Breast Cancer Selective Therapeutic Development: Lead Optimization of a Small-Molecule Inhibitor of the Breast Cancer Selective Hub Protein caPCNA
Abstract
Overarching Challenge: The Overarching Challenge being addressed in this application is to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and improve patient outcome and clinical management of the patient. Objective/Hypothesis: Our overall objective is to accelerate the optimization, development, and translation into the clinic of a novel lead compound that selectively targets breast cancer (BC) cells through inhibiting caPCNA functions. Our hypothesis is that caPCNA forms a new type of target, a molecular hub, which enables the selective killing of BC cells, through the simultaneous blockade of multiple pathways required by the BC cell for survival and proliferation using a single targeting agent. The evidence supporting our objective and hypothesis is that we have identified a series of compounds that selectively disrupts caPCNA function. We determined that our lead, AOH1996, has exquisite selectivity and nM cytotoxic activity toward human BC cells, while also having no discernible toxicity (at >100 mg/kg) toward non-malignant cells. Moreover, AOH1996 causes cell cycle arrest, enhanced sensitivity to cisplatin, is orally bioavailable, and suppresses tumor growth. What Type of Patients Will Benefit and How It Will Help Them: caPCNA is expressed by all forms of BC, including TNBC. The compound acts synergistically with DNA damaging agents such as cisplatin and topoisomerase inhibitors to block DNA repair and induce apoptosis in cancer cells without harming normal breast epithelial cells. As an adjunct to traditional DNA damaging agents, AOH1996 and its analogs have the potential to stop BC cell growth even in resistant forms of BC. Furthermore, we recently showed that AOH1996 crosses the blood-brain barrier and can stop BC cell growth that is metastatic to the brain. The Potential Clinical Applications, Benefits, and Risks: AOH1996 and its analogs will be useful as an adjunct to many forms of DNA damaging agents used in the clinic that lead to double-strand breaks and utilize homologous recombination-mediated DNA repair to recover from the damage. AOH1996 stops homologous recombination DNA repair and disrupts several other biochemical pathways in the BC cells, leading to the induction of “replication stress,” check-point controls, and ultimately initiation of the apoptotic response. Because caPCNA expression occurs in every type of cancer examined to date (i.e., 32 varieties of cancer, including several forms of BC). Despite a sustained and consistent effort to develop drug-resistant cell lines to AOH1996 over the last 2 years, we have been unsuccessful using multiple BC cell lines, suggesting that resistance to AOH1996 may not develop before apoptosis claims the cell. In addition, AOH1996 crosses the blood-brain barrier and selectively kills glioblastoma tumors in murine models of human brain tumors and is effective at killing BC that is resistant to traditional chemotherapeutic agents. Based on our CoH animal facility veterinary pathologist’s findings of necropsy tissue from 40 healthy mice treated daily with escalating doses of AOH1996 over a 2-week period, there were no observable signs in both anatomical tissue specimens and clinical chemistry data that could be attributed to AOH1996 drug treatment. Because of the cancer selective expression of the caPCNA target, the selectivity of AOH1996 for only caPCNA, and the veterinary pathology report, there appears to be little or no off-target effects when using AOH1996 as an anti-cancer therapeutic. The Projected Time It May Take to Achieve a Patient Related Outcome: Development of more potent analogs of AOH1996 will likely take an additional 2-3 years. However, the lead compound is already in Food and Drug Administration (FDA)-approved preclinical trials using murine and canine models of BC. We have a projected timeframe for entering FDA-approved Phase I clinical trials using the parent com
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910327
Entities
People
- John Perry
Organizations
- United States Army
- University of California, Riverside