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Laboratory of Molecular Pharmacology

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Overview

The main focus of the Laboratory of Molecular Pharmacology (LMP) is to explore possible connections between molecular biology alterations that drive malignant cell proliferation and potential avenues for therapy. To achieve this, LMP investigators (1) dissect the molecular interactions between effective anticancer drugs and their molecular targets; (2) identify novel genes and pathways that determine the occurrence of breast and colon cancers and their metastatic progression; (3) focus in molecular detail on chromatin, its abilities to duplicate itself and repair DNA damage, and its responses to chemotherapeutic agents. Particular targets of investigation include DNA topoisomerases, nucleosome roles in chromatin function, initiation of DNA replication, cell cycle checkpoints, centromere and kinetochore structure; (4) investigate the emerging importance of oxidant-mediated signaling in tumor growth and therapeutic response; and (5) integrate the growing knowledge of the molecular regulatory networks and genetic alterations of neoplastic cells to discover new drugs or therapeutic strategies and molecular markers that predict the response of individual tumors to particular drug therapies. The laboratory is organized into several research groups, each focusing on specific areas of interest:

- The study of topoisomerases, DNA repair and cell cycle checkpoints as targets of anticancer drugs (Yves Pommier) probes the mechanisms of action of drugs at the molecular level and compares new compounds to those that are presently used in cancer chemotherapy. Novel agents that target DNA or its activities such as replication, recombination, and repair are investigated. Human cancer cell lines are being characterized to determine the factors and genes that govern drug susceptibility. The biological roles of nuclear and mitochondrial topoisomerases are investigated with a focus on the mitochondrial topoisomerase (Top1mt).

- Investigations of genome integrity (William Bonner) include both basic and translational studies concerning DNA double-strand damage and its role in cancer formation, cancer treatment, aging, and degenerative diseases. Current research includes structural and functional studies on the phosphorylation of H2AX to form foci at sites of DNA double strand damage, translational studies on medical biodosimetric uses of H2AX phosphorylation, and studies of communication among cells during damage and disease processes.

- Analyses of DNA replication (Mirit Aladjem) focus on the molecular processes that deliver information from cell cycle regulators to the DNA duplex to insure accurate genome duplication. These studies aim to elucidate how normal and cancer cells regulate DNA replication since many regulatory feedback pathways that affect cell cycle are relaxed in cancer. Current studies combine biochemical and genetic analyses and whole genome mapping of replication initiation events to identify DNA sequences that are essential for initiation of DNA replication and probe into cellular regulators that interact with these sequences.

- Studies the structure of cancer-related genes (Vladimir Larionov) to understand why particular chromosomal regions are prone to generate genomic disorders and study the structure of centromeres whose function underlies proper chromosome segregation, which, when aberrant, leads to aneuploidy and polyploidy, which are hallmarks of many cancers. Construction of human artificial chromosomes (HACs) is actively pursued to study the functional organization of the human kinetochore and to develop novel vectors for gene function and therapeutic applications.

- Basic and translational research on the molecular biology and pharmacology of breast cancer (Patricia Steeg) with four major projects under investigation: (1) What is the role of the nm23 metastasis suppressor gene in breast cancer progression? (2) What molecular events are involved in breast cancer metastasis to the brain? (3) Develop model systems for the treatment of such breast cancer metastasis to the brain? (4) What molecular events are responsible for early neoplastic progression in the breast?

- Elucidate the role of oxidant-mediated signaling (James Doroshow) in growth factor- and drug-related inhibition of tumor cell proliferation with particular interest in the epithelial NADPH oxidase gene family and the development of novel small molecular inhibitors of these proteins.

- Studies of the integrated behavior of cell regulatory networks (Kurt Kohn) elucidate the relationship of the cellular networks/pathways and the cellular responses to chemotherapeutic agents and propose novel therapeutic strategies for cancer treatment and innovative drug associations.

- HIV integrase as a target of antiviral drugs (Yves Pommier) involves a search for novel inhibitors of this essential enzyme for retroviral replication, and determines the molecular interactions between inhibitors and HIV-1 integrase.

- The Genomics and Bioinformatics Group (managed by William Reinhold and Yves Pommier) explores relationships between the genetic makeup of malignant cells and their response to chemotherapeutic agents using multiple molecular databases at the DNA, RNA, protein levels, and drug responses for the 60 cell lines of the NCI Anticancer Drug Screen. Web-based electronic molecular interaction maps (eMIMs) (Kurt Kohn, Mirit Aladjem, Yves Pommier) are also developed in the group.

This page was last updated on 2/11/2013.