Two major clinical problems in patients with malignancies include: (1) resistance of their tumors to antineoplastic agents and (2) continued progression of their tumors (local invasion and metastases). The mechanism(s) by which these problems arise are incompletely understood. The program outlined proposes to develop a model which can be used to study both of these clinical problems. The proposed model is based on strong preliminary evidence that one way tumors develop, progress and become resistant to antineoplastic agents is through a unique mechanism for diversification of their genome. This mechanism involves excision of pieces of genomic DNA which may contain oncogenes or drug resistance genes and an origin of DNA replication. These circular molecules (episomes), when amplified may contribute to tumor progression (if the amplified gene is an oncogene) or to drug resistance (if the amplified gene is a drug resistance gene).
The specific aims of this proposal include: 1) Optimization of the methods for isolating episomes from tumor cell lines and from primary and metastatic human tumors. 2) Determination of methods to eliminate these episomes or other extrachromosomally amplified sequences from tumor cells. 3) Basic studies of the mechanisms by which currently used treatments (chemotherapy) induce episome formation. The team which has been brought together to accomplish these objectives is composed of basic and clinical scientists. We have limited the proposal to the Salk Institute, where the molecular biology expertise is centered (Dr. Wahl) and the University of Texas where there is expertise in clinical research and episome analysis in primary human tumors (Dr. Von Hoff). This proposal is a natural extension of projects which were developed during the sabbatical year spent by Dr. Von Hoff in Dr. Wahl's laboratory. With the development of the models outlined here, a clearer understanding of the mechanisms of tumor progression and drug resistance should emerge and result in new therapeutic approaches which can be rapidly applied to clinical oncology situations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA048405-01
Application #
3549165
Study Section
(SRC)
Project Start
1988-08-01
Project End
1991-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Wahl, G M (2006) Mouse bites dogma: how mouse models are changing our views of how P53 is regulated in vivo. Cell Death Differ 13:973-83
Aladjem, Mirit I; Rodewald, Luo Wei; Lin, Chii Mai et al. (2002) Replication initiation patterns in the beta-globin loci of totipotent and differentiated murine cells: evidence for multiple initiation regions. Mol Cell Biol 22:442-52
Raymond, E; Faivre, S; Weiss, G et al. (2001) Effects of hydroxyurea on extrachromosomal DNA in patients with advanced ovarian carcinomas. Clin Cancer Res 7:1171-80
Aladjem, M I; Rodewald, L W; Kolman, J L et al. (1998) Genetic dissection of a mammalian replicator in the human beta-globin locus. Science 281:1005-9
Aladjem, M I; Spike, B T; Rodewald, L W et al. (1998) ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. Curr Biol 8:145-55
Aladjem, M I; Brody, L L; O'Gorman, S et al. (1997) Positive selection of FLP-mediated unequal sister chromatid exchange products in mammalian cells. Mol Cell Biol 17:857-61
Aladjem, M I; Wahl, G M (1997) Mapping replication fork direction by leading strand analysis. Methods 13:281-92
Van Den Berg, C; Guan, X Y; Von Hoff, D et al. (1995) DNA sequence amplification in human prostate cancer identified by chromosome microdissection: potential prognostic implications. Clin Cancer Res 1:11-8
Van den Berg, C L; McGill, J R; Kuhn, J G et al. (1994) Pharmacokinetics of hydroxyurea in nude mice. Anticancer Drugs 5:573-8
Nonet, G H; Wahl, G M (1993) Introduction of YACs containing a putative mammalian replication origin into mammalian cells can generate structures that replicate autonomously. Somat Cell Mol Genet 19:171-92

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