A PRECISION MEDICINE APPROACH TO TARGET COLORECTAL CANCER

Qatar is experiencing an unprecedented increase in number of cancer patients with colorectal cancer being the second most diagnosed (QNCR, 2014). Incidentally, it is the leading cause of cancer related deaths worldwide and there is a greater risk that this might soon be true in Qatar. Two major challenges in colorectal cancer treatment are chemotherapy resistance and lack of personalized medicine targets. Differences in patients’ genetic background and intra-tumor heterogeneity often yield poor response to conventional chemotherapy leading to disease relapse with acquired resistance and metastatic phenotype. Thus, there is urgent need to identify molecular targets of prognostic and therapeutic value that could not only predict chemotherapy outcome but when inhibited could provide maximum synergy to chemotherapy. The goal of our proposed work is to characterize one such precision medicine target in colorectal cancer. The tumor suppressor protein FBW7 is a substrate adaptor for an E3 ubiquitin ligase complex, which is often mutated and/or down-regulated in colorectal cancer. Loss of FBW7 activity leads to accumulation of oncogenic proteins including c-MYC, Cyclin E, and Notch1, and accelerates tumor growth, metastasis, and mortality in mouse models of cancers. Additionally, FBW7 targets an anti-apoptotic protein—MCL1—for ubiquitylation mediated protein degradation. Thus, when FBW7 is mutated or down regulated, MCL1 accumulate in cancer cells and confers resistance against chemotherapy drugs including Taxol and Cisplatin. Because, majority of colorectal cancer patients are wildtype for FBW7, we propose restoring the levels of FBW7 protein in colorectal cancer by blocking a negative regulator of FBW7 protein stability, NRF7. We hypothesize that NRF7 inhibition in combination with Taxol will eradicate colorectal cancer in pre-clinical models. In this project, we will perform a comprehensive functional and biological characterization of protein NRF7. We will employ 3D mini-gut culture, and CRISPR/Cas9 based genomic editing as state of the art to achieve our goals. Our preliminary data strongly suggests that inhibiting NRF7 will sensitize colorectal cancer to Taxol. Additionally, we will explore the possibility of using NRF7 as a prognostic marker whose levels might predict whether a patient will or will not respond to Taxol therapy. We are confident that our proposed work will lead to significantly high impact publications in biomedical journals of international repute and these findings could be fast-tracked to clinics benefitting a large number of colorectal cancer patients in Qatar and abroad

Hamad Bin Khalifa University (HBKU)