Novel therapeutic strategies for treatment of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a median 5 year survival of just 6% despite recent advances in therapies, therefore there is a clear need for new therapeutic options. This dissertation seeks to propose novel therapeutic strategies for patients with PDAC.PD-0332991, a selective CDK4/6 inhibitor has recently received approval from the U.S. Food and Drug Administration for the treatment of advanced ER+/HER- breast cancer. Alterations of the CDK4/6 pathway are common in PDAC and potentially targetable with this new drug. This thesis investigated the efficacy of PD-0332991 and clinically useful combination in well-characterised patient-derived cells lines and xenografts of PDAC and identified high levels of retinoblastoma protein (RB) as a promising companion biomarker of treatment response. RB was highly expressed at the protein level in a significant proportion of PDAC specimens (65%), confirming that the protein could be a viable therapeutic target for tailored CDK4/6 inhibitor-based treatments. Moreover, RB expression was an independent prognostic factor for disease-specific survival in PDAC. Furthermore, PD-0332991-based therapy significantly improved survival compared to standard-of-care therapy in RB high tumours in vivo.Trastuzumab, which targets the HER2 receptor is an effective therapy for HER2-amplified breast cancer and gastric cancer. A large cohort of PDAC were analysed to explore the incidence of HER2 amplification and the clinicopathological characteristics of this phenotype. HER2 amplification was found in 2% of PDAC and was associated with a clinical phenotype characterised by metastatic spread predominantly to the lungs or brain without involvement of the liver. This thesis maps a novel strategy which extends from molecular profile to therapy, and paves the way for early translation of these findings to clinical trials. The work presents strong pre-clinical evidence that CDK4/6 inhibitor, PD-0332991, may be a promising tailored treatment option for pancreatic cancer. Characterisation of HER2-amplification in PDAC and its clinical features in this thesis further highlights anti-HER2 therapies as another attractive therapeutic target. Both molecular phenotypes can be diagnosed in clinical laboratories using detection methods that are easily translated into clinical practice. Overall, the findings may potentially have significant therapeutic implications for personalised treatment of pancreatic cancer in the future