Targeting PI3Ka Mutants for Precision Therapeutics
Abstract
About a quarter of a million women in the United States will be diagnosed this year with invasive breast cancer, and about 20% of them will have mutations in the oncogene PIK3CA, which codes for the enzyme PI3Ka. Most patients undergo surgery followed with cytotoxic chemotherapy, radiation therapy, hormonal, and/or targeted therapy to kill proliferating cells such as those in growing tumors and their metastases. However, normal non-cancerous cells in many tissues are also undergoing proliferation, making them susceptible to the drugs and resulting in the serious side effects that are typical of chemotherapy. Advances in human genome sequencing have identified mutations in genes involved in cancer growth and progression that suggest a new paradigm for the treatment of cancers. Mutations identified in the genome of a given tumor can be used to design a personalized treatment. These open a window of opportunity to design drugs that target specifically cancerous cells, sparing normal cells by "attacking" the mutant forms of the enzymes. An example of a successful breast cancer therapy already being used is trastuzumab, which target human epithelial growth factor receptor 2 (HER2)-positive breast cancer. We aim to discover drugs that will target cancer cells with mutations for an enzyme called PI3Ka. In normal cells PI3Ka, a lipid kinase, controls blood sugar levels via insulin, new blood vessel formation, and in general how cells grow and move. Mutations in PI3Ka result in unregulated cell growth and tumor progression. This proposal seeks to understand the structural differences between the normal and mutant PI3Ka. A detailed understanding of these key differences will provide us an opportunity to discover novel drugs that target new binding sites on the protein. We will take advantage of this structural knowledge to find new molecules able to selectively "switch off" the mutant protein, leaving the normal protein untouched.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610486
Entities
People
- Sandra B. Gabelli
Organizations
- Johns Hopkins University
- United States Army