Pancreatic cancer patients whose tumours carry a specific DNA repair defect could be matched to platinum-based chemotherapy, a treatment currently used without a reliable genetic test. Pancreatic cancer is notoriously difficult to treat, partly because it is not a single disease. Different patients’ tumours have different genetic faults, yet most receive the same chemotherapy. The researchers have identified a molecular signature—a set of genomic aberrations—that predicts whether a tumour will respond to platinum drugs. This signature is the most promising actionable phenotype they have found so far. If the team can define this genotype precisely and validate it in patient-derived models and genetically engineered mice, the immediate impact would be a clinical test that tells oncologists which patients will benefit from platinum therapy and which will not. That would spare patients unnecessary toxicity and improve survival in the responsive group. The same approach could later be extended to other targeted therapies, including PARP inhibitors, gradually shifting pancreatic cancer treatment from one-size-fits-all to genotype-guided precision medicine.
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1. What are the key genomic aberrations that drive pancreatic carcinogenesis? 2. Which genomic aberrations or signatures define molecular subtypes of clinical importance and can be targeted for therapy? 3. How do we implement efficient and effective molecular subtype driven personalised treatment strategies using advanced genomic technologies? The applicants overall goals are to advance innovative approaches in cancer genomics and therapeutic development with the aim of defining, unders tanding, testing and implementing personalised therapeutic strategies for pancreatic cancer. Personalised (stratified) therapeutic strategies aim to target subclasses predicted to be responsive on the basis of molecular phenotype (genotype) so that the right therapy is matched to the right patient. Integrative analysis of multidimensional datasets identifies mechanisms important in carcinogenesis for novel therapeutic development and defines actionable molecular phenotypes for rationalising, res cuing and repurposing existing therapies. Patient-derived xenografts, cell lines and genetically engineered mouse models that are extensively omically characterised and reflect important pancreatic cancer subclasses provide unique and powerful models for preclinical testing prior to assessment in human clinical trials. This proposal focuses on the most prominent actionable molecular phenotype we have identified, that which is associated with platinum responsiveness. Defining this genotype has th e potential to transform our current approach to pancreatic cancer therapy.
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