One-two Punch Impairs Chemo Resistance in Mice with Ovarian Cancer

One-two Punch Impairs Chemo Resistance in Mice with Ovarian Cancer

Platinum-based chemotherapy is a highly effective treatment approach for ovarian cancer, but most patients will eventually become resistant and stop responding to it. Now, researchers at the Wistar Institute may have found a way to prevent that resistance from developing, using a new class of drugs called bromodomain and extraterminal (BET) inhibitors.

The study, “BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer,” published in Cancer Research, shows that combining BET inhibitors with Platinol (cisplatin) significantly extends the survival of ovarian cancer mouse models by reducing the tumor’s resistance to chemotherapy.

“There is a tremendous need for novel therapeutic strategies for patients with chemotherapy-resistant ovarian cancer, given the prevalence of the clinical challenge and the limited number of other options available,” Rugang Zhang, PhD, professor and co-program leader in the Gene Expression and Regulation program at Wistar and lead author of the study, said in a press release.

“This study demonstrates how an existing class of targeted therapies could be used to potentiate the tumor suppression induced by cisplatin,” Zhang said.

Although patients with epithelial ovarian cancer initially respond well to platinum-based chemotherapy, they often relapse, which is accompanied by a decrease in sensitivity to chemotherapy.

Cancer stem-like cells have been hypothesized to contribute to the development of such resistance mechanisms, possibly through its high aldehyde dehydrogenase (ALDH) activity. Previous studies have shown that Platinol increases ALDH activity in epithelial ovarian cancer cells, which then leads to Platinol resistance. But suppressing its activity by eliminating the ALDH1A1 protein sensitizes these cells to chemotherapy.

Zang and his team have now found that the BET inhibitor JQ1 was able to suppress the activity of ALDH in epithelial ovarian cancer cells. Indeed, the researchers found that BRD4, a member of the BET family that is inhibited by JQ1, is a critical regulator of the expression of the ALDH1A1 protein.

By inhibiting BRD4, JQ1 reduced the levels of ALDH1A1, which led to a reduction in ALDH activity in the treated cells.

Next, the researchers tested the combination of JQ1 and Platinol in mice with epithelial ovarian cancer-derived tumor cells. Their results showed that mice receiving the combo treatment lived significantly longer than those receiving JQ1 alone or Platinol alone. In addition, JQ1 significantly delayed the outgrowth of Platinol-treated cancer cells both in culture dishes and in mouse models.

“The use of BET inhibitors for the treatment of cancer appears to be both safe and effective in clinical trials,” said Yuhki Yokoyama, PhD, a postdoctoral fellow in Zhang’s lab and first author of the study. “This combination appears to significantly extend the effectiveness of cisplatin, one of the most important drugs for treating ovarian cancer, and we hope our newly discovered approach will be validated in future clinical trials.”

BET inhibitors are a class of drugs with anti-cancer and immunosuppressive properties that are currently being evaluated in clinical trials in the U.S. and Europe.

In a recent study published in Cell Reports, Zhang and his team also revealed that BET inhibitors have the ability to suppress PD-L1 activity, suggesting that in addition to increasing chemotherapy sensitivity, BET inhibitors can also improve immune surveillance.

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