Exploiting p53 mutation in colorectal cancer: clinical positioning of Cdc7 inhibitors
Mutations in TP53 are present in approximately 50% of colorectal cancer (CRC) and are enriched for in the metastatic setting. As a result of TP53 mutation these tumours are limited in their ability to execute tumour-suppressive functions. Synthetic lethal targeting of pathways/ proteins on which there is an induced dependency in the presence of a TP53 mutation is an attractive potential therapeutic strategy. Cdc7 is one such protein and Cdc7 inhibition (Cdc7i) may be an appealing therapeutic approach in TP53 mutant CRC. In this thesis we aimed to explore if a novel Cdc7i (LY3143921), could be employed as a means to therapeutically exploit TP53 mutation in CRC, either alone or in combination with chemotherapy. Analyses of a CRC patient-derived xenograft study were performed alongside in-vitro mechanistic studies of LY3143921. To further enhance the therapeutic potential of Cdc7i, in-vitro analyses of LY3143921 in combination with current standard of care systemic treatments in CRC were performed and results are presented within the thesis. Importantly, in two models lacking WT TP53, combining LY343921 and chemotherapy indicated that Cdc7i could enhance the in- vitro efficacy of certain standard of care chemotherapeutic regimens. Interim analysis of the first 30 patients recruited to the first-in-human phase I trial of LY3143921 monotherapy is also discussed. Future work should explore underlying biologic mechanisms which associate with specific TP53 mutations and result in sensitivity to Cdc7i, with the aim of identifying a novel predictive biomarker of response to LY3143921. Additional pre-clinical evaluation of LY3143921 in combination with chemotherapy should also be considered, with the potential for clinical evaluation of this combination in the future.
Networked Digital Library of Theses and Dissertations