DNA damage induced by the traditional chemotherapy carboplatin is recognized by the protein XPC, which then triggers cell death. We found low XPC in melanoma, that can be reactivated by another traditional chemotherapy, azacitidine. Avelumab is a immune therapy thats allows melanoma to be recognized and removed by the patient’s immune system. We hypothesise that sequential treatment with azacitidine/carboplatin will "prime" melanomas, by inducing cell death and reactivating sensitivity to immune therapy. We are repurposing 2 chemotherapies that show no efficacy for melanoma alone, but in sequential combination produce exceptional response. Both of these drugs are off-patent and low-cost, resulting in much lower cost to the healthcare system. Treatment resistant melanoma patients have no alternative therapy, therefore rapid translation into clinical practice will occur if this project is successful.
To overcome treatment resistance in melanoma there needs to be i) decrease in the amount of disease and ii) re-establishment of tumour recognition by the immune system.