DISCONTINUED A. CDKN2 alterations commonly occur in lung cancer. A potential therapeutic approach targeting tumor cells with such lesion is the development of pharmacologic agents that might mimic the cdk4:cyclin D kinase inhibitory activity of the CDKN2 gene product (p16INK4A). Agents with in vitro CDK4:cyclin D kinase inhibitory activity have been identified by correlation of the CDKN2 status of the 60 cell lines of the NCI drug screen program with growth inhibitory activity. Further characterization of these agents demonstrates that these agents fall into 2 categories: ATP-competitive agents and p16-like inhibitors. A structure-activity relationship of one compound has further defined the requirements for inhibition. """"""""B. Genetic linkage analysis of a kindred predisposed to the development of the rare neoplasm, chordoma, has been initiated to determine if the genetic alteration associated with this rare cancer syndrome is also altered in common, sporadically-occurring tumors, such as lung cancer. Using the program SIMLINK, there is a significant probability of establishing linkage using this kindred. A genome screen for linkage using 342 autosomal STR polymorphic markers at an average spacing of 10 cM has identified four regions (each ~30 cM) of potential linkage with lod scores of ~1.5. Two of these regions are on chromosome 1 and one each on chromosome 17 & 19. Further markers from each of these regions at an average spacing of 2 cM is underway. No loss of heterozygosity in any of these areas was found among three tumor cell lines from members of this kindred."""""""" """"""""C. A cyclophilin-like gene, tentatively named PPIE, found to be near the MYCL1 gene on chromosome 1p and co-amplified frequently with MYCL1 in SCLC cell lines, has a potential RNA binding domain in its N-terminus and alternative splicing of the C-terminus. There is evolutionary conservation of PPIE and differential mRNA expression in human tissues with highest levels found in muscle and brain. Radiation hybrid mapping suggests that a gene order of RLF-PPIE-MYCL1. All 3 genes co-localize to a single 800 kb MluI fragment by pulse-field gel electrophoresis.""""""""
