Myrna R. Rosenfeld - US grants

Patients with antibody associated paraneoplastic neurologic syndromes make a profound immune response against their tumor, which cross-reacts with the nervous system and may result in neurological dysfunction. These patients provide the opportunity to study the mechanisms of the anti-tumor immune response and to elucidate the structure and function of human tumor antigens. This application focuses on the paraneoplastic syndrome, Lambert-Eaton myasthenic syndrome (LEMS). LEMS is a disorder of neuromuscular function found in high association with small cell lung cancer. Preliminary studies have resulted in the cloning of two proteins which are highly homologous to the beta subunit of the voltage gated calcium channel. These proteins are likely to represent the target of the immune response in LEMS. Studies are proposed to investigate why patients with antibody associated paraneoplastic diseases mount such a profound immune response against their tumor and how this immune response results in the disruption of neuromuscular and brain dysfunction. Experiments will focus on establishing any structural or functional differences between tumor and normal cell proteins. Cloned antigens will be characterized by DNA sequence analysis. The expression of these antigens in normal and neoplastic tissue will be studied as well as the expression of other tumor proteins that may influence the development of the immune response (i.e., MHC-I). The role of the (3 subunit in calcium channel function and the effect of LEMS IgG on this function will be examined. Of direct clinical relevance will be the development of a specific and sensitive serologic test for LEMS.

DESCRIPTION: (Applicant's Description) The primary long-term objective of this proposal is to improve the therapeutic outcome for adults with primary brain tumors. This will be accomplished by P h a se 1/11 clinical evaluations of promising new agents, biological a p proaches, and roots of administration in the treatment of primary malignancies of the central nervous system through the establishment of the consortium. This consortium is specifically designed to combine and focus experienced resources and capabilities of thirteen Outstanding medical institutions to bear on primary brain tumors. To meet this objective, the consortium will rely on the special strength and abilities that rest within each participating institution and within the consortium as a whole. The University of Pennsylvania Medical Center has 1) a large number of adult patients with primary brain tumors, 2) expert Mult-disciplinary clinical teams to care for these patients, 3) extensive clinical and laboratory researchers, 4) a striking number of on-going high quality, clinically relevant, peer reviewed and NIH funded clinical and laboratory brain tumor research projects, 5) nationally recognized expertise in Oncology, Pharmacology, new drug development, Phase I/II clinical trials, Neurosurgery, and Neuropathology, 6) extensive statistics, data management, and coordination of multi-institutional studies, and 7) exceptional reputation for excellence in clinical care and research. The consortium adds these strengths with a well defined and smoothly functioning organizational structure, and emphasis on clinical trial design, protocol development, quality control, study monitoring and data management and analysis. The secondary long-term objective of this protocol is to use this consortium to share human brain tumor specimens as well as other clinical and laboratory data to collect additional research pertaining to 1) the basic biology of primary brain tumors, 2) the Neuropharmacology of new therapies for primary brain tumors, and 3) improving the care and quality of life of adults with primary brain tumors. This objective will be reached using the strengths of the participating institutions and the NABTT correlative biology research center, the NABTT pharmacology center, and the NABTT working in scientific committees.

neoplasm /cancer chemotherapy; glioma; protease inhibitor; drug screening /evaluation; antineoplastics; pharmacokinetics; anticonvulsants; neoplasm /cancer relapse /recurrence; drug interactions; drug metabolism; enzyme induction /repression; cytochrome P450; patient oriented research; clinical research; human subject;

human therapy evaluation; neoplasm /cancer chemotherapy; drug screening /evaluation; glioblastoma multiforme; antineoplastics; clinical trial phase II; clinical trial phase I; pyrazoles; acridines; pharmacokinetics; enzyme inhibitors; mutagens; DNA topoisomerases; patient oriented research; human subject; clinical research;