Title: Identification and targeting of common regulatory mechanisms underlying major forms of human cancer
Funder: Cancer Research UK

Abstract: Cancer is the most complex genetic disease known – mutations in more than 300 genes have been associated with formation of different types of malignant tumors in humans. The large number of distinct cancer genotypes poses significant challenges to targeted cancer therapy, necessitating development of a large portfolio of compounds active against many different tumorigenic mechanisms. The development of targeted chemopreventive agents is even more complicated, as substantially decreasing the population incidence of malignant tumors will require concurrent prevention of several major forms of cancer, each of which has its own distinct driving mechanism. Nonetheless, despite the evident complexity of cancer genotypes, all cancers share a common, and simple, core phenotype - namely, the unrestricted proliferation and survival of somatic clones that expand and invade neighbouring healthy tissue and, in many cases, metastasize to distant organs. One hypothetical explanation for how so many diverse and complex genotypes can all elicit the same, relatively simple, phenotype is that driver mutations converge on a common set of core downstream mechanisms that drive growth, survival, invasion and metastasis. We have previously shown that deletion of a MYC regulatory region confers upon mice profound resistance to intestinal tumorigenesis, suggesting that a drug that would decrease MYC activity would exert a "statin-like" chemopreventive activity against cancer. However, both MYC and E2F lack small molecule binding pockets, making them difficult targets for drugs. Our aim here is to identify more druggable downstream targets of master regulators that could be targeted in cancer therapy and/or chemoprevention. Specific aims of the research program are the following: 1) Identify common mechanisms underlying multiple major forms of human cancer 2) Identify master regulators, and map pathways downstream of them 3) Target specific druggable proteins within these pathways using CRISPR/Cas9 to identify essential downstream mechanisms 4) Validate a subset of the findings using gene targeted mice The methodology of the project includes both genome-scale analyses of gene expression, and validation of the findings in cultured cells and gene targeted mice. The results will be used for identification of novel drug targets, paving the way towards development of chemotherapeutic and chemopreventive agents against multiple major forms of cancer.

Lay abstract: Cancer is the most complex genetic disease known – mutations in more than 300 genes have been associated with formation of different types of malignant tumors in humans. The large number of distinct cancer genotypes poses significant challenges to targeted cancer therapy, necessitating development of a large portfolio of compounds active against many different tumorigenic mechanisms. The development of targeted chemopreventive agents is even more complicated, as substantially decreasing the population incidence of malignant tumors will require concurrent prevention of several major forms of cancer, each of which has its own distinct driving mechanism. Nonetheless, despite the evident complexity of cancer genotypes, all cancers share a common, and simple, core phenotype - namely, the unrestricted proliferation and survival of somatic clones that expand and invade neighbouring healthy tissue and, in many cases, metastasize to distant organs. One hypothetical explanation for how so many diverse and complex genotypes can all elicit the same, relatively simple, phenotype is that driver mutations converge on a common set of core downstream mechanisms that drive growth, survival, invasion and metastasis. We have previously shown that deletion of a MYC regulatory region confers upon mice profound resistance to intestinal tumorigenesis, suggesting that a drug that would decrease MYC activity would exert a "statin-like" chemopreventive activity against cancer. However, both MYC and E2F lack small molecule binding pockets, making them difficult targets for drugs. Our aim here is to identify more druggable downstream targets of master regulators that could be targeted in cancer therapy and/or chemoprevention. Specific aims of the research program are the following: 1) Identify common mechanisms underlying multiple major forms of human cancer 2) Identify master regulators, and map pathways downstream of them 3) Target specific druggable proteins within these pathways using CRISPR/Cas9 to identify essential downstream mechanisms 4) Validate a subset of the findings using gene targeted mice The methodology of the project includes both genome-scale analyses of gene expression, and validation of the findings in cultured cells and gene targeted mice. The results will be used for identification of novel drug targets, paving the way towards development of chemotherapeutic and chemopreventive agents against multiple major forms of cancer.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS