Combining PI3K and PARP Inhibition in Breast and Ovarian Cancers
Of the 180,000 new breast cancers diagnosed yearly in the US, about 20 percent are triple negative breast cancers (TBNC), lacking the HER2 receptor, as well as ligands (binding places) for estrogen and progesterone. These cancers do not respond to hormone-based therapies, and they are typically more aggressive with shorter survival rates. Approximately 70 percent of breast cancers with a germline BRCA1 mutation are triple negative.
Many high-grade serous ovarian cancers (HGSCs) have a similar genetic profile to TNBC, and often have germline aberrations of the BRCA1 and BRCA2 genes. Somatic mutations and hypermethylation can also affect the BRCA genes. Ovarian cancer is the most lethal gynecologic malignancy, causing an estimated 15,000 deaths in the United States in 2011. Although the majority of patients achieve complete clinical remission with platinum and taxane-based combination therapy, most eventually relapse and die of the disease.
Molecular alterations affecting the BRCA1/2 genes help make these subtypes of breast and ovarian cancers vulnerable to two experimental drugs, the PARP inhibitor olaparib (AZD2281) and the PI3K inhibitor BKM120. Ursula Matulonis, MD (DFCI) is leading a multi-institutional phase I trial testing this novel combination in patients with TNBC or HGSC. The trial builds on preclinical work in DF/HCC laboratories. “We leveraged those strong results to design rational drug combinations that attack cancers at several of their vulnerable points at once,” said Matulonis.
A Rational Combination
BRCA1 is essential to the cell’s primary mechanism for repairing DNA breaks through homologous recombination (HR). However, BRCA1-deficient cells can resort to an alternate DNA repair mechanism using PARP (poly-ADP-ribose-polymerase), a nuclear enzyme that helps repair single-stranded DNA breaks. Thus, treating BRCA1-deficient cells with a PARP inhibitor shuts downs both DNA repair mechanisms, causing genomic instability that can lead to cell cycle arrest and cell death, and sensitizing the cells to further damage from chemotherapy. In several early clinical trials, PARP-inhibitors induced objective responses in patients with HGSC.
TNBC and HGSC also often have aberrant signaling in the PI3K (phosphatidylinositol 3-kinase) pathway, which is a hallmark of many cancers. Many studies are testing PI3K inhibitors in cancer therapy, but most have demonstrated only limited ability to kill cancer cells as single agents.
In preclinical studies of breast cancer at BIDMC, Gerburg Wulf, MD, and Lewis Cantley, PhD, discovered that the new pan-PI3K inhibitor BKM120 increased levels of DNA damage in cells. They determined that PI3K promotes DNA repair, and that it is essential for BRCA1 function and homologous recombination. PI3K inhibition thus down-regulates BRCA1 and DNA repair. In effect, PI3K inhibition creates a similar genomic instability as BRCA1 mutations. Wulf and Cantley hypothesized that PI3K inhibition would render even cells with intact BRCA1 sensitized to PARP inhibition.
Their laboratory then demonstrated a surprising synergy between PI3K and PARP inhibitors in a mouse model of TNCB. Combining olaparib and BKM120 had a more powerful effect on cancer cell death than either alone, shrinking or even eliminating tumors. At MGH, Jose Baselga, MD, and colleagues reached similar conclusions. With this solid pre-clinical evidence, Matulonis successfully pitched the concept of a combination trial for these still experimental agents to two pharmaceutical companies, Novartis (BKM120) and AstraZeneca (olaparib).
Objectives of the Trial
The phase 1 trial is open to patients with recurrent HGSC, TNBC, or BRCA germline mutations regardless of cancer histology. The primary outcome is to determine the maximally tolerated dose and recommended phase 2 dose of the combination of BKM120 and olaparib. Secondary outcomes are to determine the combination’s overall safety and observed toxicities, the pharmacokinetics of the drugs, and the preliminary activity of this combination at the phase 1 and 2 doses. Exploratory translational endpoints include determining the downstream signaling effects of the PI3K pathway when both PI3K and PARP are inhibited. The trial is open and accruing participants.
The study follows a dose escalation 3 + 3 trial design. The first three participants are placed on a dose the researchers expect to be safe based on previous clinical studies. If none experiences a dose-limiting toxicity (DLT) in 28 days, three additional participants will enter at the next higher dose. The original three participants will remain on the first dose but can be moved up if the second set does not experience any DLTs at the higher dose. If one participant experiences a DLT in the first cycle, another three patients will be entered at that same dose to gain more experience at that dose level. If two DLTs occur in the first cycle, the new participants will enter at a lower dose. Patients are being recruited from BIDMC, DFCI, MGH, MD Anderson Cancer Center, and Memorial Sloan-Kettering Cancer Center. The expected time frame for the study is two years.
Watching Science In Action
Matulonis is also testing inhibitors of PARP and PI3K in combination with chemotherapies. Since the inhibitors lead to the accumulation of DNA breaks, cancer cells become exquisitely sensitive to agents such as cisplatin that damage DNA.
“It’s been really thrilling to watch the science that is taking place in research labs provide such convincing leads for clinical research,” said Matulonis. “This study is a successful example of a DF/HCC laboratory discovery accelerated into an open clinical trial for patients within about a year. It’s an ideal way to do translational cancer research and clinical trials.”
Phase I Trial
Phase I of BKM120/Olaparib for Triple Negative Breast Cancer or High Grade Serous Ovarian Cancer
Ursula Matulonis, MD (DFCI)
Ibrahim, Y. H., C. Garcia-Garcia, V. Serra, L. He, K. Torres-Lockhart, A. Prat, P. Anton, et al. “PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition.” Cancer Discovery 2, no. 11 (August 22, 2012): 1036–1047. doi:10.1158/2159-8290.CD-11-0348.
Juvekar, A., L. N. Burga, H. Hu, E. P. Lunsford, Y. H. Ibrahim, J. Balmana, A. Rajendran, et al. “Combining a PI3K Inhibitor with a PARP Inhibitor Provides an Effective Therapy for BRCA1-Related Breast Cancer.” Cancer Discovery 2, no. 11 (August 22, 2012): 1048–1063. doi:10.1158/2159-8290.CD-11-0336.
Research detailed in this article was funded in part by NIH grants, including CA065164, CA120964, CA006516, GM41890, CA089021, and private funding from a Stand Up To Cancer Dream Team Translational Cancer Research Grant.