Potential Therapy Takes a Two-Prong Attack on Pancreatic Cancer

Once full of chemotherapy drugs that would wage war on cancer through full-body onslaughts, the oncology arsenal is now being stocked with more specialized weapons with particular targets in their sights. 

One drug being considered as an addition is misetionamide, also known as GP-2250. The drug inhibits the growth and spread of tumors first by selectively disrupting pancreatic cancer’s metabolism and halting its energy production.

How Does It Work?

Cancer cells depend on a process called aerobic glycolysis to generate large amounts of energy (ATP). Normal cells can use the much more efficient production of ATP through oxidative phosphorylation, a capability cancer cells have lost. GP-2250 reduces the ATP that cancer cells require by inhibiting the key enzymes in aerobic glycolysis. This causes all sorts of stress on the cells, leading to cell death. It also affects additional downstream processes, such as the TCA cycle and the inhibition of ACC (the rate-limiting enzyme in the synthesis of new fat), further limiting the synthesis of essential cell components.

As the cancer cells are weakened by this lack of energy, GP-2250 delivers a second punch, to a key tumor promoter that regulates inflammatory and immune responses, among other functions.  By limiting the cancer’s ability to transcribe DNA and make new proteins, it effectively restricts the cancer’s ability to grow and spread, and eventually induces apoptosis (cell suicide). 

Better Together

Initial testing in human pancreatic cancer cell lines (both ductal and neuroendocrine tumors) and patient-derived xenograft mouse models were encouraging.

The most promising results came when the drug was combined with the commonly used chemotherapy drug gemcitabine. Preclinical studies showed that GP-2250 substantially increased the sensitivity of pancreatic tumors when used alongside gemcitabine.

“The added synergy with standard chemotherapy is a promising advancement, amplifying our ability to combat tumors effectively,” said Anup Kasi, M.D., M.P.H., Associate Professor of Medical Oncology at the University of Kansas Cancer Center (Kansas City, Kansas).

Panavance Therapeutics Inc. has now begun testing GP-2250 in humans, with a phase I trial in patients with advanced pancreatic cancer previously treated with 5-fluorouracil-based chemotherapy.

The purpose of the trial is to test the safety and tolerability of GP-2250 alone and with gemcitabine, and to determine ideal doses for further study. Researchers will also study the drug’s efficacy and how it works in the body (pharmacokinetics), measuring biomarkers like the antigen CA-19-9.

Additional clinical studies are expected to start in 2024: a phase II/III study of GP-2250 for the treatment of ovarian cancer and a pivotal phase III clinical trial as a first-line maintenance therapy for non-BRCA mutated pancreatic cancer patients, a population for which there are no FDA-approved agents.

The hope is that GP-2250 might not only provide new options for therapy, but that it might also help overcome the hurdle of resistance to gemcitabine, which often develops within weeks of starting treatment.

“Our primary focus extends beyond anti-tumor activity—it’s about enhancing patients’ quality of life for longer, better lives,” adds Kasi, the overall lead investigator on the phase I study. “GP-2250’s remarkable side effect profile and unique mechanism of action ensures selectivity for cancer cells while sparing healthy ones, allowing patients to sustain treatment and preserve their quality of life and functionality.”

Read the story “A Clinical Trial Gives Me Hope” from Dennis Rues, who participated in this trial.

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