In the second study, Lewis C. Cantley, Ph.D.; Gerburg Wulf, M.D., Ph.D.; and colleagues used an endogenous mouse model of BRCA1-deficient breast cancer. They observed that mice with a BRCA1 mutation also had molecular indicators of strong activation of the PI3-kinase pathway, suggesting that the tumors might be vulnerable to PI3-kinase inhibitors.
When the mice were treated with a PI3-kinase inhibitor, tumor doubling was delayed from five to 26 days. Given that BRCA-mutated tumors are also known to respond to PARP inhibitors, the researchers combined the two medications and found that this delayed tumor doubling to more than 70 days.
"We saw in vivo synergy that led to dramatic prolongation of progression-free survival in these mice of more than two to three months, which in the life of a mouse is very long," said Wulf, staff physician in the division of hematology and oncology at Beth Israel Deaconess Medical Center. "This is an unusual observation that makes us hopeful that it is worthwhile to explore in an early-phase clinical trial."
Both studies received funding from Stand Up To Cancer Dream Team Translational Research Grants.
Cantley, who conducted the research while director of the cancer center at Beth Israel Deaconess Medical Center in Boston, and his colleagues have worked with Novartis and AstraZeneca, the two companies that manufacture the PI3-kinase inhibitor (BKM120) and the PARP inhibitor (Olaparib) to initiate a clinical trial combining the two drugs in humans.
Cantley said it is extremely unusual for two unapproved drugs to be combined in a cancer clinical trial, especially when the two drugs are produced by separate companies. Yet the preclinical results were sufficiently compelling to accelerate the initiation of th
|Contact: Jeremy Moore|
American Association for Cancer Research