NEO212 Provides Better Effectiveness For Treatment of Metastatic Melanoma Containing MGMT Overexpression

A Novel Temozolomide Analog, NEO 212, Demonstrates Enhanced Activity Against MGMT-Positive Melanoma In Vitro and In Vivo.

Authors: Thomas C. Chen¹, Hee-Yeon Cho¹, Weijun Wang¹, Jenny Nguyen², Niyati Jhaveri³, Rachel Rosenstein-Sisson³, Florance M. Hofman³, and Axel H. Schönthal².

Melanoma incidence continues to increase. Consequently, those whose cancer then metastasizes is also on the rise. For those who cancer metastasizes to the brain, therapeutic options remain few. Traditionally, the first-line of treatment for metastatic melanoma has included Temozolomide (TMZ). Several other pharma-therapeutics have been approved but responses to these new drugs are frequently short-lived, and many patients with advanced metastatic melanoma do not obtain a long-lasting clinical benefit. TMZ, therefore, remains an important part of current treatment regimens.

However, the emergence of treatment resistance in metastatic melanoma is very common and is frequently linked to the overexpression of MGMT (O6-methyl-guanine DNA methyltransferase), a DNA repair protein that removes alkyl groups located at the O6-position of guanine, one of the four main nucleobases for DNA. An overexpression of MGMT in a metastasized melanoma can protect tumor cells from the cytotoxic impact of TMZ and contribute to treatment resistance.

To counteract this NeOnc Technologies performed a study to determine if its NEO 212 conjugate of TMZ with Perillyl Alcohol (POH) would be able to counteract the effect of this overexpressed MGMT. In the study, human melanoma cells with variable MGMT expression levels were treated with NEO212 both in vitro and in vivo, and markers of DNA damage and apoptosis, and tumor cell growth were investigated. NEO212 displayed substantially greater anticancer activity than any of the other treatments. It reduced colony formation of MGMT-positive cells up to eight times more effectively than TMZ alone and produced greater cancer cell death.

¹Department of Neurosurgery, University of Southern California, Los Angeles, CA, United States, ²Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, United States, and ³ Department of Pathology, University of Southern California, Los Angeles, CA, United States