Loretta Li, MD
Loretta Sze-Mun Li, MD
Dana-Farber Cancer Institute
Mentor: David Weinstock, MD (2006 YIA)
Defining Mechanisms of Resistance to Type II JAK2 Inhibitors in B-cell Acute Lymphoblastic Leukemia (B-ALL)
Approximately 10-15% of adults and children with B-cell acute lymphoblastic leukemia (B-ALL) have a high-risk form of this disease characterized by alterations involving the CRLF2 gene. When treated with conventional chemotherapy agents, these patients have inferior outcomes. Despite our understanding that their leukemia is dependent on an enzyme called JAK2 for survival, no targeted therapies with proven efficacy are currently available. The only FDAapproved JAK2 inhibitor, ruxolitinib, and other JAK2 inhibitors that act similarly (type I JAK2 inhibitors) have limited activity against JAK2-dependent B-ALL. A new class of drugs called type II JAK2 inhibitors help keep the JAK2 enzyme inactive. We have unique access to CHZ868, the first type II JAK2 inhibitor that can be tested in mouse models of JAK2-dependent leukemia. Our data suggest that CHZ868 is more potent than the type I inhibitors in killing JAK2-dependent BALL cells and also improves overall survival in mice with JAK2-dependent B-ALL. Single-agent CHZ868 therapy was not curative though, and all mice ultimately succumbed to progressive leukemia. We now propose to use JAK2-dependent B-ALL cells and mouse models of B-ALL to study how leukemia becomes resistant to treatment with CHZ868. These studies will provide insight into how CHZ868 may be combined with other agents to prevent or overcome resistance and to guide the design of the next generation of type II JAK2 inhibitors. Our work provides the foundation for trials of type II JAK inhibitors in patients with relapsed or refractory JAK2- dependent B-ALL.
Loretta Li, M.D. is a third year pediatric hematology/oncology fellow at the Dana-Farber Cancer Institute and Boston Children's Hospital. She first became interested in studying acute lymphoblastic leukemia (ALL), the most common form of cancer in children, as a high school student. Working in the laboratory of Janet Rowley, M.D., she sought to identify sequence polymorphisms within the MLL breakpoint cluster region that might predispose some patients to developing therapy-related leukemia after topoisomerase II inhibitor treatment. This early research experience served as a catalyst for her decision to embark on a career dedicated to medical research combined with clinical care. She graduated cum laude from Yale University, receiving a B.S. with distinction in Molecular, Cellular, and Developmental Biology. She then received her M.D. from Harvard Medical School. While in medical school, she was awarded a Howard Hughes Research Training Fellowship, which allowed her to devote a year to investigating differentiation therapy as an alternative or adjunct to cytotoxic therapy for acute myeloid leukemia (AML). She completed her Pediatrics training in the Boston Combined Residency Program (Boston Children's Hospital and Boston Medical Center) prior to joining her current Pediatric Hematology / Oncology Fellowship Program. Loretta is pursuing her post-doctoral research in the laboratory of David Weinstock, M.D. and has been studying mechanisms of response and resistance to a new class (type II) of Janus Kinase 2 (JAK2) inhibitors which may be beneficial to a high-risk subset of leukemia patients. She has co-authored four manuscripts and previously presented her research at the American Society of Hematology and American Association for Cancer Research annual meetings. Loretta is committed to a physician-scientist career. She is interested in the development of more targeted therapies and the practice of personalized cancer medicine. In the future, she would like to use her dual training in clinical medicine and laboratory research to more expeditiously bring promising novel therapies to clinical trials for patients.
January 23, 2017 Update
Dr. Loretta Li was born in New York City but grew up in Naperville, IL. She graduated cum laude from Yale University, receiving a B.S. with distinction in Molecular, Cellular, and Developmental Biology. She then received her M.D. from Harvard Medical School. While in medical school, she was awarded a Howard Hughes Research Training Fellowship, which allowed her to devote a year to investigating differentiation therapy as an alternative or adjunct to cytotoxic therapy for acute myeloid leukemia. She completed her Pediatrics training in the Boston Combined Residency Program (Boston Children's Hospital and Boston Medical Center) and her Pediatric Hematology / Oncology Fellowship at Boston Children's Hospital and the Dana-Farber Cancer Institute.
Dr. Li is now a junior faculty member who continues to pursue research in the laboratory of David Weinstock, M.D. She has been leading efforts to study mechanisms of response and resistance to type II Janus kinase 2 (JAK2) inhibitors in B-cell acute lymphoblastic leukemia, the most common form of cancer in children. She is co-first author of a manuscript published in Cancer Cell describing the activity of CHZ868, the first type II JAK2 inhibitor amenable to in vivo use. Unfortunately, CHZ868 cannot be tested in humans. Encouraged by the promise of this class of compounds, she is now collaborating with Nathanael Gray's lab at the Dana-Farber Cancer Institute to validate the preclinical activity of novel type II JAK2 inhibitors. In the future, she would like to use her dual training in clinical medicine and laboratory research to more expeditiously bring promising novel therapies to clinical trials for patients. Outside of work, Dr. Li enjoys spending time with family and friends, baking, and taking barre classes. She also serves as a volunteer physician at the Hole in the Wall Gang Camp for children with cancer and life-threatening illnesses for a week each summer.
Dr. Li's research is focused on B-cell acute lymphoblastic leukemia (B-ALL), the most common form of cancer in children. Approximately 5-10% of children with B-cell acute lymphoblastic leukemia (B-ALL) have a high-risk form of this disease characterized by rearrangements in a gene called CRLF2. Children with Down syndrome are at increased risk for developing B-ALL with CRLF2 rearrangements. When treated with conventional chemotherapy, patients with CRLF2 rearrangements do poorly. We know that their leukemias are dependent on a protein called Janus kinase 2 (JAK2) for survival, but no targeted therapies with proven efficacy currently exist. Ruxolitinib, the only FDA-approved JAK2 inhibitor, has almost no activity in these cases because other proteins similar to JAK2 can find a way to bypass the drug, activate JAK2, and promote abnormal cell growth.
Dr. Li and her team previously tested a new drug called CHZ868, which acts differently from ruxolitinib by preventing these other proteins from activating JAK2. We showed that CHZ868 turns off JAK2 activity, potently kills JAK2-dependent leukemia cells, and improves overall survival in mice injected with human leukemias. Unfortunately, CHZ868 is not able to be used in humans. To the knowledge of Dr. Li and her team, and based on reviewing the literature, there are no large pharmaceutical companies working on developing JAK2 inhibitors that act similarly to CHZ868. This leaves open an important niche to be filled by academic researchers. Through screening a collection of over 5000 different chemicals, Dr. Li and colleagues found a promising compound called HG7-150-01 that blocks JAK2 in the same way as CHZ868. They are now developing improved versions of both CHZ868 and HG7-150-01, testing these chemicals, and determining whether they inhibit growth and block JAK2 in our cell lines and mouse models. This work will serve as the basis for testing new and better JAK2 inhibitors in clinical trials for patients with leukemia.
When Dr. Li and her team previously tested CHZ868 in their mouse models of JAK2-dependent leukemia, the drug was not curative, and all mice eventually died of relapsed leukemia. They are now studying how cells become resistant to CHZ868. They have generated additional B-ALL cell lines that are resistant to CHZ868 by culturing cells in escalating doses of this drug. Two cell lines are growing in high concentrations (10 µM) of CHZ868 and there are plans to sequence the DNA and RNA of the resistant cells to look for changes that could confer the resistance. Dr. Li and her team are also performing experiments to identify which other proteins are capable of activating JAK2, even in the presence of a JAK2 inhibitor. These data will allow them to devise strategies to prevent or overcome resistance and improve design of new JAK2 inhibitors.
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