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Oncology Abstracts (2019) 1 P009 | DOI: 10.1530/oncolabs.1.P009

PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)

Targeting stromal remodelling and cancer stem cell plasticity overcomes chemoresistance in metastatic triple negative breast cancer

Aurélie Cazet 1, , Mun Hui 1, , Benjamin Elsworth 1 , Sunny Wu 1 , Daniel Roden 1 , Chia-Ling Chan 1 , Sandra O’Toole 1, , D Neil Watkins 1, , Renea Taylor 5 , Thomas Cox 1 , Michael Samuel 6 , Miguel Martín 7 & Alexander Swarbrick 1

1The Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; 2The Chris O’ Brien Lifehouse, Camperdown, New South Wales, Australia; 3Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia; 4St Vincent’s Hospital, 2010 Darlinghurst, NSW, Australia; 5Monash Biomedicine Discovery Institute Cancer Program, Monash University, Clayton, Australia; 6Tumour Microenvironment Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, Australia; 7Hospital General Universitario Gregorio Marañón, Madrid, Spain. *These authors contributed equally to this work.

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.

Volume 1

7th International Pacific Rim (PacRim) Breast and Prostate Cancer Meeting

17 Mar 2019 - 20 Mar 2019

PacRim Breast and Prostate Cancer Group 

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