Colorectal Cancer (CRC) is the second most frequent cause of death from cancer in Ireland. 5-Fluorouracil (5-FU)-based chemotherapeutic regimens are the standard treatment for these patients. Combining 5-FU with the newer chemotherapies such as oxaliplatin has improved response rates for advanced CRC to 40-50%. Resistance to chemotherapy however still limits the effectiveness of current cancer therapies. Drug resistance can be intrinsic or acquired during treatment and is believed to result in treatment failure in over 90% of patients with metastatic cancer. Furthermore, drug resistant micrometastatic tumor cells are believed to reduce the effectiveness of adjuvant chemotherapy. Therefore, overcoming drug resistance is one of the main challenges of current cancer research. Research at CSM focuses on the role of defective apoptosis signalling in tumour resistance.
Colorectal cancer is the second leading cause of cancer-related deaths in the developed world. Regorafenib, a newly approved tyrosine kinase inhibitor is active in metastatic colorectal cancer (mCRC) patients for whom no other treatment options exist. Nevertheless, as not all patients respond to treatment, the elucidation of a patient subset most likely to derive clinical benefit is of high priority. Herein, a state of the art mCRC Patient Derived Xenograft (PDX) discovery platform will be established to enable the systematic interrogation of predictive ‘omic and imaging markers of intrinsic resistance. The effect of Regorafenib in a cohort of metastatic mCRC PDX models will be characterized using imaging and immunohistochemistry. An integrated whole exome sequencing /Reverse Phase Protein Array strategy will identify putative biomarker signatures & interrogate cellular signaling pathways using statistics and systems pathway analyses. Functional Magnetic Resonance Imaging will be assessed in novel orthotopic PDX models as a possible predictive imaging response marker. Demonstration that mCRC PDX models may be used as a robust tool in integrative biomarker discovery studies may have a significant impact on future biomarker discovery approaches. ColoForetell has identified the discovery & verification of predictive pharmaco-‘omic & imaging biomarker methods for Regorafenib as a primary goal.
The Coloforetell team is composed of cancer researchers and clinicians from across Europe.
Flanders Interuniversity Institute for Biotechnology (VIB)
Prof. Diether Lambrechts – Diether.Lambrechts@vib-kuleuven.be
Institute for Cancer Research and Treatment University of Torino School of Medicine
Prof. Livio Trusolino – firstname.lastname@example.org