Sarah Tasian, MD
Sarah Tasian, MD
Children's Hospital of Philadelphia
Mentor: Mignon L. Loh, MD
Predicting Biochemical and Genetic Responses to JAK Inhibitor Therapy in Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia
B-precursor acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy of childhood. Despite significant advances in curing ALL in the majority of children, approximately 20% of children with ALL will relapse, and most patients suffering from relapsed ALL will die. Additionally, adults with ALL generally have poor outcomes. Our research thus focuses upon studying human ALL samples with the goal of improving our understanding of the functional consequences of high-risk genetic mutations. This research will investigate how specific B-precursor ALL cells are "wired" and how we may disrupt these faulty wiring networks with novel medications to result in improved therapies for patients with leukemia. We have previously used a specialized laboratory technique called phosphoflow cytometry to examine whether or not different proteins within the wiring networks are turned "on" in leukemia cells following stimulation with different types of physiologic signals. In this research, we will pursue several goals. We first plan to apply this technique to study a population of children with high-risk ALL in which recently identified genetic mutations (e.g., CRLF2 and JAK2) have been found to confer particularly poor outcomes. We have already identified distinct signaling patterns in human cell lines with these genetic mutations, as well as in patient samples harboring these mutations. Secondly, we will characterize specific high-risk genetic mutations in children with relapsed leukemias and myeloproliferative neoplasms for whom a new Phase I clinical trial of targeted therapy recently opened through the Children's Oncology Group (ADVL1011). We will measure the persistence or resolution of those mutations over time in children receiving new treatment with a small molecule inhibitor medication on this trial. We will further use phosphoflow cytometry to study the faulty wiring in leukemia samples from these study patients in order to correlate biochemical effects with clinical responses. Thirdly, we will use specialized mouse models of these human leukemias to test other relevant small molecule inhibitor drugs. Through this work, we hope to improve our understanding of the biochemical mechanisms critical for the development of targeted therapeutics for children with specific high-risk leukemias.
January 23, 2017 Update
Dr. Sarah Tasian is a pediatric oncologist and academic physician-scientist at the Children's Hospital of Philadelphia. Her long-term career goal is to develop molecularly-targeted therapies for children with high-risk leukemias to improve survival and minimize toxicities. She has prior research training in the laboratories of Dr. Crystal Mackall at the National Cancer Institute (HHMI-NIH medical student fellowship), Dr. Mignon Loh at UCSF (post-doctoral fellowship), and Dr. Martin Carroll and Dr. Stephan Grupp at the University of Pennsylvania (Penn) and Children's Hospital of Philadelphia (CHOP) (mentored junior faculty). Her translational research program focuses upon novel therapeutic approaches for high-risk childhood leukemias via (1) characterization of signal transduction networks and preclinical testing of kinase inhibitors for subtypes of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), (2) preclinical testing of leukemia antigen-redirected chimeric antigen receptor (CAR) T cell immunotherapy for AML, and (3) early phase clinical trial testing of targeted therapies for children with leukemia through the Children's Oncology Group (COG) and other consortia. The Tasian laboratory has substantial expertise in preclinical investigation of kinase inhibitors and CAR T cell immunotherapy in patient-derived xenograft models of childhood leukemias, as well as in phosphoflow cytometric analyses of leukemia signaling and measurement of molecular responses to kinase inhibitors. Successful integration of these bench-based and clinical studies has led to several clinical trials testing targeted therapies in children with high-risk leukemias. Dr. Tasian has leadership roles in the COG ALL and AML disease committees and is the COG DVL Vice Chair of Biology for Hematologic Malignancies. She also chairs the international COG phase 2 trial AALL1521 testing JAK inhibition in children with Philadelphia chromosome-like ALL, and she co-leads development of institutional trials of CAR T cell immunotherapies for children with relapsed AML.
Dr. Tasian's 2011 Conquer Cancer Foundation/Strike 3 Foundation YIA funded important correlative biology studies for a Children's Oncology Group phase 1 clinical trial (ADVL1011), which assessed the safety of a targeted medicine called a JAK inhibitor that was tested for the first time in children with relapsed or chemotherapy-resistant leukemias and solid tumors. In ADVL1011, Dr. Tasian and her team learned that a JAK inhibitor (called ruxolitinib) could be given to children without causing a lot of undesirable side effects, and ruxolitinib dosing was able to be safely increased to the highest level. These CCF/Strike 3 Foundation-funded research studies also showed that ruxolitinib inhibited signaling proteins within leukemia cells, suggesting that this drug was 'hitting its target.' Results from these ADVL1011 studies helped Dr. Tasian to develop the successor phase 2 clinical trial AALL1521, which is currently testing ruxolitinib and chemotherapy in children with acute lymphoblastic leukemia (ALL) that have JAK signaling pathway mutations. In just a few years, Dr. Tasian has been able to translate her CCF/Strike 3 Foundation-funded research findings in the laboratory during her post-doctoral fellowship to chairing an international clinical trial focused on precision medicine treatments for children with high risk leukemias.
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