Blood Cancers

Current Projects
Alex Kentsis, MD, PhD

Dr. Kentsis [Richard Lumsden Foundation Clinical Investigator] focuses on the discovery and development of novel therapeutic strategies for patients with refractory cancers, with immediate emphasis on therapy-resistant acute myeloid leukemia (AML). Recent advances in genomic technology revealed a daunting complexity of genetic lesions in some cancers, and surprising dearth of gene mutations amenable to therapy in others. As a physician caring for children with hematologic and solid tumors, his goal is to accelerate advances in AML therapy, by developing functional genomic and proteomic technologies to determine the principal molecular lesions driving AML cells. Using preclinical models, he is defining the mechanisms by which aberrant signaling controls gene expression and therapy resistance in AML and testing therapeutic agents to block AML cell growth and survival.

Project title: "Mechanism and function of regulatory signaling in acute myeloid leukemia"
Institution: Memorial Sloan Kettering Cancer Center
Named Award: Richard Lumsden Foundation Clinical Investigator
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Ross Levine, MD, and Scott A. Armstrong, MD, PhD
Cancer Type: Blood
Research Area: Carcinogenesis
Michael A. Koldobskiy, MD, PhD

Dr. Koldobskiy studies the ways that cancer cells rely on “epigenetic” modifications, or chemical marks that modify the expression of genes without a change in the genetic sequence itself. Variability of epigenetic marks allows cancer cells flexibility in turning genes on and off, and may account for resistance to treatment. By dissecting the mechanisms of epigenetic modification in pediatric acute lymphoblastic leukemia (ALL), the most common cancer in children, he aims to identify new targets for treatment.

Project title: "DNA methylation stochasticity in pediatric pre-B cell acute lymphoblastic leukemia"
Institution: The Johns Hopkins University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Andrew P. Feinberg, MD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
David M. Kurtz, MD

Despite improved outcomes for patients with non-Hodgkin lymphoma over the last two decades, a significant number of patients - about 40% in the most common type of lymphoma - will ultimately die from their disease. One of the major reasons for this is a lack of response to chemotherapy. Predicting how an individual patient will respond to treatment remains a major challenge. Current methods rely on risk factors measured prior to therapy; however, cancer is a dynamic process with dramatic changes throughout therapy. Dr. Kurtz aims to develop methods that use emerging blood-based biomarkers to measure changes in cancer patients over time. This technology allows the creation of tools for precise prediction of outcomes to therapy from a simple blood test. Ultimately, this technology could help doctors make personalized treatment decisions and tailor therapy to individual patients.

Project title: "Response prediction and personalized therapy from mathematical modeling of circulating tumor DNA in non-Hodgkin lymphoma"
Institution: Stanford University
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Arash A. Alizadeh, MD, PhD
Cancer Type: Blood
Research Area: Biomedical Engineering
Kathrin Leppek, PhD

Dr. Leppek [Layton Family Fellow] aims to combine RNA and ribosome biology with developmental biology to investigate how cells regulate protein synthesis through a process called translation. This process requires regulatory mechanisms to fine-tune when and where genes are expressed. Defective expression of certain genes gives rise to uncontrolled growth and metastasis of cancer cells. She will identify and characterize molecular components that play a functional role in mediating translational control during embryogenesis. This will be invaluable for our understanding of how deregulation of accurate gene expression underlies human diseases such as cancer.

Project title: "Mechanistic characterization of 5’UTR RNA elements that confer translational specificity to shape vertebrate embryonic development"
Institution: Stanford University
Named Award: Layton Family Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Maria Barna, PhD
Cancer Type: Blood, Gastric, Gynecological, Breast, Colorectal, Lung, Pancreatic
Research Area: Developmental Biology
Loretta S. Li, MD

Approximately 10-15% of pediatric and adult patients with B-cell acute lymphoblastic leukemia (B-ALL) have a high-risk form of the disease characterized by rearrangements of a gene called CRLF2. Alterations of this gene result in increased expression of the CRLF2 protein and promote leukemia development. When treated with conventional chemotherapy, patients with CRLF2 gene alterations do poorly. Their leukemias are dependent on an enzyme called JAK2 for survival, yet no targeted therapies with proven efficacy are currently available. Dr. Li has unique access to a new drug called CHZ868, which turns off JAK2 enzyme activity, potently kills B-ALL cells, and improves overall survival in mice with JAK2-dependent B-ALL. Treatment with CHZ868 alone is not curative, however, and all mice eventually succumb to progressive leukemia. Using JAK2-dependent B-ALL cells and mouse models, she will study how leukemia becomes resistant to JAK2 inhibitors. Her goal is to identify combinations of agents that can prevent or overcome resistance to a single therapy and also guide the development of new JAK2 inhibitors for patients.

Project title: "Mechanisms of disease and resistance in CRLF2-rearranged B-cell acute lymphoblastic leukemia"
Institution: Dana-Farber Cancer Institute
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): David M. Weinstock, MD
Cancer Type: Blood, Pediatric
Research Area: Cancer Genetics
Christine Mayr, MD, PhD

[Island Outreach Foundation Innovator of the Damon Runyon-Rachleff Innovation Award]

Cancer is thought to arise through a series of genetic mutations in the DNA sequence. Depending on the location of these errors and the genes that are affected, these mutations lead to the many different features that characterize cancer cells such as uncontrolled proliferation, escape from cell death and metastasis.

Dr. Mayr proposes the existence of a new type of anomaly that can lead to cancer: non-genetic aberrations induced by modifications of RNAs, which have so far been excluded from large-scale cancer genomics efforts. She has developed a new method to identify this type of aberration in different cancers and will investigate its frequency and functional consequences for tumor growth. Her studies will help to broaden the understanding of cancers and may also help in the design of new therapeutics.


Project title: "A functional atlas of lymphoma specific aberrations generated by RNA processing"
Institution: Memorial Sloan Kettering Cancer Center
Named Award: Island Outreach Foundation Innovator
Award Program: Innovator
Cancer Type: Blood
Research Area: Cancer Genetics
Robert K. McGinty, MD, PhD

Dr. McGinty is using protein chemistry and structural biology to study epigenetic changes to the composition and structure of chromatin, the physical state of the DNA in each cell’s genome. These epigenetic modifications are chemical marks that modify the expression of genes without a change in the genetic sequence itself. Divergent patterns of gene expression lead to the development of diverse cell types and functions, and their inappropriate regulation is correlated with many human diseases, especially cancer.   

Project title: "Structural studies of the MLL1 Core Methyltransferase complex"
Institution: Pennsylvania State University
Award Program: Dale Frey Scientist
Cancer Type: Blood
Research Area: Chromatin Biology
Rand M. Miller, PhD

Dr. Miller is interested in understanding the mechanisms by which cancers become resistant to chemotherapeutic agents. Many cancers acquire resistance to drugs by overproducing molecular “pumps” called multidrug resistance (MDR) proteins, which actively export the toxic drug molecules out of cells. Using a variety of chemical techniques, he will investigate how these pumps mediate drug resistance in cancers, as well as their roles in the maintenance of healthy cellular function. Ultimately, this work may facilitate the design of better compounds targeting MDR pumps to overcome drug resistance.

Project title: "Chemistry-based dissection of multidrug resistance efflux pump mechanisms in living cells"
Institution: The Rockefeller University
Named Award: Illini 4000 Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Tarun M. Kapoor, PhD
Cancer Type: Blood, Other Cancer, Breast, Colorectal
Research Area: Chemical Biology
Ann Mullally, MD

Myeloproliferative neoplasms (MPN) are a type of blood cancer sometimes considered to be "pre-leukemias" which can progress to leukemia and are also lethal cancers in their own right. A population of rare hematopoietic stem cells (HSC), called MPN disease-propagating cells, typically harbor mutations that cause the cells to overproliferate. These mutated HSC produce abnormal cancerous blood cells that over time can eliminate the normal blood cells in the bone marrow. In MPN, the cancerous blood cells secrete an excess of substances called growth factors that allow cancer cells to survive.

Dr. Mullally aims to understand which of the growth factors help the mutated HSC to survive and to then use drugs to block the activity of these growth factors, thus killing the mutated HSC. This approach will lead to more successful treatments for MPN and leukemia, resulting in a higher cure rate for patients. 

Project title: "Determining the role of aberrant growth factor signaling in maintaining disease-propagating cells and mediating JAK2 inhibitor resistance in myeloproliferative neoplasms"
Institution: Brigham and Women's Hospital
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Benjamin L. Ebert, MD, and Jerome Ritz, MD
Cancer Type: Blood
Research Area: Stem Cell Biology
Sigrid Nachtergaele, PhD

Dr. Nachtergaele [HHMI Fellow] is investigating the roles of a chemical modification of mRNA called methylation. Many enzymes that add and remove RNA modifications impact developmental processes and cancer proliferation, but how they are regulated remains a mystery. She aims to identify the mechanisms by which mRNA methylation alters gene expression and eventually results in altered cell signaling and growth. Her goals are to understand these regulatory principles, to uncover how they become misregulated in disease, and to exploit these processes to identify novel cancer therapeutic targets.

Project title: "The dynamic N1-methyladenosine methylome in eukaryotic mRNA"
Institution: The University of Chicago
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Chuan He, PhD
Cancer Type: Blood, Breast, Lung
Research Area: Chemical Biology
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