by Delthia Ricks , Medical Xpress

Credit: CC0 Public Domain

Ovarian cancer is the deadliest gynecologic malignancy globally and is increasing in incidence and mortality with currently more than 300,000 new cases and 200,000 deaths annually, according to data from the World Health Organization.

Among those cancers is a high-grade tumor type that is stealthy, frequently drug resistant—and inevitably complex. Worse, there are no durable treatments that can force high-grade ovarian malignancies into long-term remission. But an experimental medication is being analyzed for this form of cancer in studies led by the Penn Ovarian Cancer Research Center at the University of Pennsylvania.

That drug—colforsin daropate—is still in early laboratory research and has yet to be tested in women with ovarian cancer. And despite its newness to gynecologic oncology, it is a familiar pharmaceutical that has been in use as an approved drug since the mid-1990s for acute heart failure. Cancer biologists hope to eventually repurpose the medication for treatment of an exceptionally lethal tumor subtype.

The type of ovarian cancer that is drawing researchers’ attention is formally known as high-grade serous ovarian cancer, or HGSOC. Doctors also refer to it as epithelial high-grade serous ovarian cancer.

Among subtypes of ovarian cancer, HGSOC affects a large swath of women and bears an extraordinarily unfortunate reputation for high rates of recurrence and low survival. In addition, HGSOC has no early detection biomarkers and is difficult to treat.

Images of HEYA8 subcutaneous tumors and graphs of individual intraperitoneal tumor kinetics. Credit: Science Signaling (2024). DOI: 10.1126/scisignal.ado8303

“Epithelial high-grade serous ovarian carcinoma is the most common and deadliest subtype of ovarian cancer, accounting for approximately 70% of cases diagnosed, and 75% of ovarian cancer deaths,” writes cancer researcher Dr. Matthew J. Knarr of the Penn Ovarian Cancer Research Center, and lead author of the new analysis.

“Its high mortality rate is due to the absence of early symptoms, resulting in 80% of patients being diagnosed at later stages often after metastatic progression throughout the peritoneal cavity,” Knarr added, noting that 80% of these cancers recur within five years.

Reporting the results of the study in the journal Science Signaling, Knarr and a team of cancer biologists emphasized that new therapeutics are desperately needed for this difficult-to-treat cancer. And that’s why it is important to leave no stone unturned, according to advocates for ovarian cancer patients, who praise efforts like those of the Penn team, which searched the existing pharmacopeia for something new.

Knarr and colleagues examined the effects of colforsin daropate on cell lines and in animal models. Their research demonstrated that the heart drug can kill ovarian cancer cells and shrink tumors when combined with the standard chemotherapy agent, cisplatin. The medication also has the added benefit of acting only on cancer cells while leaving healthy tissues unscathed.

“Given that ovarian cancer cells tend to metastasize as drug-resistant spheroids, we also wanted to determine whether colforsin daropate could cause cell cycle arrest and/or cell death in HGSOC spheroids,” Knarr continued.

Ovarian cancer spheroids are solid, spherical clusters of cancer cells that emerge as the disease progresses. Spheroids can spread throughout the peritoneal cavity and attach to tissues.

Relapses are common even if an HGSOC patient has an initial positive response to standard platinum/taxane therapy. Recurrent chemo-resistant tumors have limited treatment options, Knarr added, noting that the experimental therapy has piqued scientific interest not only because it might offer a new option, but because it offers a unique mechanism of action.

Colforsin daropate works by suppressing a cancer-linked protein known as MYC, which tends to be hyperactive in HGSOC. The heart drug apparently diminishes MYC’s activity.

More research is needed to tease apart how colforsin daropate, an experimental compound in ovarian cancer, decreases MYC levels in women with the disease. Data so far suggests that colforsin daropate inhibits MYC signaling.

In their search for a drug that could attack HGSOC cells, the team of scientists first examined the drug forskolin, which has potent anti-cancer properties. The trouble with forskolin is that it didn’t translate in the laboratory into a clinically useful medication for ovarian cancer.

The team then turned to a forskolin derivative, colforsin daropate, which possessed far more favorable drug properties that zeroed in on the molecular mechanisms driving the cancer.

“Forskolin has been used in the clinic for the treatment of glaucoma and is being investigated for the treatment of asthma, heart failure, and obesity,” Knarr asserted, adding that forskolin isn’t water soluble, and therefore not ideal for the kind of medication needed to treat HGSOC.

Water-soluble colforsin daropate, has potent anti-cancer activity and was deemed a strong candidate to address the unique properties of the malignancy.

Additionally, because colforsin daropate was already approved for the treatment of acute heart failure, it became a strong candidate. If it continues to perform in the laboratory the way it has to date, the medication may find its way into clinical testing in the not-too-distant future, scientists say.

In the journal report, colforsin daropate defeated ovarian tumors by arresting the cell cycle and inducing cell death in cultured HGSOC cells and spheroids. When given to mice, the compound slowed the growth of tumors and extended the animals’ survival.

Along with Knarr and scientists at Penn Ovarian Cancer Research Center, other team members hailed from the University of Michigan and the Department of Translational Molecular Medicine at Saint John’s Cancer Institute in Santa Monica, California.

“We observed here that the colforsin daropate-treated spheroids showed a reduction in adhesion signaling and tended to be less compact,” Knarr and colleagues conclude. “It is likely that colforsin daropate decreases important intrinsic pro-survival signals in the spheroids that depend on cell-to-cell adhesion.

“This also allows the drug greater access to more tumor cells than would otherwise be possible. Future studies will need to investigate in detail the mechanisms by which colforsin daropate disrupts ovarian cancer sphere adhesion.”

More information: Matthew J. Knarr et al, Repurposing colforsin daropate to treat MYC-driven high-grade serous ovarian carcinomas, Science Signaling (2024). DOI: 10.1126/scisignal.ado8303

Journal information:Science Signaling

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