Blood Cancers

Current Projects
Jay F. Sarthy, MD, PhD

Dr. Sarthy is developing new easy-to-use and affordable methods for studying DNA packaging and epigenetics (modification of gene expression) in pediatric cancers with a special focus on diffuse midline gliomas and neuroblastoma. These methods may help explain the drivers of pediatric malignancies and allow clinicians to better monitor response to treatment with the goal of developing new drugs that restore the cell’s ability to package DNA correctly.

Project title: "Characterization of the epigenomic landscape of diffuse midline gliomas"
Institution: Fred Hutchinson Cancer Research Center
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Steven Henikoff, PhD
Cancer Type: Blood, Other Cancer, Pediatric, Brain
Research Area: Epigenetics
Neel H. Shah, PhD

Tyrosine kinases are enzymes that act as “on” and “off” switches for signals in cells and are important in regulating cellular activity, such as cell division. They can become mutated, stuck in the "on" position, and cause unregulated growth of the cell, which is a necessary step for the development of cancer. Kinase inhibitors have been developed as cancer treatments, but they have not been sufficiently effective and are susceptible to drug resistance.  Dr. Shah seeks to identify new activities and modes of regulation that distinguish oncogenic and non-oncogenic tyrosine kinases, with the goal of identifying more specific drug targets.

Project title: "Identifying divergent mechanisms of oncogenicity in tyrosine kinases"
Institution: Columbia University
Award Program: Dale Frey Scientist
Cancer Type: Blood
Research Area: Structural Biology
Melody Smith, MD

Bone marrow transplant (BMT) is a treatment approach where cells from a healthy donor are given to a patient with blood cancer who has not responded to other treatments. Unfortunately, there are risks to this procedure such as graft-versus-host disease (GVHD), which occurs if the cells from the donor attack the "foreign" patient tissue; this can cause serious organ damage and is life-threatening. Melody is investigating an approach to decrease GVHD while also maintaining the benefits of BMT, specifically graft versus tumor (GVT). She utilizes T immune cells from the donor and enables them to express a B cell marker, CD19; these cells can induce complete remissions in patients with CD19-positive leukemia and lymphoma. Administration of these cells following BMT mediates persistent GVT and decreased GVHD. Given that donor T cells are the culprits that cause GVHD, the finding of decreased GVHD in her model was paradoxical. She will now translate these pre-clinical findings to a clinical trial in order to benefit patients.

Project title: "CD19 targeted donor T cells improve graft versus tumor activity and reduce graft versus host disease"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Marcel R.M. van den Brink, MD, PhD
Cancer Type: Blood, Other Cancer
Research Area: Immunotherapy
Catherine C. Smith, MD

Acute myeloid leukemia (AML) is one of the deadliest blood cancers. Mutations in the FLT3 gene are the most common of all mutations in AML and are associated with poor outcomes in both adult and pediatric patients. Despite the importance of FLT3 mutations in AML, we still do not understand the way in which FLT3 is regulated and the functional impact of novel FLT3 mutations identified in recent large AML sequencing studies. Drugs targeting FLT3 have been successful in achieving remissions in AML patients but are limited by the rapid development of drug resistance, particularly due to reactivation of abnormal cancer signaling through the oncogene RAS.  Dr. Smith [Richard Lumsden Foundation Clinical Investigator] proposes studies to better understand how mutations found in AML patients cause dysregulation of FLT3 function and how activation of RAS signaling contributes to drug resistance and AML development. Her goal is to cultivate novel treatment strategies to target FLT3 in patients that will optimize response rates and prevent disease relapse.

Project title: "Defining structure, function and therapeutic impact of oncogenic FLT3 mutations"
Institution: University of California, San Francisco
Named Award: Richard Lumsden Foundation Clinical Investigator
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Neil P. Shah, MD, PhD
Cancer Type: Blood
Research Area: Signal Transduction
Alexey A. Soshnev, MD, PhD

Dr. Soshnev [HHMI Fellow] studies how genetic information is packaged in the nucleus and how such packaging is interpreted by the cellular machinery. Changes in nuclear architecture may simultaneously affect the function of thousands of genes and are a hallmark of cancer. This research focuses on a family of small nuclear proteins termed "linker histones," which are thought to orchestrate higher-order folding of DNA in the nucleus. Understanding the molecular connection between the nuclear architecture and gene regulation will shed new light on the processes underlying oncogenic transformation.

Project title: "The study of linker histone H1 in transcriptional regulation and genome organization"
Institution: The Rockefeller University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): C. David Allis, PhD
Cancer Type: Blood, All Cancers
Research Area: Chromatin Biology
Yadira M. Soto-Feliciano, PhD

Pediatric acute myeloid leukemia (AML) has the lowest survival rate among all pediatric cancers. MLL gene rearrangements (MLL-r) occur in about 20% of children diagnosed with AML. This subtype of leukemia is exquisitely sensitive to inhibition of the interaction between MLL and the chromatin adaptor Menin. Dr. Soto-Feliciano is combining genetic, genomics, and mouse modeling approaches to identify factors that regulate the function of Menin in MLL-r and non-MLL-r leukemia. The identification of cellular mechanisms that mediate the response to Menin-MLL inhibitor-based therapies (already in pre-clinical studies), will inform us about the molecular mechanisms driving acute leukemia. She anticipates that the results of these experiments will provide a better understanding of gene expression programs and chromatin landscapes governing the leukemic state. In addition, this project has the potential to identify novel dependencies that can lead to development of novel drug targets for the treatment of pediatric leukemia.

Project title: "Dissecting the role of Menin in acute leukemia"
Institution: The Rockefeller University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): C. David Allis, PhD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Anthony D. Sung, MD

We share our bodies with trillions of microorganisms: the microbiota. The microbiota interacts with our bodies to affect health and disease, including cancer development and response to therapies. For example, in patients receiving hematopoietic stem cell transplantation as treatment for leukemias, lymphomas, and other blood cancers, disruptions in the microbiota have been linked to disease relapse, infections, treatment complications, and survival. Given these serious effects, it is important to understand how to manipulate the microbiota through therapies like prebiotics: carbohydrates that can be ingested to stimulate the growth and maintenance of various bacteria. The challenge is that different people have different microbiotas and therefore may respond differently to the same prebiotic. To address this challenge, Drs. David and Sung have developed a novel microfluidic platform to isolate individual bacteria from a patient’s stool sample and grow them against selected prebiotics, allowing an understanding of how a given patient’s microbiota may respond to different prebiotics. To do this using conventional techniques would take a stack of petri dishes as tall as the Empire State Building and months of work; their innovative system can do it in a single day. They believe that by using this novel system, they will be able to predict the best prebiotic for a given patient, thereby manipulating their microbiota and improving cancer outcomes. They will test this strategy using patient samples in their artificial gut “bioreactor” as well as in mouse models. The success of this project would lead to clinical trials of personalized prebiotics.

Project title: "Personalized prebiotics to optimize microbiota metabolism and improve transplant outcomes"
Institution: Duke University
Award Program: Innovator
Cancer Type: Blood, All Cancers
Research Area: Microbiology
Sakiko Suzuki, MD

Myelodysplastic syndromes (MDS) are a heterogeneous group of blood disorders characterized by abnormal maturation of the hematopoietic blood cells and premature death of these immature cells leading ultimately to bone marrow failure. Patients with MDS are also at increased risk of developing acute myelogenous and acute lymphoblastic leukemias. Currently available treatments for MDS include serial blood transfusions for refractory anemia, hematopoietic cell growth hormone therapy, and eventually chemotherapy and bone marrow transplantation. However, bone marrow transplants are not an option for some patients due to lack of a matched donor. Additionally, not all patients are eligible for this treatment because of significant risks for long-lasting and severe side effects. New effective treatments are therefore needed.

Mutations in mRNA splicing factors, including SF3B1 and SRSF2, are the most common genetic alterations found in MDS patients. MDS is associated with an inflammatory gene signature suggesting that chronic inflammation contributes to disease pathogenesis. Dr. Suzuki will test whether these mutations sensitize blood cells to necroptosis, an inflammatory form of cell death, resulting in systemic inflammation that contributes to MDS disease propagation. She will also ask whether inhibiting necroptosis can rescue cells with SF3B1 or SRSF2 mutations and allow them to mature normally. If she proves that necroptosis plays a significant role in MDS disease, her work could then be rapidly translated to benefit MDS patients by using necroptosis inhibitor therapies that are currently being tested in the clinic for other diseases. These studies could lead to novel therapeutic options for MDS patients.

Project title: "Inflammatory cell death pathways in Myelodysplastic Syndromes"
Institution: University of Massachusetts Medical School
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Michelle A. Kelliher, PhD, and Peter E. Newburger, MD
Cancer Type: Blood, Other Cancer
Research Area: Experimental Therapeutics
Christina M. Termini, PhD

Dr. Termini aims to improve the success of hematopoietic stem cell transplants, which are used in the curative treatment of the majority of patients with leukemia or lymphoma. Prior to transplant, patients must undergo radiation therapy to decrease the number of cancerous blood cells. In order for hematopoietic stem cells to effectively repopulate the blood and immune systems of the transplant recipient, the stem cells must reach the bone marrow where they can expand. Her research focuses on how radiation regulates the abundance of molecules called proteoglycans within the bone marrow and how this impacts stem cell repopulation following transplant. Using in vivo transplantation models and super-resolution microscopy techniques, she will visualize and quantify how proteoglycans regulate stem cell interactions with the bone marrow. Her aim is to identify molecular targets that can be used to accelerate patient recovery following transplantation. 

Project title: "Proteoglycan remodeling of the bone marrow niche regulates hematopoietic stem cell regeneration"
Institution: University of California, Los Angeles
Award Program: Fellow
Sponsor(s) / Mentor(s): John P. Chute, MD
Cancer Type: Blood, Other Cancer
Research Area: Stem Cell Biology
Albert G. Tsai, MD, PhD

Dr. Tsai is developing next-generation diagnostics for low abundance cellular cancer samples. By measuring 40 or more markers simultaneously on individual tumor cells deposited on glass slides, he hopes to enable definitive diagnoses of blood and lymph node cancers without the need for invasive surgery or a histopathology laboratory. These methods will also provide a unique way to study these cancers, by merging traditional light microscopy with automated antibody-based multi-marker analysis.

Project title: "Diagnosis of hematologic malignancies from paucicellular aspirate material using highly multiplexed single cell analysis"
Institution: Stanford University
Award Program: Fellow
Sponsor(s) / Mentor(s): Sean Bendall, PhD
Cancer Type: Blood
Research Area: Pathology
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