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

Rectal cancers account for 30% of colorectal cancer (CRC) cases, and are increasingly recognised as a separate cancer entity. Surgery is the mainstay therapy for rectal cancer. Patients with advanced rectal cancer routinely receive neo-adjuvant, 5-FU-based radio chemotherapy to downstage their tumour prior to surgery. However responses to chemoradiation can 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 that identify patients who will or 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 our team of systems engineers, molecular biologists and clinicians developed and clinically tested a systems medicine tool, Dr_MOMP, which incorporates the complex biochemical interactions of Bcl-2 family proteins and calculates the sensitivity of tumour cells to undergo apoptosis. Using quantitative data of just five Bcl-2 family proteins as model input we demonstrated that Dr_MOMP predicted with high confidence the chemotherapeutic dose, n, that was required to induce cell death in tumour vs. matched normal tissues of individual CRC patients, enabling patient stratification into those with favourable and those with unfavourable clinical outcome (p=0.0099). We here propose to clinically validate DR_MOMP in the setting of rectal cancer, and test its sensitivity and specificity as a prognostic marker for therapy responses. Furthermore, we will integrate patient-specific genetic and cell signalling signatures into the 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.