MABS SPECIFIC TO HUMAN TUMOR SUPPRESSOR PROTEIN P53

RECENT EVIDENCE SUGGESTS THAT MUTATIONAL INACTIVATION OF SPECIFIC "TUMOR SUPPRESSOR" GENES CONTRIBUTED TO THE FORMATION OF SEVERAL HUMAN CANCER TYPES INCLUDING RETINOBLASTOMA (RB), OSTEOSARCOMA, SMALL CELL LUNG CARCINOMA, AND ADENOCARCINOMAS OF BREAST AND COLON. THE TUMOR SUPPRESSOR GENES, RB, P53, AND DCC HAVE BEEN CLONED. THE P53 GENE WAS ORIGINALLY THOUGHT TO BE A DOMINANT ONCOGENE. HOWEVER, RECENT DATA SUGGEST THAT P53 IS A TUMOR SUPPRESSOR GENE. MANY PROPERTIES OF P53 PROTEIN ARE SIMILAR TO THOSE OF THE PROTOTYPE TUMOR SUPPRESSOR RB PROTEIN. WE HAVE RECENTLY DEVELOPED ANTI-RB MAB-BASED IMMUNOASSAYS TO STUDY RB PROTEIN EXPRESSION IN HUMAN OSTEOSARCOMAS AND OTHER SOFT-TISSUE SARCOMAS. OUR RESULTS REVEAL THAT THE ABSENCE OF RB PROTEIN IN THESE TUMORS MAY HAVE A SIGNIFICANT PROGNOSTIC VALUE. THE PRIMARY GOAL OF THIS PROJECT IS TO PRODUCE A PANEL OF MABS AGAINST DISTINCT EPITOPES OF THE HUMAN P53 PROTEIN. THESE MABS WILL BE USED IN THE DEVELOPMENT OF SENSITIVE AND SPECIFIC IMMUNOASSAYS FOR P53-RELATED CANCERS. THESE MABS WILL ALSO BE USEFUL FOR ASSESSING THE FUNCTION OF THE P53 PROTEIN IN HUMAN NEOPLASIA. THE SPECIFIC AIMS OF THIS PROPOSAL ARE: 1) TO GENERATE A PANEL OF MABS RECOGNIZING DISTINCT EPITOPES OF HUMAN P53 PROTEINS; 2) TO ISOLATE THE AUTHENTIC HUMAN P53 PROTEINS; 3) TO CHARACTERIZE THE EPITOPES RECOGNIZED BY HUMAN P53-SPECIFIC MABS; AND 4) TO DEVELOP SENSITIVE AND SPECIFIC IMMUNOASSAYS FOR P53-RELATED CANCER DIAGNOSIS. THE KNOWLEDGE DERIVED AND THE TEST(S) DEVELOPED FROM THESE MABS WILL BE VERY IMPORTANT FOR PHASE II CLINICAL APPLICATIONS SUCH AS PROSPECTIVE OR PROGNOSTIC STUDIES.