A systems-based patient stratification tool of Bcl-2 family protein interactions to evaluate acute treatment responses in rectal cancer patients

Patients with advanced rectal cancer routinely receive neoadjuvant, 5-FU-based radio-chemotherapy to downstage their tumour prior to surgery. However responses to chemoradiation vary dramatically between patients, with 15-27% of patients achieving complete pathological responses, but 30-40% showing no response. Radiochemotherapy imposes significant patient burden and health costs, but may also delay surgical treatment if unsuccessful. Hence novel prognostic tools identifying patients who will/will not benefit from chemoradiation are of significant clinical importance. Genotoxic agents and radiation therapy kill cancer cells by initiating apoptosis, a biological process controlled by Bcl-2 family proteins. Recently we developed and clinically tested a systems medicine tool, Dr_MOMP, which incorporates the complex biochemical interactions of Bcl-2 family proteins and calculates sensitivity of tumour cells to undergo apoptosis. We propose to clinically validate DR_MOMP in the setting of rectal cancer, and test its sensitivity and specificity as prognostic marker for therapy responses. Furthermore, we will integrate patient-specific genetic and cell signalling signatures into computational platform in order to develop further improved systems-based prognostic tools of therapy responses. Finally, we will perform important proof-of-concept studies to demonstrate that DR_MOMP can be employed as a new generation stratification tool to evaluate responses to Bcl-2 antagonists in future clinical trials.

This project is funded by HRB.