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Thoracic Oncology Section
Division of Clinical Sciences
Surgery Branch
CLINICAL STAFF
Dr. David S. Schrump graduated from the University of Connecticut School of Medicine and completed his General Surgery Residency at the University of Chicago as well as a three-year research fellowship in Human Cancer Immunology at Memorial Sloan-Kettering Cancer Center. Following completion of his Thoracic Surgery residency at the University of Michigan in 1993, Dr. Schrump was appointed Assistant Professor of Thoracic Surgery at the M.D. Anderson Cancer Center, where he gained expertise in the molecular biology and clinical management of thoracic malignancies. In 1997, he was appointed Head of Thoracic Oncology Section, Surgery Branch, National Cancer Institute, National Institutes of Health. Dr. Schrump is a Fellow of the American College of Surgeons, and an active member of the Society of Thoracic Surgeons, American Joint Committee on Cancer, American Association for Cancer Research, and the International Association for the Study of Lung Cancer.
Dr. Dao M. Nguyen obtained his Medical Degree from McGill University in 1986, and completed the General Surgery and Cardiothoracic Surgery Residency Training programs at McGill in 1992, and 1994, respectively. He obtained a Master's Degree in Experimental Surgery at the same institution in 1993. He also completed a 2-year post-residency research/clinical fellowship in Thoracic Surgical Oncology at M.D. Anderson Cancer Center where he studied vector development and p53 tumor suppressor gene therapy for non-small cell lung cancer. He returned to McGill University as an Assistant Professor of Surgery in 1996, and was recruited to the NCI Surgery Branch in 1998. He is board-certified in general surgery and thoracic surgery. He is a fellow of the Royal College of Physicians and Surgeons of Canada and a member of the Society of Thoracic Surgeons, the American Association for Cancer Research, and the Associate Group of the American College of Surgeons.
Ms. Jean A. Tretler received a Bachelor of Science degree from the State University of New York in 1983, and received a Bachelor of Science in Nursing from The Catholic University of America in 1992. She then completed a one year training program in oncology nursing at the National Cancer Institute. After six years of clinical oncology nursing at the National Institutes of Health, she was appointed Research Nurse Specialist, NCI Surgery Branch, to coordinate clinical protocols in the Thoracic Oncology Section.
CURRENT RESEARCH EFFORTS
The inability of current treatment modalities to alter the natural history of lung and esophageal cancers, together with the prevalence of these malignancies, underscores the need for more fundamental appreciation of molecular mechanisms of aerodigestive tract carcinogenesis. In previous studies we have utilized recombinant viral vectors to demonstrate the impact of restoration of cyclin D1 p16, and p53 expression in lung and esophageal cancer cells. These mutations, which disrupt Gl Restriction Point control are known to occur early during multistep aerodigestive tract carcinogenesis, hence they are appropriate targets for intervention in established malignancies as well as their precursor lesions.
Although gene therapy is a major focus of our laboratory work, recent efforts have been devoted to the evaluation of pharmacologic agents which might achieve molecular end points without the complexities and limitations of gene therapy mediated by viral vectors. We have observed that the synthetic flavone, flavopiridol, induces profound cell cycle arrest and apoptosis in esophageal cancer cells irrespective of histology or tumor suppressor gene status, and markedly enhances their sensitivity to paclitaxel. These data have provided the rationale for the evaluation of flavopiridol in conjunction with paclitaxel in esophageal cancer patients.
Approximately 30% of lung and esophageal cancers overexpress the erbB-2/p185 oncogene which is believed to mediate resistance to chemotherapeutic agents such as cisplatin or paclitaxel. Recently, we have observed rapid, dose-dependent depletion of p185 protein in lung and esophageal cancer cells treated with the ansamycin analogue 17-allylamino geldanamycin (17-AAGA). Reduction of p185 expression by 17-AAGA markedly enhances paclitaxel-mediated cytotoxicity in these cells. These preclinical data support the evaluation of 17-AAGA in combination with paclitaxel in patients with thoracic neoplasms.
In additional studies we have attempted to utilize novel demethylating agents and histone deacetylase inhibitors to induce expression of tumor suppressor genes such as p16 and ARF which are frequently inactivated by promoter hypermethylation in thoracic neoplasms. Interestingly, these experiments have converged with parallel studies in our laboratory demonstrating induction of NY-ESO-1 and MAGE-3 cancer-testis antigen expression in lung cancer cells by 5 Aza-2' deoxycytidine (decitabine). Our studies have shown that cancer testis antigen expression is more readily induced in lung cancer cells relative to normal human bronchial epithelial cells, fibroblasts, or EBV transformed lymphocytes. Exposure of lung cancer cells to decitabine facilitates their recognition by cytolytic T cells specific for NY-ESO-1. Additional studies have shown that the histone deacetylase inhibitor, depsipeptide, exhibits significant toxicity in lung cancer cells, and enhances the effects of decitabine in these cells; we have observed similar results in esophageal cancer and malignant pleural mesothelioma cells. Thus, sequential decitabine/depsipeptide treatment may be a novel strategy to simultaneously induce growth arrest and apoptosis in thoracic malignancies, and augment antitumor immunity in patients with these neoplasms.
Nearly 20% of all cancer patients succumb to isolated pulmonary metastases, and additional efforts in our Section have been directed toward the evaluation of regional drug delivery to the lungs. A sheep model of isolated lung perfusion (ILuP) has been established, and pharmacokinetics of paclitaxel administered by ILuP have been characterized. Additional studies have shown that moderate hyperthermia (39.5° C) markedly enhances paclitaxel-mediated toxicity in cancer cells, but not normal bronchial epithelial cells. These preclinical experiments have provided the rationale for analysis of isolated lung perfusion utilizing paclitaxel and moderate hyperthermia in patients with unresectable pulmonary malignancies. Additional efforts have been devoted to the evaluation of chemotherapeutic agents administered by novel inhalation techniques. Preclinical studies have revealed pronounced uptake of drug into the lungs with negligible systemic toxicity in dogs with spontaneous lung cancers or pulmonary metastases.
The following clinical protocols submitted by the Thoracic Oncology Section are open or expected to be open for patient accrual in the near future:
Information regarding eligibility criteria for these trials can be obtained by calling 301-496-2127, or visiting our website at http://cancernet.nci.nih.gov/trialsrch.shtml
NATIONAL CANCER INSTITUTE
January 2000