Molecular Cancer Therapeutics
Richard Moran, Ph.D.
(804) 828-5783
rmoran@vcu.edu
John D. Roberts, M.D.
(804) 628-1940
jdrobert@vcu.edu
Scientific goals
The underlying theme of the Molecular Cancer Therapeutics Program is to apply the tools of structural and chemical biology to an understanding of key macromolecules that are proven or potential targets for therapeutic intervention and to apply molecular and cellular approaches to analysis of the mechanism of existing therapeutic agents. The membership of the MCT program have in common the use of pharmacologic and structural tools to perform analysis of pathways intrinsic to cancer therapeutics, including energy metabolism, angiogenesis, receptor-mediated signaling, apoptosis, folate enzymology, DNA interstrand crosslinks, transcription factor interactions, epigenetics and transcriptional interference. As would be expected, the research projects pursued by the membership are heavily interactive with investigators in the Cancer Cell Biology, Radiation Biology and Oncology, and Immune Mechanism programs.
The main scientific goals of the members of the MCT Program are:
- Understanding the mechanisms of small molecular weight drugs on processes required for the proliferation and survival of cancer cells.
- Searching for new classes of drugs that affect survival of tumor cells by fundamentally new mechanisms.
- Studying the structure of macromolecules that represent current targets or potential targets for therapeutic intervention.
- Studying the basic phenomena that limit the response of tumor cells to drugs.
Program objectives
The programmatic goals of the MCT Program are to:
- Enable research in program members’ laboratories by discussion, interactions and easing access to research infrastructure.
- Foster collaborative interactions and maintain a framework in which collaborations happen.
- Furnish a hub of activity in structural biology, molecular modeling and chemical biology in cancer research and allow access of members of other programs within the cancer center to the approaches offered by these disciplines.
- Recognize the potential for collaborative interactions within the MCT Program and with members of the other programs of the Massey Cancer Center and facilitate the initiation of such collaborative interactions.
- Furnish an environment in which the careers of graduate students, M.D./Ph.D. students and postdoctoral fellows are nurtured and in which they are brought into contact with all phases of cancer research during their studies.
Research focus
The MCT Program has three overlapping areas of focus: new drug and target discovery, molecular analysis of the biology of existing drugs, and structural biology. The MCT Program has evolved from a program previously organized as a developmental therapeutics program as emphasis turned from empirically developed cytotoxic drugs to agents selected and developed by structure-based drug discovery and by molecular analysis of the effects of cancer genotypes on sensitivity to classes of agents. The MCT Program has served as a focal point for studies that are more chemical and pharmacological in nature and that have increasingly been aimed at discovery of potential targets at an earlier stage of development.
During the past half decade, the human and mouse genomes have been sequenced, as have the genomes of several species central to our current understanding of the principles of life. The impact of this genome data on how we view cancer has been immense, and we are currently in a transition phase during which we are learning how to best use the information. As a result of the genome projects, the emphasis of basic research in cancer has changed from cloning and sequencing unknown genes to understanding the functions of sequenced genes and to understanding how these functions interact to form networks of carefully controlled processes and of interactions between macromolecules.
Eight of the laboratories in Massey’s MCT Program focus on the structures of proteins and nucleic acids and how these structures dictate function. These laboratories have formed one focus group of the MCT Program. Structural information comes from three approaches: X-ray crystallography, high field multidimensional nuclear magnetic resonance and molecular modeling/computational chemistry; all of these disciplines are represented in the MCT Program. The more recent designs of mass spectrometers also add a new dimension to the research at the Massey Cancer Center by giving information on what proteins are involved in functional complexes and whether and how these proteins are modified after protein synthesis. All four of these approaches are used by MCT Program member-scientists in their attempts to understand the biochemical and biological behavior of components of the malignant cell.
The structure of a protein can be very helpful in understanding how it works, and it can also give a direct route to the design and synthesis of small molecules or peptides that are inhibitors of protein function. As we come to understand the cellular control features that are lost by mutation, epigenetic silencing or physical loss of tumor suppressor genes from the human genome, and the mutations that activate cancer-causing genes (oncogenes), targets of therapeutic potential are suggested. Drugs aimed against these targets offer tremendous hope of being selective for tumor cells by virtue of the fact that they are directly involved in causing the malignant behavior of the human cancers. The challenge has been to recognize which of the proteins that are mutated in cancers maintain the behavior of the cancer cell and to select those specific proteins for drug design. The selection of new drug targets is an integral part of the activities in the MCT Program, as is the study of the properties of drugs currently used in clinical care.
A major purpose of the Program has been to link structure and function of proteins and other macromolecules essential for tumor development and, when appropriate, to put this information to use for therapeutic purposes. More recently, the Program’s membership has incorporated the emergent discipline of chemical biology as an exciting and essential part of the mission of this Program. Chemical biology involves applying chemical principles as investigative tools in biology, and often uses small molecular weight libraries of compounds as probes of biological processes. One of the offshoots of such studies is the identification of lead compounds for new drug design.
The recruitment of six new investigators to the MCT Program has resulted in a focused enhancement of our capabilities in angiogenesis and angiopoietin-receptor interactions, cancer drug discovery, Toll-like receptors, chemical library development and screening, and transcription factor complexes as therapeutic targets — all topics of great interest in current cancer research. The investigators of the MCT Program have been key to the development of infrastructure in X-ray crystallography, high-field NMR and modeling as well as the application of these technologies for cancer-related projects in the Cancer Center.
