Grant: Project Grant

Triple-negative, a subtype of breast cancer (TNBC), represents ~15% of breast cancers but is the most aggressive with poorest outcome. This is in part through lack of targeted therapy for this breast cancer subtype and treatment is predominantly chemotherapy prior to surgery, called neoadjuvant therapy. Despite initial responses, up to 40% of patients with TNBC still develop resistance to this therapy which is associated with increased risk of recurrence and distant metastasis which is more difficult to treat. To improve outcomes, we believe that treatment presurgery (neoadjuvant) represents a unique untapped window of opportunity to improve therapy response, quality of life and long-term survival. TNBC that develop resistance to current neoadjuvant chemotherapy, transition through a state that we propose, and will test in this grant can be sensitive to some therapies approved for other cancers as well as new therapeutic strategies. For these studies we have developed unique patient derived TNBC breast cancer models. We have shown that a subset of tumor cells called drug tolerant persister cells promote tumor relapse and give rise to metastatic progression following chemotherapy. In this application we will develop a comprehensive understanding of these aggressive tumor cells to unravel mechanisms and develop therapeutic interventions that prevent resistance and TNBC progression. This proposal aims to develop new therapeutic intervention strategies to eliminate resistance to chemotherapy early. This approach is a key step to rigorously test new transition state biomarkers during current chemotherapy as actionable biomarkers in the clinic, to inform new treatment strategies.