Misetionamide is effective in targeting and killing BRAF-mutated melanoma cells while preserving normal cells
BRAF-mutated melanoma accounts for approximately 50% of all melanomas
BERWYN, PA, Nov. 21, 2023 (GLOBE NEWSWIRE) -- Panavance Therapeutics Inc. (“Panavance” or the “Company”), a clinical-stage pharmaceutical company advancing the development of a novel oncology therapeutic intended to improve the outcomes and quality of life for patients, today announced publication of positive data in the peer-reviewed International Journal of Molecular Sciences in a manuscript titled, “In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes.”1 The publication by Gambichler, et al. (2023) details the anti-tumor activity of the GAPDH inhibitor misetionamide (GP-2250) in BRAF-mutated melanoma cell lines and benign melanocytes. Mutated BRAF is a potent oncogene involved in sending signals inside cells which are involved in directing cell growth and is overexpressed in melanomas, non-small cell lung cancer, and other tumor types.
Misetionamide is a tumor cell selective drug that is broadly active in multiple cancer models with a unique mechanism of action that suppresses cancer by disrupting its energy metabolism, leading to cancer cell death while not affecting normal cells. This activity occurs due to misetionamide’s targeting at least 3 key enzymes in the aerobic glycolysis pathway as well as downstream effects on other enzymes, transcription factors and tumor suppressor genes. Misetionamide’s inhibition of hexokinases, GAPDH (glyceraldehyde 3-phosphate dehydrogenase), and PVD (pyruvate dehydrogenase) during aerobic glycolysis greatly inhibits ATP production for cancer cells, setting up oxidative, metabolic and hypoxic stresses within the cancer cell. Additionally, misetionamide’s inhibition of key transcription factors such as NFkB and enzymes further impair the ability for the cancer cell to provide sufficient energy for cellular reproduction for proliferation and survival. It also induces tissue hypoxia by inhibiting new blood vessel development in tumors.2 This study demonstrated that misetionamide may be a promising add-on therapy in BRAF-mutated melanomas, which account for approximately 50% of all melanomas.
“Given the anti-tumor activity observed in misetionamide as recently published from our studies in Merkel cell carcinoma cells as well as in cutaneous squamous cell carcinoma cell lines, I was eager to study the impact in BRAF-melanoma due to its GAPDH inhibition. The results demonstrated that misetionamide is able to downregulate the gene and protein expression of aberrant tumorigenic pathways in melanoma cell lines and could represent a promising therapy for tumors such as melanoma,” said Prof. Thilo Gambichler, former Head of the Skin Cancer Center of the Ruhr-University Bochum.
This research was conducted at Skin Cancer Center Ruhr-University, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, Germany with support from the Company. Results of this preclinical study showed misetionamide has anti-neoplastic effects in BRAF-mutated melanoma cell lines regarding tumor cell viability, proliferation, and apoptosis/necrosis. These findings also extend the mechanism of action activity of misetionamide to include STAT, COX2, and NOTCH 1,2, and 3 in melanoma cells in addition to the known effects on GAPDH, Hexokinases, NFkB, and others. The team studied three melanoma cell lines and one primary melanocyte cell line (Ma-Mel-61a, Ma-Mel-86a, SH-4, and ATCC-PCS-200-013, respectively) which were exposed to different misetionamide doses. All three melanoma cell lines (Ma-Mel-62a, Ma-Mel-86a, SH-4) showed a dose-dependent response to misetionamide during BrDU testing and the MTT viability assays, whereas proliferation as well as viability were drastically reduced by a misetionamide concentration of 500 μmol/L.
“We are very excited to see the cancer cell killing benefits of misetionamide demonstrated in this study. These results further broaden the mechanism of action into yet another potential oncology target in BRAF-mutated melanoma. The high incidence of BRAF-mutated melanoma of approximately 50% indicates that it could be an attractive therapeutic target in addition to the company’s current focus on pancreatic and ovarian cancers,” said Greg Bosch, Chairman and CEO.
About Panavance Therapeutics
Panavance Therapeutics Inc. is a privately held, clinical-stage pharmaceutical company developing a novel oncology asset, GP-2250 (also known as misetionamide). Panavance was formed in 2021 as a US-based, wholly-owned carve out of Geistlich group, a family owned Swiss company, to focus on GP-2250 and the oncology business.
GP-2250 is a tumor cell selective and broadly active small molecule with a unique dual mechanism of action of selectively disrupting the energy metabolism of cancer cells leading to cancer cell death as well as impacting nuclear factor-κB (“NFκB”) which effects cancer cells’ ability for protein synthesis and DNA transcription thereby restricting cancer cell growth and proliferation. The Company is advancing towards the initiation of two registration directed clinical studies expected: a Phase 2/3 study of GP-2250 for the treatment of platinum resistant ovarian cancer and a pivotal Phase 3 clinical trial as a first-line maintenance therapy for non-BRCA mutated pancreatic cancer patients. Extensive preclinical studies have demonstrated that GP-2250’s broadly anti-neoplastic MOA has the potential to be effective in additional indications, including melanoma, squamous cell, breast, and colorectal cancers.
For more information, please visit panavance.com and connect with the Company on Twitter, LinkedIn, and Facebook.
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1Gambichler, Thilo & Harnischfeger, Friederike & Skrygan, Marina & Majchrzak-Stiller, Britta & Buchholz, Marie & Müller, Thomas & Braumann, Chris. (2023). In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes. International Journal of Molecular Sciences. 24. 15336. 10.3390/ijms242015336.
2Majchrzak-Stiller, B.; Buchholz, M.; Peters, I.; Waschestjuk, D.; Strotmann, J.; Höhn, P.; Hahn, S.; Braumann, C.; Uhl, W.; Müller, T.; et al. GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells. J. Cell. Mol. Med. 2023, 27, 2082–2092.
