Treatment of melanoma via pharmacological inhibition of the pro-survival protein BCL2A1 — ASN Events
  1. Schedule
  2. Session 12: Poster Session D - Including Happy Hour & Trade Display
  3. Treatment of melanoma via pharmacological inhibition of the pro-survival protein BCL2A1

Treatment of melanoma via pharmacological inhibition of the pro-survival protein BCL2A1 (#425)

Erinna F Lee 1 , Leona Rohrbeck 1 , Mathias Lang 1 , Lin Tai 1 , David CS Huang 1 , Andreas Strasser 1 , Marco J Herold 1 , Walter D Fairlie 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

Overexpression of the pro-survival members of the Bcl-2 protein family has been implicated in the initiation/sustained growth of cancers. It has been shown that the pro-survival protein BCL2A1 is amplified in >30% of human melanoma samples and is associated with variable clinical responses and relapse following standard chemotherapy. Given that melanoma is one of the fastest growing cancers in the world, there is an urgent need to improve such therapies.

A class of anti-cancer therapeutics known as “BH3-mimetics” exert their efficacy by antagonising pro-survival Bcl-2 proteins. Currently available BH3-mimetics include ABT-737, Navitoclax and ABT-199, and are in clinical trials for the treatment of cancers such as leukaemia and lymphoma. However, such compounds are limited to tumours reliant on Bcl-xL, Bcl-2 or Bcl-w for their survival and tumours such as melanoma for which BCL2A1 is a survival factor remain resistant. Given the restricted expression of BCL2A1 to the haematopoietic compartment, a drug selective for this protein should not only be effective against a number of tumours (such as melanoma) that are unresponsive to currently available BH3-mimetics but also display reduced side-effects. 

We have developed a BCL2A1-specific peptide antagonist that provides useful proof-of-principle for a similarly acting drug. We demonstrate that inducible expression of this BCL2A1-specific peptide kills several melanoma-derived cell lines. Furthermore, whilst antagonism of the BRAF/MEK pathway (such as with the small molecule PLX4032 – which inhibits the mutated form of the B-raf kinase found in ~50% of malignant melanomas) is promising, this still leads to poor clinical outcomes attributable to elevated BCL2A1 levels. As such we envisage that inhibition of BCL2A1 together with PLX4032 could improve melanoma treatment. We provide strong evidence for the development of BH3-mimetics against BCL2A1 for the treatment of cancers such as melanoma, which are dependent on this pro-survival protein for their survival. We envisage that such a compound will enable us to profile other tumour types that will benefit from BCL2A1 antagonism.