Message from the Chairman
The mission of the Department of Systems Biology is to translate our rapidly maturing understanding of the genetic and epigenetic defects that underlie the initiation and progression of cancer to improved patient management. The goal of the department is to provide an interface between the basic and clinical sciences at the MD Anderson Cancer Center facilitating this process.
The departmental mission will require an ability to link cancer genetics, molecular diagnostics, genomics, proteomics and signal transduction to molecular therapeutics and individualized patient care. Molecular Therapeutics provides a supportive environment for a programmatic approach by basic scientists, clinician scientists, clinicians, postdoctoral and clinical fellows, as well as graduate students. The research thrust is thoroughly integrated with the excellent basic, clinical and clinical research programs already in place at the MD Anderson Cancer Center, providing a resource for the institution. The department has been designated a Basic Science department emphasizing the role in translation between basic and clinical sciences.
Originally created as the Department of Molecular Oncology, the Department of Systems Biology currently consists of two sections:
- Molecular Therapeutics
- Cellular and Molecular Growth Regulation
The underlying principle of the Section of Molecular Therapeutics is that targeting the underlying defects and, particularly, signal transduction pathways in cancer cells will result in effective non-toxic molecular therapeutics which will improve the outcome in cancer patients. The recently recruited Dr. Francois-Xavier Claret and his visiting scientist, Dr. Rajasekhar Vinagolu, are investigating the role of JAB1 and phosphorylation of steroid receptors in tumorigenesis and in sensitivity / resistance to chemotherapy. Drs. Hong-Ji Xu, Lei Jiang and Jian-Ping Wang are applying the retinoblastoma tumor suppressor gene to gene therapy, evaluating its mechanism of action and have initiated studies aimed at identifying new tumor suppressor genes. These studies are currently in clinical trials using a truncated retinoblastoma gene in bladder cancer.
Drs. Gordon Mills, Yiling Lu, Xianjun Fang, Astrid Eder and Jon Wiener (adjunct assistant professor) concentrate on the molecular changes underlying epithelial ovarian cancer and breast cancer as well as on the regulation of T-lymphocyte activation. They have recently demonstrated that there are multiple genetic abnormalities in the phosphatidylinositol 3-kinase (PI3K) signaling cascade specific to ovarian, breast and head and neck cancers, suggesting that this pathway is a particularly important and attractive target for therapy in these cancers. They are investigating a number of commercially available and novel locally identified compounds at the preclinical and animal model stage. One of their earlier observations contributed to the development of a CTEP trial of rapamycin, which targets the PI3K pathway.
This group has also demonstrated that lysophosphatidic acid (LPA) and a number of related lysophospholipids are both therapeutic targets and potential early markers for ovarian and breast cancer. A series of lead compounds targeting specific LPA receptors have been identified. Importantly, a multicenter study to evaluate LPA as a diagnostic marker in ovarian cancer has just been initiated in collaboration with Atairgin Technologies. A similar study to evaluate a potential breast cancer diagnostic marker is under development.
This group also plays a major role, in collaboration with faculty members in the Department of Gynecological Oncology, in studying genomics, expression profiling and proteomics of ovarian cancer in collaboration with Millennium Pharmaceuticals. These studies have provided a major portion of the basic and translational science contributing to the recent funding of a SPORE in ovarian cancer and of an ongoing PPG in Ovarian Cancer. They were also critical for the funding of a U19 project on genetically identified high-risk individuals and a Congressionally mandated PO1 on chemoprevention of ovarian cancer. Dr. Nam Dang (cross-appointed from Lymphoma) is investigating the role of cell surface molecules on leukemia and lymphoma cells in preclinical and clinical models patient therapy. Dr. Zhen Fan (cross-appointed from Experimental Therapeutics) explores the role of the epidermal growth factor receptor family in the underlying mechanisms and molecular therapeutics of bowel and ovarian cancer.
The premise of the Section of Cellular and Molecular Growth Regulation, consisting of Drs. Jordan Gutterman and Valsala Haridas, is that plants have evolved to manufacture a wide variety of secondary metabolites that act as deterrents for dangerous predators. Many of the target pathways of these plant metabolites have been preserved in evolution from yeast to Drosophila to man and may be important constituents of the malignant phenotype.
Discovery of plant metabolites that interrupt critical pathways in a cancer cell should yield exciting new leads for drug discovery. This project is part of a collaboration with the University of Arizona (chemistry) and Boyce Thompson Plant Institute at Cornell University (plant biology). The major emphasis during the past 24 months has been on the biochemical and biological characterization of a triterpene glycoside with an unusual ester linkage obtained from a desert legume plant from Australia. This compound which has been purified to homogeneity induces cytotoxicity against a wide range of hematopoietic and solid tumor cell lines as well as freshly isolated ovarian cancer cells. It is minimally cytotoxic in vitro against nontransformed cells. In vivo, the compound is extremely active in two chemopreventive models: the initiation and promotion phases of the murine dimethylbenzanthracene (DMBA) mouse skin carcinogenesis model as well as the rat aberrant colonic crypt assay. The mechanism of action is being investigated and focuses on the induction of apoptosis.
The apoptotic process is related to changes in mitochondrial function as well as inhibition of the PI3K pathway. The plant triterpenoid also has potent in vitro and in vivo anti-inflammatory effects and appears to inhibit activation of NF-kappaB. Present and future work in cellular and molecular growth regulation includes the complete purification and structural characterization of the triterpene glycoside, metabolic labeling studies, continued work on mechanism of action (including effects on endothelial cells, angiogenesis and cholesterol metabolism) and genetic studies of sensitive and resistant cells by RNA analysis on microarrays and DNA chips.