PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblast (CAF) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) reverses this phenotype, downregulates CSC markers expression and sensitizes tumours to docetaxel, leading to markedly improved survival and reduced metastatic burden. These promising preclinical study results led us to establish the EDALINE Phase I trial of docetaxel chemotherapy in combination with the SMOi Sonidegib in patients with metastatic TNBC. Twelve patients who had previously failed on standard of care treatments with taxanes and/or anthracyclines were enrolled. 3 patients derived clinical benefit, with one experiencing a complete response. Importantly, markers of pathway activity correlated with response. These studies identify Hh signalling to CAFs as a novel mediator of cancer stem cell plasticity and represent the first clinical demonstration of therapeutic benefit derived from targeting cancer-associated fibroblasts in the metastatic setting. Interestingly, Hh signalling seems to follow a similar pattern of activation in the prostate and could represent an exciting relevant therapeutic target in prostate cancer.
17 Mar 2019 - 20 Mar 2019