Approach to improve survival of mice with ovarian cancer

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Approach to improve survival of mice with ovarian cancer

Postby whbio » May 02 2017 6:48 am

Platinum-based antineoplastic drugs are chemotherapy medications used to treat cancer. For example, carboplatin falls into this category and it works by interfering with duplication of DNA. Because of its efficacy, carboplatin is used to many cancer types such as ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. But cancer cells may become resistant to platinum drugs, leading to cancer recurrence. Now a new study from University of California provides a way to overcome platinum resistance in the treatment of ovarian cancer.

The study, “Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy,” appears online in Precision Oncology. Led by Dr. Sanaz Memarzadeh, the team has found that when combined with an agent that targets the mechanism of platinum resistance, platinum drugs may effectively treat platinum-resistant HGSC. This work is carried out in mice, and the team will conduct clinical trials on people to test the safety and effectiveness of the combination treatment in the near future.

High-grade serous carcinoma (HGSC) is the most malignant form of ovarian cancer, accounting for 70% cases. Most patients with this form of ovarian cancer have a therapeutic response to platinum drugs, which are now a mainstay of cancer therapy. However, despite the initial favorable response, the majority of patients relapse within 16 months after treatment. Clinically, patients with platinum-resistant ovarian cancer tend to have a worse prognosis.

In previous work, Memarzadeh’s team found that high levels of cIAPs in the CA125 negative cancer-initiating cells induce platinum resistance. cIAPs, which is short for the cellular inhibitor of apoptosis proteins, are a family of related proteins that serve as endogenous inhibitors of programmed cell death (apoptosis). The study showed that upregulation of cIAPs is one mechanism that enables evasion of platinum-induced cell death in CA125-negative HGSC cells, and that combining an inhibitor of cIAPs, birinapant, and a platinum anti-cancer agent, carboplatin, can improve disease-free interval in mice with human HGSC tumors.

For the current study, the researchers continued evaluating the effect of the combination therapy. They conducted experiments not only in cell lines (S8-GODL, S9-GODL, S1-GODL and Ovcar-3) but also in animals. They administrated either birinapant or carboplatin or both to mice that had human ovarian cancer tumors, and found that the birinapant and carboplatin co-therapy significantly prolonged survival in mice, regardless of whether they had carboplatin-resistant or carboplatin-sensitive tumors.

The study indicates that that supplementing platinum drugs with agents that inhibit cIAPs might be a potential therapeutic strategy for platinum-resistant ovarian cancer, and that levels of cIAP protein may help determine which patients would benefit from the combination therapy. (Cusabio offers various proteins such as CA125.

Other researchers of the study include V. La, R. Fujikawa, D. M. Janzen, M. Nunez, L. Bainvoll, L. Hwang, K. Faull, and G. Lawson.
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