Targeted Therapy for Triple-Negative Breast Cancer
Abstract
The prospects for women diagnosed with metastatic triple-negative breast cancer (TNBC) are grim. While targeted therapies are available for the other major subtypes of breast cancer (estrogen receptor positive, progesterone receptor positive, and HER2 positive), such targeted therapies are not widely employed for TNBC. Thus, women stricken with this disease are relegated to chemotherapy drugs developed decades ago, general cytotoxic agents that are hard on the patient and largely ineffective. Our goal is quite simple: We seek to bring targeted therapy to TNBC patients. Such an advance would bring TNBC treatment into the modern era of targeted medicines that offer dramatic improvements in overall survival and are typically well-tolerated. As such, we are addressing two of the Breast Cancer Research Program s (BCRP s) stated Overarching Challenges: Revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective, and eliminate the mortality associated with metastatic breast cancer. In 2006 we discovered a novel compound (called PAC-1) that selectively kills TNBC cells through a new mechanism of action. PAC-1 turns on a key protein in the cell death cascade, and because this protein is present in significantly higher amounts in TNBC cells relative to normal cells, it is highly selective for TNBC over normal cells. Because PAC-1 kills cancer cells in a unique manner, it has the opportunity to be successful where other drugs for breast cancer have failed. In the last 9 years we have conducted the laborious, time-consuming, and expensive preclinical experiments to move PAC-1 from the research laboratory to the clinic. And, this focus has paid off; in 2015 the Food and Drug Administration (FDA) approved the Phase I clinical trial of PAC-1, and eight late-stage cancer patients have now taken PAC-1. The clinical trial is ongoing and is taking place at the University of Illinois Cancer Center in Chicago, and at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center; listing on clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT02355535 We now seek to bring PAC-1 to metastatic TNBC patients. We will use funds from the BCRP to collect the last pieces of preclinical data that will inform the clinical trial in TNBC patients. Specifically, we will capitalize on recent advances in the biology of TNBC, advances that have revealed that there are six distinct molecular subtypes of TNBC. We will evaluate PAC-1 in cell culture and mouse models of these six different subtypes. Based on these results, patients in those TNBC subtypes where PAC-1 is most effective will be enrolled in the TNBC-specific portion of the Phase I clinical trial. This portion of the trial will be a Dose Expansion Cohort (DEC) of the ongoing Phase I trial, as such all approvals (FDA, Institutional Review Board, etc.) are already in place. In a DEC, a specific subtype of cancer patients (in this case, TNBC) are treated with a novel therapeutic. This PAC-1 DEC in TNBC would be paid for by Vanquish Oncology. Therefore, the information we collect as part of the BCRP-funded study will be used to directly inform the treatment of TNBC patients, and we anticipating treating late-stage TNBC patients a mere 18 months after the start of this funding. Thus, there will be a direct and rapid application of this work. We believe the potential benefits to TNBC patients are substantial. We have treated over 50 pet dogs with cancer with PAC-1, and we have induced substantial tumor regression at anatomical sites (lungs, brain, lymph nodes) that are common in metastatic TNBC, and have significantly extended the lives of these canine cancer patients. In the Phase I human clinical trial, PAC-1 has been extremely well-tolerated (no adverse events), and even at the lowest dose, we have observed a clinical response in a late-stage bone cancer patients with metastases to the lungs. And, o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610264
Entities
People
- Paul J. Hergenrother
Organizations
- United States Army
- University of Illinois Urbana–Champaign