Accession Number : AD1050242


Title :   Targeting Increased Polyamine Transport of Resistant Melanomas


Descriptive Note : Technical Report,01 Aug 2016,31 Jul 2017


Corporate Author : Lankenau Institute for Medical Research Wynnewood United States


Personal Author(s) : Gilmour, Susan


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1050242.pdf


Report Date : 01 Aug 2017


Pagination or Media Count : 26


Abstract : BRAF mutations are present in over half of all melanoma tumors. Although BRAF inhibitors (BRAFi) elicit rapid anti-tumor responses in the majority of patients with mutant BRAFV600E melanoma, the tumors inevitably relapse after a short time and are resistant to further treatment with these drugs. Thus, new therapeutic strategies are urgently needed to overcome the acquired resistance to BRAF inhibitors. Our goal is to test whether melanomas, which develop resistance to BRAF inhibitors, can be successfully treated using a novel arylpolyamine (AP) drug that is cytotoxic upon cellular internalization via the polyamine transport system (PTS). We found that human and murine BRAFV600E melanoma cells demonstrate greater PTS activity and increased sensitivity to AP compared to BRAFWT melanoma cells. Treatment with DFMO upregulates PTS activity in BRAFV600E melanoma cells and further increases their sensitivity to AP. Human BRAFV600E melanoma WM983B-BR subline with acquired BRAFi resistance (following chronic in vitro exposure to the BRAFi, PLX4720) demonstrated increased PTS activity compared to the parental BRAFi-sensitive WM983B cells. Preliminary animal tumor studies have revealed that co-treatment with the BRAF inhibitor, PLX4720, and AP plus DFMO delays the recurrence of BRAFV600E melanoma tumors that occurs in animals treated with PLX4720 alone.


Descriptors :   mutations , skin cancer , neoplasms , inhibitors , drug resistance , macrophages , stem cells , toxicity


Subject Categories : Medicine and Medical Research
      Pharmacology
      Biochemistry


Distribution Statement : APPROVED FOR PUBLIC RELEASE