Invited Speaker 35th Lorne Cancer Conference 2023

State-gating cancer: a new therapeutic strategy to prevent and treat chemotherapy-resistant disease    (#17)

Christine Chaffer 1
  1. Garvan Institute of Biomedical Research, Sydney, NSW, Australia

Treating aggressive triple-negative breast cancer is a major clinical challenge due to poorly defined subtypes and a paucity of matched targeted therapies. Here, we show that an androgen receptor signalling network defines a cohort of triple-negative breast cancer patients with poor overall survival. Further, we demonstrate that cytoplasmic androgen receptor expression is a new biomarker capable of predicting poor prognosis, and, the first biomarker that predicts pathologic complete response in early triple negative breast cancer. In pre-clinical triple-negative breast cancer models, we show that AR is required for the maintenance of the aggressive cancer stem cell state. It is also required for chemotherapy-induced cell state changes of non-cancer stem cells into cancer stem cells. These ‘state-gating’ effects are mediated through inhibition of canonical and non-canonical androgen receptor signalling. Accordingly, anti-androgen therapy combined with chemotherapy significantly inhibits primary and metastatic tumour growth, and the emergence of chemotherapy resistant disease. Thus, cytoplasmic androgen receptor expression has the potential to inform a new clinical subtype of triple negative breast cancer, allowing oncologists to escalate treatment to targeted anti-androgen therapy in combination with best standard care in both early and advanced settings. A clinical trial is now underway testing the anti-androgen agent seviteronel combined with chemotherapy to treat metastatic triple-negative breast cancer. State-gating therapies have transformative clinical potential across multiple cancer types.