Cancer Cell Biology Program
Steven Grant, M.D.
(804) 828-5211
stgrant@vcu.edu
Sarah Spiegel, Ph.D.
(804) 828-9762
sspiegel@vcu.edu
The central research objective of the Cancer Cell Biology Program is to discover novel therapeutic targets or modalities and translate these into clinical practice. Thus, one goal of the Program’s investigators involves defining key molecular mechanisms underlying cancer pathogenesis, including both genetic and epigenetic changes as well as alterations in signal transduction pathways, and determining the manner in which these mechanisms influence specific tumor phenotypes, such as cell division, differentiation, apoptosis, resistance to conventional therapies, induction of angiogenesis and metastasis. A second goal is then to identify novel targets in these cancer-specific pathways and establish a transition from preclinical studies in cell culture and animal models to clinical trials. Indeed, investigators in this Program have a strong record of translating their basic science into clinical practice, and the Program will continue to foster a collaborative scientific environment that encourages the successful translation of cancer therapy from the bench to the bedside.
Scientific objectives
The primary scientific objectives of the CCB Program are therefore:
- To identify key signaling pathways that are perturbed in cancer cells.
- To identify genetic and epigenetic changes that lead to transformation and contribute to the neoplastic phenotype.
- To understand the interactions between metabolites, proteins, genes and environment that affect tumorigenesis.
- To identify patterns of gene expression changes in tumor cells that have predictive or prognostic significance.
- Ultimately to identify potential therapeutic strategies based upon an understanding of cancer cell signaling and the genetic and epigenetic changes in cancer.
- To develop a rational basis for combining inhibitors of these targets with conventional agents or other targeted therapies.
Programmatic objectives
The main programmatic objectives of the CCB Program are:
- To enhance and strengthen research in the areas identified above.
- To identify potential areas of collaborative research within the CCB Program as well as with members of the other Massey Cancer Center programs.
- To foster an interactive scientific environment that facilitates the development of these collaborations.
- In particular, to encourage interactions and collaborations between basic science and clinical investigators to promote translation of knowledge into clinical practice.
- To ensure ready access of members to state-of-the-art technologies.
- To provide new opportunities for medical, graduate and postdoctoral students, as well as physician-scientists, in interdisciplinary cancer research.
The CCB Program has maintained a strong translational thrust, with the central goal of developing new therapeutic approaches to cancer treatment that act by modulating various signal transduction pathways to enhance either conventional or more novel cancer therapies. In the past decade, the approach to cancer therapy has been revolutionized by the identification of a variety of novel signal transduction targets amenable to therapeutic intervention. These targets were identified based on an improved understanding of the molecular mechanisms of action of second messengers and other components of signal transduction pathways.
A critical insight that has evolved is that disruption of such signaling pathways can be an extremely potent apoptotic stimulus in neoplastic cells. In particular, it has become apparent that simultaneous interruption of these signaling cascades may, in some cases, serve as a more effective initiator of cell death than conventional cytotoxic agents. An alternative approach that has become a focus of interest, and which is supported by considerable experimental evidence, is based on the concept that interruption of signal transduction or cell cycle regulatory pathways can synergize with and enhance the lethal actions of conventional chemotherapeutic drugs. With further identification of new targets and the development of pharmacologic and biologic inhibitors of signaling or cell cycle regulatory pathways, the number of such novel therapeutics deserving clinical evaluation will clearly increase.
Research components
The basic research component of the CCB Program includes strong research programs in various aspects of cell signaling and in cancer genetics and epigenetics, each having the long-range goal of identifying novel approaches for the treatment of cancer. Areas of particular strength include the role of bioactive lipid signaling in cancer cells, analysis of mechanisms regulating cell survival and apoptosis, the role of p53 mutation in tumorigenesis and tumor progression, telomeres and tumor cell senescence and epigenetic regulation of gene expression.
The clinical research component consists primarily of laboratory-based Phase I and Phase II trials focusing on the rational integration of novel agents into the therapeutic armamentarium. These initiatives fall into two major categories. The first involves efforts to employ inhibitors of survival signal transduction pathways to enhance the antitumor activity of more conventional cytotoxic agents. The second approach, which has become a major focus of interest among Massey Cancer Center investigators, stems from the laboratory-based hypothesis that tumor cells are ill-equipped to survive simultaneous interruption of multiple survival signaling or cell cycle regulatory pathways. This initiative has led to the development of a number of multi-institutional Phase I and II trials in which novel signal transduction inhibitors are combined in the treatment of various malignancies. These trials have involved patients with both solid tumors and hematologic malignancies. In each of these trials, the majority of which have been supported by CTEP/NCI, a major emphasis has been placed on the conduct of correlative laboratory studies to test the underlying hypotheses upon which the trials are based.
A large majority of investigators in the CCB Program have peer-reviewed funding support from cancer-related agencies. Their individual work is focused either on factors that directly contribute to the neoplastic phenotype, including those that determine response to treatment, or on fundamental cell control mechanisms essential for transformation. Several of these investigators have placed a primary emphasis on translating their research into the development of diagnostic and/or therapeutic clinical applications, particularly those whose research is focused on the molecular genetics of cancer or on growth factors and signal transduction. While some investigators working on fundamental regulatory mechanism have obtained funding from other agencies, all of them are involved in collaborative studies in cancer cell-specific processes. Although a primary goal of this Program is to translate basic research to clinical practice, it is also designed to illuminate fundamental cancer cell processes that can contribute to a better understanding of the transformed phenotype. Thus, investigators in the Program share a common interest in determining the underlying factors contributing to the neoplastic cell phenotype and in using this information to develop novel therapies for the successful diagnosis and treatment of cancer.
