Sir Peter MacCallum Department of Oncology - Theses
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ItemMechanisms of FOLFOX Resistance in Metastatic Colorectal Cancer( 2022)Over half of patients diagnosed with colorectal cancer develop liver metastases during the course of their disease. In patients with metastases isolated to the liver, surgical resection offers the only chance of cure, improving 5-year survival rates from 13% with chemotherapy alone, to 33-55% if all sites of disease can be resected. A substantial proportion of patients receive neoadjuvant FOLFOX (5-Fluorouracil/oxaliplatin/leucovorin) prior to surgery, either to downstage to enable surgical resection or reduce the risk of recurrence. Unfortunately, the majority of patients progress during treatment or recur following liver resection. Despite its widespread usage and toxicity, the molecular mechanisms that contribute to FOLFOX resistance remain poorly understood. Improved understanding of FOLFOX resistance could enable better patient selection and/or the identification of combination regimens that may improve response rates and survival outcomes. In this thesis, a biobank of patient-derived tumour organoids (PDTOs) from patients with metastatic colorectal cancer (mCRC) was generated to study resistance mechanisms to FOLFOX. Using a combination of phenotypic, transcriptomic and genomic analyses of both tumour samples derived from patients with mCRC and matching PDTOs, a novel FOLFOX resistance signature was identified. Resistant PDTOs, identified after in vitro exposure to FOLFOX, manifested elevated expression of genes involved in the E2F pathway as well as activated TP53-independent S phase, G2/M and spindle assembly checkpoints (SAC). Colorectal liver metastases collected from patients with progressive disease during neoadjuvant FOLFOX demonstrated similar molecular features, highlighting the relevance of this finding. In parallel, results of a large (n=423 compounds), PDTO kinase inhibitor screen indicated that drugs targeting regulators of the DNA damage response, G2M checkpoint and SAC had cytotoxic effects on PDTOs generated from patients whose disease progressed during FOLFOX treatment. The combined results of this thesis indicate that targeting DNA damage induced and TP53-independent S-phase or G2M cell cycle checkpoints may significantly improve response rates to FOLFOX in patients with mCRC.