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?
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 May 2016 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.
BRCA in Pancreatic Cancer
BRCA mutations, especially BRCA2, convey an increased risk of developing pancreatic adenocarcinoma. Risk is estimated to be 2.2-fold in persons with BRCA1 mutations and 3.4- to 10-fold in those with BRCA2 mutations. While BRCA mutations are rare in the general population of patients with pancreatic adenocarcinoma—5% to 8%—their frequency rises to as high as 16% in patients of Ashkenazi Jewish heritage and perhaps to 19% in persons with familial pancreatic adenocarcinoma (i.e., at least one first-degree relative with the disease).
PALB2, a partner and localizer to BRCA2 mutations, occurs in a smaller fraction (1%–3%) of cases of advanced pancreatic adenocarcinoma, but it is still important. The PALB2 protein stabilizes the BRCA2 protein and anchors it to the nucleus, allowing it to carry out its DNA repair function. More recently, PALB2 has been shown to associate with the BRCA1 protein as well, providing a linkage between BRCA1 and BRCA2 in homologous recombination repair of double-stranded DNA breaks.
DNA repair, however, can be compromised through PARP inhibition, and this might be harnessed therapeutically in pancreatic adenocarcinoma. PARP inhibition leads to transformation of single-strand breaks into double-strand breaks that are cytotoxic in cells and renders them unable to be repaired through homologous repair. BRCA-deficient pancreatic cell lines are sensitive to cisplatin, mitomycin, and PARP inhibitors, and patients with BRCA mutations are sensitive to DNA-damaging agents, earlier studies have shown.
Study of Veliparib
Veliparib is a potent oral irreversible small molecule inhibitor of PARP 1 and 2. It is being evaluated in three non-randomized trials in combination with cisplatin-based therapy in previously treated and also untreated patients with known BRCA or PALB2 mutations, or a very strong personal or family history of pancreatic, breast, and ovarian cancer that suggests these mutations may be present.
Data have been analyzed for the phase IB lead-in dose-finalization study of this triplet combination, and Eileen M. O’Reilly, MD, Associate Director of Clinical Research at the Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York presented the findings at the American Association for Cancer Research (AACR) in October 2014.
The study evaluated 17 patients with locally advanced or metastatic pancreatic adenocarcinoma, 9 of whom had a BRCA mutation and 10 who were BRCA wild-type. Four dose levels of veliparib were evaluated, in combination with cisplatin and gemcitabine.
“The triplet combination showed high activity in BRCA-related pancreatic adenocarcinoma,” Dr. O’Reilly said. “The majority of patients are still alive.”
In the BRCA-mutated subgroup, six patients responded, for an objective response rate of 66%, and three patients achieved stable disease, yielding a disease control rate exceeding 88%. Responses were observed in both BRCA1- and BRCA2-mutated patients.
“We saw a very high level of activity, with six partial responses, many of which were sustained and several are still ongoing,” she said. The duration on study for all but one of the responders was at least 9 months. The exception was a patient who was recently treated for breast cancer, which might have dampened her response to the regimen, the investigators believe.
In contrast, no significant activity was observed in non-BRCA-mutated patients. There were no responses, and the duration on treatment was less than 3 months.
Other PARP Inhibitors
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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