Isaiah J. Fidler, D.V.M., Ph.D.

R. E. “Bob” Smith Distinguished Chair in Cell Biology
Professor of Cancer Biology and Urology
Director, Cancer Metastasis Research Center
Operational Director, Smith Research Building

Research in my laboratory continues to focus on the biology and therapy of cancer metastasis. The outcome of cancer metastasis depends on the continuous interaction of unique tumor cells with the host-organ microenvironment. For example, prostate cancer metastases are most commonly found in bone, where their growth rate exceeds that observed for primary tumors. The expansion of bone metastases, however, is dependent on vascular supply, i.e., angiogenesis. The onset of angiogenesis involves a change in the local equilibrium between positive and negative regulatory molecules.
The platelet-derived growth factor (PDGF) is a major stimulator of cancer cell division and survival. The PDGF-receptor (PDGF-R) is a member of the family of protein tyrosine kinases that includes many oncogenes and protooncogenes. PDGF is a potent mitogen of both normal and tumor cells. Coexpression of PDGF and its receptors is found in many human carcinomas, including those of the stomach, pancreas, lung and prostate. The binding of PDGF to its receptor can stimulate cell division, migration and angiogenesis. Moreover, activation of PDGF-R has been shown to inhibit some apoptotic pathways in normal and tumor cells. Hence, inhibition of PDGF-R activity can lead to a decrease in cell proliferation and an increase in cell death.

STI571 (Imatinib mesylate, Gleevec), a derivative of 2-phenylaminopyrimidine, is a potent tyrosine kinase inhibitor of c-KIT and the PDGF-R tyrosine kinases inhibiting cell proliferation and inducing cell death. Since PDGF and PDGF-R play a critical role in the osteotropism of human prostate cancer cells, we determined whether oral administration of STI571 (alone or in combination with injectable taxol) to nude mice with human prostate cancer cells growing in the bones will produce regression of prostate cancer bone and lymph node metastases. Treatment of mice with STI571 and taxol produced a significant decrease in the number of dividing tumor cells in bone lesions. PDGF is known to depolymerize microtubules during the initiation of DNA synthesis and cell division. STI571 inhibits PDGF-mediated receptor phosphorylation and hence stabilizes microtubules in the target cells, a process similar to the mechanism of action of taxol, i.e., lowering the critical concentration of tubulin monomers for polymerization and promotion of tubulin assembly into distinct microtubule bundles with stability against depolymerization.

Immunohistochemical analysis of tumor cells growing in the bone concluded that cells growing adjacent to the bone express the PDGF ligand and the PDGF-R. Moreover, endothelial cells with PDGF+ lesions expressed activated PDGF-R, whereas endothelial cells in uninvolved bone did not express PDGF-R. Therapy with STI571 therefore is not toxic to endothelial cells in normal, uninvolved organs. The translation of these findings to the clinical reality is currently underway.

Patients with prostate cancer bone metastases that are androgen-insensitive are treated with chemotherapeutic agents, e.g., taxol or taxotere. In most patients, however, the tumors develop resistance to the drugs, and the tumors then progress to the demise of the patients. Our colleagues at the MD Anderson Cancer Center, Department of Medical Urological Oncology, have placed several patients into a compassionate IND to receive oral STI571 and injectable taxotere (at a reduced dose). In all evaluable patients, the level of serum PSA decreased significantly, and in patients treated for at least six months, the response has been dramatic, recommending a multi-institutional phase III trial which is now underway.

Colin P. N. Dinney, M.D.

Professor of Urology
Professor of Cancer Biology

I will continue my research into the regulation of bladder cancer metastasis by EGFR signaling pathways in collaboration with Drs. Menashe Bar-Eli and David McConkey of Cancer Biology. Together with Drs. David McConkey of Cancer Biology and Randall Millikan of GU Medical Oncology, I am evaluating the role for interferon therapy for bladder cancer, and specifically how interferon modifies death receptor expression. We are also collaborating on studies to develop proteasome inhibitors as therapy for metastatic bladder cancer. As part of collaboration with Dr. William Benedict of GU Medical Oncology and and Dr. Liana Adam of Urology, I am evaluating the development of interferon gene therapy for superficial bladder cancer. This will be translated into a clinical trial of adenoviral mediated interferon gene therapy.

Lee M. Ellis, M.D.

Professor of Cancer Biology
Chair ad interim, Department of Cancer Biology
Professor of Surgery
William C. Liedtke, Jr., Chair in Cancer Research

The overall goal of our laboratory is to investigate mechanisms of tumor growth and metastasis of gastrointestinal (GI) malignancies with a focus on angiogenesis. The primary tumor system under study in our laboratory is metastatic colorectal cancer, although we also study other tumor types including pancreatic adenocarcinoma, gastric cancer and carcinoid tumors.

For the past 14 years, our laboratory has investigated the role of VEGF in tumor growth, metastasis and angiogenesis. We have recently focused our efforts on determining the role of VEGF receptors on tumor cells. We are currently investigating the role of VEGF receptor-1, neuropilin-1 and neuropilin-2 on colon cancer cells. Investigations in these areas may help elucidate mechanisms of action of anti-VEGF therapy, which is currently approved for several tumor types by the FDA for patients with metastatic disease. In addition, we are currently investigating angiogenic mechanisms in specific organs relevant to colon cancer metastasis.
Continuing along our translational themes, we are also investigating mechanisms of resistance to standard chemotherapy for colon cancer. We have established chemotherapy resistant colon cancer and gastric cancer cell lines. Initial investigations demonstrated that oxaliplatin resistant colon cancer cells led to epithelial to mesenchymal transition (EMT).

Although targeted therapy for GI malignancies has demonstrated promise in clinical trials, we strongly believe that it is important to validate new targets for the next generation of anti-neoplastic regimens. We are also investigating the role of cancer stem cells in chemoresistance. Lastly, we have developed a number of neuroendocrine tumor cell lines in order to develop targeted therapies or metastatic carcinoid tumors.

Roy S. Herbst, M.D.

Associate Professor of Medicine
Associate Professor of Cancer Biology

My research focus is on the diagnosis and treatment of lung cancers, and my research program is focused on the biology and therapy of lung cancer metastasis. Formally a physician-scientist under the co-mentorship of Dr. Waun Ki Hong and Dr. Isaiah J. Fidler, I have worked to develop a clinical/translational research program designed to test new therapies preclinically and then rapidly introduce them to the clinic to be studied in a scientific fashion using surrogate endpoints of tissue biopsy and imaging studies. We have now developed and perfected a working orthotopic model of human lung cancer (adenocarcinoma, squamous and small cell), which we are using to study the effects (both at the macroscopic and molecular level) of several compounds, which could impact lung cancer therapy, including PKI-166 (and EGFR antagonist), ZD6474, and STI-571 (an inhibitor of CKIT and the PDGF receptor), working in close collaboration with the laboratory of Dr. Michael S. O’Reilly.

Molecular studies on tissue specimens have demonstrated a biologic effect of these agents. In addition, during this year, we have begun to utilize our large clinical and pathologic database (including the lung SPORE program) to analyze molecular pathologic markers in human cancer tissues with the full collaboration of Dr. Cesar Moran and the Department of Pathology.

Curtis A. Pettaway, M.D.

Associate Professor of Urology
Associate Professor of Cancer Biology

The theme of my research is to define the molecular phenotype of advanced/metastatic prostate cancer in animal models and patient specimens of prostate cancer. The studies performed over the past year build upon our knowledge gained in characterizing the molecular events associated with prostate cancer progression in an orthotopic mouse model of human prostate cancer progression. Expression of matrix metalloproteinases, vascular endothelial growth factor E-cadherin and several other genes have been evaluated in radical prostatectomy specimens and found to be highly associated with advanced prostate cancer, subsequent to radical prostatectomy. Over the past year, we have evaluated the expression of two other genes associated with angiogenesis, basic fibroblast growth factor (bFGF) and interleukin-8 (IL-8). We have correlated expression with Gleason sum and pathologic stage and found a significant association in the case of IL-8 but not bFGF. A preliminary study has also been completed comparing the expression of MMP-2, MMP-9 and E-cadherin expression in prostate biopsies with their corresponding expression in the radical prostatectomy specimens. We have found that the correlation is good and that biopsy gene expression could enhance the prediction of pathologic stage compared with Gleason score, clinical stage, or serum prostate specific antigen (PSA) levels. We are currently evaluating racial variation in the expression of these same genes.

A second project has studied the functional effects of overexpression of prostate specific antigen in human prostate carcinoma cells over the past year. Overexpression of PSA subsequent to transfection resulted in enhanced tumor growth but not metastasis. This effect was correlated with a higher proliferative index in cells with high PSA expression. A third project is related to exploring the role of Bcl-2 in androgen independent prostate cancer cell proliferation. We have shown over the past year that Bcl-2 contributes to androgen independent proliferation in LNCaP cells by enhancing the transcriptional activity of androgen-regulated genes. Thus, we describe a novel function for Bcl-2 in prostate cancer progression.