The aim of the REAP 843630 was to understand the molecular principles underlying the tumor’s differential treatment response to platinum drugs and to identify novel predictive and prognostic markers.
In gastrointestinal cancers, unlike in any other type of solid tumors, the responsiveness to oxaliplatin is superior to cisplatin. Hence, colon cancer is one of the few cancer types exclusively treated with oxaliplatin. Still, the sensitivity of colon tumors to this platinum drug varies between patients. The specificity of oxaliplatin for gastrointestinal cancers was not mechanistically explained to date and there were no clinical markers identified to pre-select oxaliplatin-susceptible patients to achieve the best treatment results. In order to address these points, we set to comprehensively explore the cellular processes that recognize and remove oxaliplatin and cisplatin-DNA lesions. Generation of DNA damage is the main mechanism of platinum drugs leading to tumor inhibition and DNA repair processes modulate the tumor response. We, therefore, hypothesized that cancer-specific differences in the repair of these lesions could explain distinct clinical efficiencies of platinum drugs.
We observed that a subset of colon tumors is deficient in removing oxaliplatin-DNA lesions by one of the main DNA repair pathways, global-genome nucleotide excision repair (GG-NER). This pathway is represented by the rate-limiting activity of XPC protein. Based on this observation, we formulated three main objectives: Objective 1: Identify factors determining diverse XPC behavior on oxaliplatin versus cisplatin lesions. Objective 2: Identify the molecular mechanism of XPC regulation in oxaliplatin and cisplatin lesions recognition, and Objective 3: Identify DNA repair molecular signature in cancer patients’ tumors, related to treatment response to oxaliplatin.
