Mechanisms of Drug Resistance and Their Reversal
Dr. Francis Ali-Osmanís research interest is in understanding fundamental cellular and molecular mechanisms that drive therapeutic response and failure in human cancer, particularly, those of the central nervous system; and the translation of this knowledge into better detection, diagnosis, treatment and prevention of these malignancies. A major part of this research is on the GSH (glutathione) and GSTs (glutathione S-transferases) and their role in drug resistance, signaling, cell survival/cell death, tumor progression and oncogenesis. The superfamily of GSTs catalyze Phase II metabolism and inactivation of many anticancer agents, and thus is a major cause of tumor drug resistance. In addition, GSTs, in particular, GSTP1, are potent inhibitors of downstream signaling cascades, notably, the MAP kinases JNK, and thus decrease apoptotic response and enhance the ability of tumor cells to survive under hypoxic and other stress conditions.
Dr. Ali-Osmanís laboratory has been at the forefront of elucidating the molecular nature of these critical proteins. He was first to clone allelic variants of the GSTP1 gene and to demonstrate their functional differences, and thus provided the basis for a large body of research into the role of this gene in cancer. His current research is on the transcriptional and post-translational regulation of this gene and in defying its role in regulating cell signaling and suppression of apoptosis in tumor cells. Since coming to Duke, Dr. Ali-Osman completed a study in collaboration with Drs. Darell Bigner, Henry Friedman, James Herndon and Roger McLendon that demonstrated that the GSTP1C allelic variant and a deletion of the GSTT1 gene together were associated with worse survival in gliomas. These findings are being extended to examine interactions with these other genes.
A major recent focus of Dr. Ali-Osmanís research program is the rational discovery of novel anticancer therapeutics that are directed against the molecular and cellular defects in cancer, with a particular emphasis on CNS tumors. The approach combines structure-based computer modeling and high throughput screening of combinatorial libraries and focused chemical libraries, to identify agents with high affinity to relevant target proteins, block the action of these proteins, and exhibit antitumor activities. Leads are optimized by combinatorial chemistry, and candidates with potential for clinical activity are identified in vitro/in vivo efficacy studies. Using this approach, his group recently produced first-generation small molecules that target the electrophile-binding site of the GSTP1 protein and showed them to have significant antiglioma activity. Collaborations with Drs. Darell Bigner, David Reardon and Henry Friedman are a central part of these drug discovery activities and, since coming to Duke, Dr. Ali-Osman has established additional strong collaborations with Dr. Patrick Caseyís laboratory in these efforts.
Another major interest of Dr. Ali-Osmanís is in the elucidation of the molecular pathways, such as NER, BER, and MMR, involved in the repair of DNA lesions induced in the tumor cell genome by alkylating agents and free radical generators used clinically to treat brain and other human cancers. He is collaborating with Drs. Henry Friedman, Paul Modrich and Michael Colvin to define the mechanisms underlying the formation and repair of these lesions, their role of these as determinants of patient response to therapy and how to optimally target them as novel therapeutics and therapeutic strategies. Their studies on the DNA repair protein, O6-alkylguanine DNA alkyltransferase (AGT), have been critical to the development of more optimal clinical protocols for gliomas, such as those using the AGT inhibitor, O6-benzylguanine and the novel therapeutic agent, temozolomide (Temodar). Since coming to Duke, Dr. Ali-Osman has initiated collaborative efforts with the Institute for Genome Sciences and Policy on the pharmacogenomics of cancer therapy that are aimed at identifying and defining the role of functional naturally occurring polymorphisms, microdeletions and/or germline and somatic mutations in critical genes involved in tumor cell growth, progression, and therapeutic response.
Dr. Henry Friedmanís research efforts focus on an elucidation of the mechanisms of resistance to methylating agents, specifically temozolomide. Mechanisms under investigation include the role of mono-adduct repair by O6-alkylguanine-DNA alkyltransferase, DNA mismatch repair deficiency, and novel mechanisms such as base-excision repair or aberrant signaling of apoptosis.
An additional area of research is the mechanisms/pathways of repair of BCNU-induced DNA interstrand crosslinks. Work is focusing on nucleotide excision repair as the primary target.