A breast cancer tumor and its microenvironment is shown in a live mouse model. Image by NIH
More than 60 percent of breast cancer cases involve defects in the same biochemical chain of events within cancer cells — known as the PI3 kinase (PI3K) pathway — but efforts to develop therapies targeting this pathway have met with little success after hundreds of mostly failed clinical trials. And researchers still don’t understand why.
Now, using an innovative, unbiased laboratory method, UC San Francisco scientists may have finally cracked the case. The researchers identified a protein that cancer cells use as a shield to protect the PI3K pathway against targeted drugs, and showed that blocking this protein using a second drug (itself already in phase 2 clinical trials) allowed multiple previously ineffective therapies to slow cancer cell growth and shrink tumors. The researchers now plan to pursue clinical trials to determine if these combination therapies can extend the lives of patients with advanced, recurrent breast cancer.
“The failure of PI3 kinase drugs has been a huge mystery,” said senior author Sourav Bandyopadhyay, PhD, assistant professor of bioengineering and therapeutic sciences and a member of the UCSF Helen Diller Family Comprehensive Cancer Center. “Every pharma company in the cancer space has tried to target the PI3 kinase pathway, with little success. Now we may know why.”
“This work has immediate clinical implications, and we hope this study spurs interest in combining these two classes of embattled cancer drugs. These data clearly warrant clinical testing and we are working to put together a phase 1 clinical trial to test such drug combinations in patients,” Bandyopadhyay added.
Kinase Protects Cancer from Many Targeted Drugs
The new study focused on kinases, a diverse family of more than 500 different enzymes that drive important biological events, such as cell division. Malfunctioning kinases spur destructive tumor growth in many forms of cancer, and have therefore become a major focus of drug development. The PI3K pathway in particular (comprising PI3 kinase, AKT, and mTOR proteins as well as associated genes such as PTEN) has been implicated in a majority of breast cancer cases, and has long been regarded as a promising pharmaceutical target for a variety of cancers.
Researchers have tested hundreds of compounds that target the PI3K pathway and theoretically ought to cause cancers to self-destruct, but virtually all of these drugs have failed to even slow the cancers down. One drug in this class — Novartis’s Afinitor (everolimus) — has been approved for treatment of advanced, recurrent breast cancer by the U.S. Food and Drug Administration, but even this drug typically only prolongs survival in breast cancer patients by mere months.