Linda Malkas, Ph.D.
- Cancer Biology
- Peptides Directed Against Cancer Associated PCNA Has Therapeutic Potential in Breast Cancer
- New Molecular Target for Neuroblastoma Therapy
- NIH/NCI Cancer Center Support Grant
- A Structure/function analysis of a tumor specific protein
- caPep: mechanistic evaluation of an agent for neuroblastoma
- Development of novel agents, technologies, and markers for the better diagnosis, prognosis, screening, prevention, and treatment of breast cancer
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 epithelial cells has a significantly decreased DNA synthesis fidelity, (exhibiting a more error-prone synthesis process), than the complex of non-malignant epithelial cells. We demonstrated that this occurs in intact epithelial cells as well. We also showed that non-malignant human 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.
- Molecular and Cellular Biology
- Comprehensive Cancer Center Leadership
- "caPep:evaluation of an agent that targets MYCN-amplified neuroblastoma." Role: Principal Investigator. Total Cost $ 100,000.
- Department of Defense Medical Research and Development Command Breast Cancer Research Program (2010-2013) “Peptides Directed Against Cancer Associated PCNA Has Therapeutic Potential in Breast Cancer”. Role: Principal Investigator
- Department of Defense Medical Research and Development Command Research Program (2011-2014)
- 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. Role: Principal Investigator
- NIH/NCI Cancer Center Support Grant [Friedman (PI)] (2012-2017) This project supports the research programs that have been established to allow successful collaboration among basic and clinical researchers. Roles: Deputy Director for Basic Research and Co-Leader--Molecular Oncology Program
- St. Baldrick’s Foundation (2013-2014) National Institutes of Health/National Cancer Institute Public Health Service Award (2007-2014) "A Structure/function analysis of a tumor specific protein (R01)" 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.
- Indiana University Purdue University Indianapolis Signature Center Award (2010-2013) 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. Role: Director/Principal Investigator - signed award over to another PI upon leaving Indiana University
- DOD Center of Excellence (BC030400) [Sledge (PI)] (2004-2011) “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). Role: Co-Leader
June 30, 2017
March 18, 2015
February 16, 2015
February 10, 2015
February 02, 2015
November 21, 2014
October 27, 2014
March 16, 2014
January 11, 2014
July 17, 2013
March 08, 2013