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New Combo Treatment for Triple-Negative Breast Cancer

PI3-kinase inhibitors sensitize tumors to PARP inhibitors (Nov. 12)

The simultaneous inhibition of two separate and seemingly unrelated pathways could potentially provide an effective treatment for women with triple-negative breast cancer, according to the results of two studies published in the November issue of Cancer Discovery.

Triple-negative breast cancer does not express three common targets of breast cancer treatments: the estrogen receptor, the progesterone receptor, and HER2/neu. As a result, women with triple-negative breast cancer have few treatment options. In early-phase clinical studies, women with triple-negative breast cancer with BRCA1 gene mutations received some clinical benefit from treatment with poly-ADP-ribose-polymerase (PARP) inhibitors. However, the activity of PARP inhibitors is short-lived.

In a new study, researchers hypothesized that inhibiting PI3-kinase — a key component of a signaling pathway often activated inappropriately in triple-negative breast cancer — would replicate the conditions present in BRCA-mutated breast cancers, thereby increasing sensitivity to PARP inhibitors.

They found that if PI3-kinase function was blocked in a BRCA-proficient triple-negative breast cancer cell line, DNA damage would occur because of BRCA protein down-regulation, and that this resulted in activation of PARP to repair the damage.

In a second study, investigators 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, which suggested 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 5 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 it delayed tumor doubling to more than 70 days.

The PI3-kinase inhibitor (BKM120) was developed by Novartis, and the PARP inhibitor (olaparib) was developed by AstraZeneca.

Lewis C. Cantley, PhD, said it is unusual for two unapproved drugs to be combined in a cancer clinical trial, especially when the two drugs are produced by separate companies. However, the preclinical results were sufficiently compelling to support the initiation of a clinical study in patients with triple-negative breast or ovarian cancer, which is now enrolling participants.

Source: American Association for Cancer Research; November 12, 2012.

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