Hedgehog pathway in prostate cancer progression : a novel therapeutic approach to ongoing adaptive responses

• Main Author: Ghaffari, Mazyar
• Language: English
• Published: University of British Columbia 2016
• Online Access: http://hdl.handle.net/2429/57761

Prostate cancer is the most commonly diagnosed cancer in North American men. While ever-improved androgen ablation therapies prolong life in men with advanced disease, remissions are temporary. Identifying targetable pathways underlying castration-resistant progression is essential for improving survival of patients with advanced disease. Hedgehog signalling may be one such pathway. The central hypothesis of this thesis examines the importance of adaptive responses during progression of prostate cancer to castration resistance and subsequent metastasis by reactivating developmental cues. We demonstrate that key Hedgehog pathway regulatory proteins are elevated in advanced prostate cancer compared to benign and untreated. This over-expression of Hedgehog signalling may be an adaptive response, which leads to a transition from a paracrine to autocrine Hedgehog signalling modality. Inhibition of this pathway disrupts progression of androgen sensitive, LNCaP tumours to castration-resistant prostate cancer. This inhibition has no effect on viability or key Hedgehog pathway regulators in vitro and no change in tumour specific Hedgehog genes in vivo, yet by examining host specific murine GLI1, 2 and PTCH1, key regulators of the Hedgehog pathway, we observe significant inhibition. These results suggest that Hedgehog expression promotes castration-resistant prostate cancer progression through reciprocal paracrine signalling within the tumour microenvironment. However, inhibiting the Hh pathway in our castration-resistant prostate cancer models induced down-regulation of the downstream Hh targets, in vitro. This inhibition hinders the migration and invasion of these cell lines in vitro and abrogates their invasive potential in vivo. These results taken with data from our prostate cancer patient cohort that show a significantly higher recurrence rate for patients with elevated SHH and GLI2 levels suggests a higher metastatic capacity driven by ligand-dependant autocrine Hedgehog signalling. Finally, we examine the role of Hedgehog signalling inhibition in sensitizing advanced prostate cancer to palliative therapeutic modalities. Smoothened antagonist in combination with docetaxel demonstrated significant reduction in tumour growth of both LNCaP recurrent and PC3 models, compared to single therapy. These results demonstrate the integral role of Hedgehog signalling as prostate cancer tumours adapt to castration and subsequent therapeutic modalities. Targeting these adaptive responses becomes an integral part of novel cancer therapy in prostate cancer === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate