I have expertise and an established track record in the areas of human cell DNA replication/repair, breast cancer and cancer cell biomarker and therapeutic target discovery and development. I am currently a Professor of Molecular and Cellular Biology at the Beckman Research Institute of City of Hope. I am also the Associate Director for Basic Science of the City of Hope Comprehensive Cancer Center. In 2011 I co-founded and co-lead the Molecular Oncology Program at the Cancer Center.
Since first establishing my independent laboratory in 1990, my laboratory has focused on elucidating the mechanisms underlying cancer cell DNA damage accumulation, which has also been correlated with disease progression. Our laboratory was the first to successfully isolate an intact multiprotein DNA synthesis complex that is both stable and fully functional, (termed the DNA synthesome), from a variety of mammalian cell lines and tissues. Subsequent work demonstrated that the synthesome of malignant breast epithelial cells has a significantly decreased DNA synthesis fidelity, (exhibiting a more error-prone synthesis process), than the complex of non-malignant breast epithelial cells. We demonstrated that this occurs in intact breast epithelial cells as well. We also showed that non-malignant human breast cell transformation to a malignant state is accompanied by an alteration of a specific protein component of the synthesome, namely proliferating cell nuclear antigen (PCNA). Different isoforms of PCNA that display both acidic and basic isoelectric points (pI) have been demonstrated. These analyses also revealed that an additional acidic form of PCNA was highly expressed in cancer cells (referred to as the cancer-associated PCNA or caPCNA). An antibody was developed to caPCNA that proved to be highly selective for this isoform in cancer cells. In the course of our studies we have identified a small caPCNA related peptide (caPeptide), as well as small molecule compounds targeting caPCNA, that promote cancer cell cytotoxicity with great specificity. These agents have the potential ability to block the binding of several cellular proteins that participate in DNA replication, repair, cell cycle control, transcription, and chromosomal recombination in cancer cells. The binding of full length caPCNA to the proteins mediating these processes is disrupted when the caPeptide or small molecule compounds are allowed to compete with these proteins for their naturally occurring binding site on caPCNA. This disruption in the function of vital cellular processes would render caPeptide or small molecule compounds cytotoxic by themselves, or in combination with other agents, such as, DNA damaging cancer chemotherapeutic drugs. These agents, either alone or in combination with other cancer therapy agents are potentially useful cancer chemotherapeutics or augmentors of the pharmacodynamic effect of specific anti-cancer chemotherapeutics. Our work has been continuously funded through the years by NCI RO1 type grants on which I have served as the PI.
“Peptides Directed Against Cancer Associated PCNA Has Therapeutic Potential in Breast Cancer”.
New Molecular Target for Neuroblastoma Therapy. The goal of this project is to evaluate the isoform of proliferating cell nuclear antigen (caPCNA), expressed by cancer cells and tumor tissue, as a potential therapeutic target for the treatment of neuroblastoma.
This project supports the research programs that have been established to allow successful collaboration among basic and clinical researchers.
- “A Structure/function analysis of a tumor specific protein.” The goal of this project is to show that the unique structure and function of an isoform of proliferating cell nuclear antigen (caPCNA), expressed by breast cancer cells and tumor tissue, plays an important role in the proliferation and progression of these cancer cells. This application received a score of 134 in the February 2007 NIH study section meeting giving it a percentile ranking of 2.2%.
- The Indiana Signature Center for Breast Cancer Research. The spectrum of studies to be performed includes the development of novel agents, technologies, and markers for the better diagnosis, prognosis, screening, prevention, and treatment of breast cancer.
“Center of Excellence for Individualization of Therapy for Breast Cancer” The purpose of the Center of Excellence was to combine the emerging technologies of genomics, proteomics, and pharmacogenetics / pharmacogenomics to predict the response to commonly used chemotherapeutic agents and novel targeted agents in the setting of advanced breast cancer. The predicted outcome of such analyses was therapeutic individualization (the matching of individual agents to specific patients most likely to benefit in the least toxic possible manner).
“Targeted Peptidomimetic Evaluation”.
(These funds supported neuroblastoma related research studies in the laboratory.)