Virtual Flash Talk & E-Poster Presentation 34th Lorne Cancer Conference 2022

The AR antagonist seviteronel sensitises triple-negative breast cancer to chemotherapy by targeting cancer stem cells (#38)

Beatriz Perez San Juan 1 2 3 , Soroor Hediyeh-zadeh 4 , Laura Rangel 1 2 3 , Vanina Rodriguez 1 2 , Heloisa Helena Millioli 1 2 3 , Felix Kohane 1 5 , Lesley Castillo 1 , Abigail Bunkum 1 , Anie Kurumlian 1 , Carley Purcell 1 2 3 , Elgene Lim 1 3 , Vinod Ganju 6 , Rachel Dear 2 , Sandra O'Toole 1 , Cristina Vargas 7 , Theresa Hickey 8 , Leonard Goldstain 1 2 3 , John Lock 5 , Melissa Davis 4 9 10 , Christine Chaffer 1 2 3
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. The Kinghorn Cancer Centre, Sydney, NSW, Australia
  3. St Vincent’s Clinical School Faculty of Medicine, Sydney, NSW, Australia
  4. Walter and Eliza Hall Institute of medical Research, Melbourne, Victoria, Australia
  5. Department of Pathology, UNSW Medicine, Sydney, NSW, Australia
  6. Monash University, Melbourne, VIC, Australia
  7. Pathology Lab, Douglas Hanley-Moir, Maquire University, Sydney, NSW, Australia
  8. Dame Rome Mitchel cancer research laboratories, Adelaide University School, Adelaide University, Adelaide, SA, Australia
  9. Department of medical biology , Univesity of Melbourne, Parkville, Melbourne, VIC, Australia
  10. Department of biochemistry, Faculty of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia

Therapeutic strategies that improve survival outcomes for advanced-stage breast cancers have proven a major clinical challenge. This is in part due to the lack of understanding of the underlying biology of disease progression. Cancer stem cells (CSCs) drive tumour initiation, metastatic spread and chemoresistance, hence eradicating these cells should lead to developing effective therapies. Triple-negative breast cancer (TNBC) is enriched in CSC subpopulations, as non-CSCs readily convert into CSCs through activation of non-genetic molecular mechanisms, which accounts for its aggressiveness. Through transcriptomic analysis of non-CSC and CSC cell subpopulations, we have defined the signalling network that governs the maintenance and formation of TNBC CSCs, and determined that the androgen receptor (AR) signalling is a major driver. In response to chemotherapy, AR activation switches cells into a cancer stem cell state, while AR antagonism suppress cell-state switching and cancer stem cell function. In vivo, the dual AR antagonist, seviteronel (VT-464/INO-464), enhances chemotherapy effectiveness, restricting tumour growth and metastasis development. Interestingly, we discovered that metastases and xenografted tumours with a CSC profile express high cytoplasmic AR levels. Analysis of 3 independent TNBC patient cohorts identified that cytoplasmic AR, which currently is not scored in the clinic, prognosticates poor survival in treatment-naïve patients and predicts lack of response to chemotherapy. In line with our findings, retrospective analysis of data from a Phase II clinical trial, showed that seviteronel treatment­ followed by chemotherapy improves survival for cytoplasmic-AR+ TNBC patients. Together, our work has shed light on the mechanisms that drive cancer stem cell biology, identifying a novel biomarker and therapeutic strategy with the potential to change clinical practice and improve TNBC patient’s outcomes. A clinical trial derived from this work has begun in Australia (NCT04947189).