Columbia University
Named Award: William Raveis Charitable Fund Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Emmanuelle Passegué, PhD
Cancer Type: Blood
Research Area: Carcinogenesis
Haripriya Vaidehi Narayanan, PhD

Immune B cells defend the human body from infections by quickly dividing to increase their numbers and mutating their immune receptors to adapt to new pathogens. However, such frequent division and mutation creates a high risk of blood cancers, like lymphomas and myelomas. Every B cell makes an important decision about its fate – to die, to divide a certain number of times, or to differentiate into an antibody-producing cell – based on the affinity of its receptor to an oncoming pathogen. Currently, it is not understood how the B cells’ receptor affinities influence their internal gene networks to determine their fates. By combining microscopy, genomics, and computational models, Dr. Narayanan aims to discover the precise mechanisms underlying the B cell immune response, so that we can predict, prevent, or alleviate B cell-related cancers without compromising immunity.

Dr. Narayanan is applying multi-scale dynamical systems modeling to understand mechanisms driving B cell immunity and lymphomagenesis. The challenge is to relate stochastic spatial interactions between cells to signaling and gene expression dynamics within each cell. Her strategy is to integrate ODE- and agent-based numerical methods to simulate B cell evolutionary lineages, which encode the mechanisms that generated them, and then compare predicted lineage trees to experimental observations. Using live microscopy and image analysis, she tracks B cell interactions, signals, and resulting lineages at single-cell resolution in vitro. In parallel, she uses statistical inference on genomic data to reconstruct in vivo lineages. By fusing both data streams, she will compare observed and simulated tree shape statistics to validate the mechanistic model predictions.

Project title: "Developing a mechanistic multi-scale framework relating signaling and spatiotemporal dynamics in B-cell affinity maturation and lymphomagenesis"
Institution: University of California, Los Angeles
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Alexander Hoffmann, PhD, and Roy Wollman, PhD
Cancer Type: Blood
Research Area: Basic Immunology
Mounica Vallurupalli, MD

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.

Project title: "Defining the mechanistic implications of SF3B1 mutations in MDS"
Institution: Dana-Farber Cancer Institute
Named Award: David M. Livingston MD Physician-Scientist
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Todd R. Golub, MD
Cancer Type: Blood
Research Area: Cancer Genetics
Aaron D. Viny, MD

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.

Project title: "Epigenetic coupling of DNA methylation and chromatin structure on leukemic transformation and therapeutic response"
Institution: Columbia University
Named Award: Damon Runyon-Doris Duke Clinical Investigator
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Emmanuelle Passegué, PhD, and Joseph G. Jurcic, MD
Cancer Type: Blood
Research Area: Chromatin Biology
Elvin Wagenblast, PhD

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.

Project title: "Untangling the evolutionary dependency of childhood leukemia"
Institution: Icahn School of Medicine at Mount Sinai
Award Program: Innovator
Cancer Type: Blood, Pediatric
Research Area: Stem Cell Biology
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