Promising cancer drug exploits BRCA genetic mutations

When genes that normally repair DNA damage are mutated, they can transform from cancer suppressors into cancer promoters.

But what if a targeted cancer drug could exploit this genetic defect, making cancer cells become so unstable that they self-destruct?

domchek-susan
Susan Domchek

That's the concept behind an experimental drug called rucaparib, being developed by Clovis Oncology. In studies, it has shown effectiveness against advanced ovarian cancer in patients with inherited BRCA mutations.

Now,  rucaparib looks promising against an even more formidable BRCA-related malignancy -- pancreatic cancer, according to clinical trial results presented on Saturday at the annual ASCO oncology conference by University of Pennsylvania BRCA researcher Susan M. Domchek.

The trial treated 19 pancreatic cancer patients -- 11 men and eight women -- who had BRCA mutations and had relapsed despite as many as three prior chemotherapies. Six of those patients (32 percent) showed benefit from rucaparib. One had a complete response (meaning the cancer became unmeasurable) that was ongoing at 36 weeks; one had cancer tumor shrinkage that was ongoing after 49 weeks; and four had stable disease. Common serious side-effects included anemia and fatigue. 

About 9 percent of percent of pancreatic cancer patients carry BRCA mutations -- about the same as the percentage of breast cancers that are linked to BRCA. Inherited BRCA mutations are also known to increase the risk of prostate cancer in men.

Domchek said the encouraging pancreatic cancer results "demonstrate the clinical significance of the BRCA cancer genes outside of breast and ovarian cancer, and not just in women."

Rucaparib is part of a new class of drugs called PARP inhibitors, which interfere with an enzyme used by cells to repair damage to their DNA. Mending DNA is crucial to prevent cancer, but it is also a way that fast-dividing cancerous cells use to survive the DNA damage caused by radiation therapy and chemotherapy.

Tumor cells that arise because of BRCA defects are particularly prone to DNA damage. PARP inhibitors are believed to worsen this damage, causing the tumor cells to become so unstable that they die. Domchek's analogy: the cell becomes like a three-legged stool that has lost two legs.

One PARP inhibitor is already on the market: AstraZeneca's olaparib (brand name Lynparza). It was approved in 2014 to treat advanced ovarian cancer in women with BRCA mutations who have received three or more prior chemotherapy drugs. Patients are required to undergo BRCA mutation testing before they can take olaparib.

Several other PARP inhibitors are in late-stage testing, and some studies are not limited to BRCA patients. Rucaparib, for example, is being explored for use in patients with other DNA repair deficiencies. 


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