Melissa Burns, MD
Melissa A. Burns, MD
Dana-Farber Cancer Institute
Mentor: Alejandro Gutierrez, MD; Thomas Look, MD
Smoothened as a Therapeutic Target in High Risk T-cell Acute Lymphoblastic Leukemia
Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer, affecting approximately 2,900 children in the United States each year. T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL that occurs most commonly in adolescents. Despite improvements in survival, 20% of children with T-ALL will not respond to current treatments, and the majority of these patients will ultimately die of their disease. This dismal prognosis highlights the need for new, targeted therapies for patients with treatment-resistant T-ALL.
To identify drug targets, I sequenced cancer cell DNA from children with T-ALL and identified frequent mutations within the Hedgehog pathway. Moreover, I found that these mutations were associated with a poor response to treatment. The Hedgehog pathway is an important developmental signaling pathway and has been shown to be mutated in some cancers, but mutations in this pathway have not been previously identified in T-ALL. The Hedgehog pathway is an ideal candidate for targeted therapy, as several small molecule inhibitors of the pathway are available, including the FDA-approved vismodegib. The goal of this project is to understand how Hedgehog pathway activation leads to cancer cell growth and survival, as well as to define its association with treatment failure. Furthermore, this project will test the therapeutic utility of vismodegib in a mouse model of T-ALL. Ultimately, I fully expect that results of this work will not only further our scientific understanding of T-ALL, but moreover, will reveal a new and effective treatment strategy for children with T-ALL who fail conventional treatment.
Biography
Dr. Melissa Burns completed her undergraduate studies at Cornell University in 2003, earning a Bachelor of Arts in Biology with a concentration in Genetics and Developmental Biology. She received her medical degree in 2009 from New York Medical College, where her academic achievements earned her induction into the Alpha Omega Alpha Medical Honor Society. As a medical student, Melissa was the recipient of an HHMI Medical Student Research Training Fellowship, which she completed in the laboratory of Dr. Todd Golub at Dana Farber Cancer Institute and the Broad Institute. She subsequently completed her training in General Pediatrics at the Boston Combined Residency Program at Boston Children's Hospital/Boston Medical Center in 2012. Melissa is currently a Pediatric Hematology/Oncology fellow at Dana Farber Cancer Institute and Boston Children's Hospital, and is expected to graduate in June 2015. Following her clinical training in Pediatric Hematology/Oncology, Melissa will become an Instructor in Pediatrics at Harvard Medical School, as well as an Attending Physician at Dana Farber Cancer Institute and Boston Children's Hospital. Currently, Melissa is a postdoctoral fellow in the laboratory of Dr. Alejandro Gutierrez at Boston Children's Hospital. Her research interests are focused on defining and understanding critical signaling pathways that lead to the development of high risk subsets of T-cell acute lymphoblastic leukemia (Tcell ALL) through a combination of human cancer genomics, functional genetics, and in vivo therapeutic approaches in order to identify and develop novel treatment strategies that can be tested in early phase clinical trials. Specifically, Melissa is currently investigating the role of aberrant Hedgehog pathway activity in chemotherapy-resistant T-cell ALL, as well as the potential therapeutic efficacy of Hedgehog pathway inhibition using the FDA-approved small molecule inhibitor, vismodegib, in an in vivo model of PTCH1-mutant T-cell ALL.
January 23, 2017 Update
BIOSKETCH
Dr. Melissa Burns is a pediatric oncologist at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center in Boston, MA. Dr. Burns completed her undergraduate studies at Cornell University, earning a Bachelor of Arts in Biology with a concentration in Genetics and Developmental Biology. She then received her medical degree from New York Medical College. As a medical student, Dr. Burns' was the recipient of an HHMI Medical Student Research Training Fellowship, which allowed her to devote a year investigating an approach to screen human cancers for abnormal kinase signaling, a hallmark of dysregulated growth and survival in cancer that can be exploited for therapeutic targeting, in the laboratory of Todd Golub, MD at Dana Farber Cancer Institute and the Broad Institute. This experience served as the catalyst for Dr. Burns' decision to pursue a career in translational cancer research. Following medical school, Dr. Burns completed her training in General Pediatrics at the Boston Combined Residency Program at Boston Children's Hospital/Boston Medical Center, and her Pediatric Hematology/Oncology fellowship at Dana Farber Cancer Institute and Boston Children's Hospital. She is currently an Instructor in Pediatrics at Harvard Medical School and an Attending Physician at Dana Farber Cancer Institute and Boston Children's Hospital. In addition, Dr. Burns continues to pursue her research interests combining genomics, functional genetics, and in vivo therapeutic approaches as a postdoctoral fellow in the laboratory of Dr. Alejandro Gutierrez at Boston Children's Hospital. Specifically, Dr. Burns is investigating the role of aberrant Hedgehog pathway activity in chemotherapy-resistant T-cell acute lymphoblastic leukemia (T-ALL). Dr. Burns' was the recipient of a 2015 Young Investigator Award from the Conquer Cancer Foundation and Strike 3 Foundation for her work on this project, entitled "Smoothened as a therapeutic target in T-cell acute lymphoblastic leukemia." Ultimately, through unraveling the critical events underlying molecular oncogenesis in T-ALL, Dr Burns hopes to identify novel treatment strategies that can be rapidly translated into early phase clinical trials, an approach that will ideally lead to improved clinical outcomes for children with this treatment resistant disease.
RESEARCH UPDATE
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, affecting approximately 2,900 children in the United States each year. T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL that occurs most commonly in adolescents. Despite improvements in survival, 20% of children with T-ALL will not respond to current treatments, and sadly the majority of these patients will ultimately die of their disease. This dismal prognosis highlights the need for new, targeted therapies for patients with treatment-resistant T-ALL.
To identify drug targets, Dr. Burns sequenced cancer cell DNA from children with T-ALL and identified frequent mutations within the Hedgehog pathway. Interestingly, these mutations were common among patients who did not respond to conventional therapy. The Hedgehog pathway is an important developmental pathway and is known to be mutated in some cancers, but mutations in this pathway are not known to cause T-ALL. The Hedgehog pathway is an ideal candidate for targeted therapy, as several small molecule inhibitors of the pathway are available, including the FDA-approved vismodegib. Thus, the goal of this project is to understand how Hedgehog pathway activation leads to cancer cell growth and survival, as well as to define its association with treatment failure. Furthermore, this project will test the therapeutic utility of vismodegib in a mouse model of T-ALL.
Thus far, through the support of her CCF/Strike 3 Foundation Young Investigator Award, Dr. Burns has shown that activation of the Hedgehog pathway in human T-ALL cancer cells increases survival and prevents cell death. Moreover, the results demonstrate that these effects on cell survival and cell death lead to resistance to doxorubicin, a mainstay of T-ALL treatment. These results provided a compelling reason to pursue testing of vismodegib in PTCH1-deficient mouse model that closely mimics human disease. An initial experiment determined that vismodegib is safe and well tolerated in these mice. Unfortunately, a follow up study failed to show an improvement in survival in mice that developed human T-ALL treated with vismodegib compared to placebo control. Dr. Burns is currently in the process of validating a different mouse model of PTCH1-mutant human T-ALL and plans to proceed with a follow up study to look at the efficacy of vismodegib in combination with doxorubicin.
In parallel, Dr. Burns is also exploring mechanisms by which Hedgehog pathway activation causes T-ALL and chemotherapy resistance. Dr. Burns previously identified the known oncogene, MYCN, as a target of the Hedgehog pathway. Her recent studies have demonstrated that while MYCN is a downstream target, it is not a crucial mediator of oncogenic Hedgehog signaling. She is currently in the process of pursuing additional studies to better characterize the mechanisms by which Hedgehog pathway activation causes T-ALL.
Ultimately, Dr. Burns expects that results of this work will not only further our scientific understanding of T-ALL, but moreover, will reveal a new and effective treatment strategy that can be immediately tested in clinical trials for children with T-ALL who fail conventional treatment.
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