Combining a Novel Pan-Raf Inhibitor with MEK Inhibition in Pediatric, Adolescent, and Young Adult Acute Myeloid Leukemia (AML)
Abstract
This proposal aims to study a common type of cancer in children, adolescents, and young adults called acute myeloid leukemia (AML). Many AML patients in this age group have genetic mutations in their cancers that activate a biochemical pathway called the Ras pathway, making their cancer cells highly aggressive and difficult to treat. Despite many decades of research, there has been little success at targeting this pathway in an effort to combat these patients’ cancer cells. Over the last 1-2 decades, several drugs have been developed against this pathway that have some anti-cancer activity, but patients’ cancer cells usually outsmart them and evade inactivation by the drugs after a short period of time. This proposal aims to investigate a new type of anti-Ras pathway drug called belvarafenib, which has numerous important advantages over existing drugs, in AML for the first time. By combining belvarafenib with another FDA-approved drug (cobimetinib) targeting in this pathway, I anticipate that AML will lose its ability to outsmart therapy. I hypothesize that the combination of these two agents will be safe and effective in a mouse model of AML, laying the foundation for first-ever clinical trials of these drugs in humans. Dr. Levinson is a promising young physician-scientist who has already made significant contributions to the field of pediatric oncology despite being only 1 year out of her fellowship training. Her professional goals are to merge the direct care of children, adolescents, and young adults with leukemia with basic science research aimed at improving outcomes in this disease. This award will serve to solidify Dr. Levinson’s scientific foundation and expertise in the fields of preclinical therapeutics and Ras biology in leukemia. AML affects over 20,000 patients annually and comprises approximately 20% of childhood leukemias. Cure rates for AML are poor and have not meaningfully improved in many decades, with 30%-40% of children, adolescents, and young adults dying from leukemia or complications of treatment. Outcomes are far worse for older adults. Existing treatments are highly toxic and cause life-threatening side effects, both in the short and long term; thus, there is a great need for novel therapies that are more effective and cause less harm to patients. Targeted therapies, or drugs that specifically act on pathways mutated in a particular patient’s cancer cells, have the potential advantage of sparing healthy cells, and therefore may be less toxic. While cancer tends to outsmart single-agent targeted agents, combinations of targeted therapies may be able to overcome this phenomenon, leading to improvements in survival with an associated decrease in toxicity in certain AML patients. The Fiscal Year 2021 Peer Reviewed Cancer Research Program Overarching Challenge this proposal will address is: Transform cancer treatment through the identification of novel biomarkers and new targets, especially for advanced disease (metastatic and/or recurrence), improve immunotherapy, and eliminate the risks of therapy associated toxicity. Young adults are a primary demographic in the military. Improving outcomes and reducing therapy-associated toxicity in aggressive cancers that affect this demographic, such as AML, is a critical unmet need.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211017
Entities
People
- Anya Levinson
Organizations
- United States Army
- University of California, San Francisco