Abstract

This Project will focus on the development of a robust mouse model in which drugs used clinically in organ transplant patients enhance cutaneous non-melanoma skin carcinogenesis. To develop this model we first will identify combinations of mouse strains, anti-rejection drugs, and ultraviolet radiation in which drugs and UV synergize in enhancing growth of transplanted immunogenic tumor cells. Such synergistic combinations then will be tested in long-term photocarcinogenesis studies to identify combinations in which drugs enhance this process. Since transplant patients nearly always have HPV infections, we also will assess such combinations in K14-HPV16 transgenic mice. Mechanisms by which the drugs enhance carcinogenesis will be assessed first with an integrated and comprehensive series of studies of the effects of these drugs on DNA repair. In addition, the role of drug-induced immunosuppression will be assessed in mice of the standard model which additionally have been made genetically immunodeficient by breeding in of the TCR delta or RAG2 knockout alleles. The effects of rapamycin also will be compared with those of more traditional anti-rejection drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
1P01AR050440-01
Application #
6824693
Study Section
Special Emphasis Panel (ZAR1)
Project Start
2003-09-26
Project End
2008-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2003
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Fleming, Jessica L; Dworkin, Amy M; Allain, Dawn C et al. (2014) Allele-specific imbalance mapping identifies HDAC9 as a candidate gene for cutaneous squamous cell carcinoma. Int J Cancer 134:244-8
Kang, Hio Chung; Quigley, David A; Kim, Il-Jin et al. (2013) Multiple self-healing squamous epithelioma (MSSE): rare variants in an adjacent region of chromosome 9q22.3 to known TGFBR1 mutations suggest a digenic or multilocus etiology. J Invest Dermatol 133:1907-10
Kang, Hio Chung; Wakabayashi, Yuichi; Jen, Kuang-Yu et al. (2013) Ptch1 overexpression drives skin carcinogenesis and developmental defects in K14Ptch(FVB) mice. J Invest Dermatol 133:1311-20
Akhurst, Rosemary J; Hata, Akiko (2012) Targeting the TGF? signalling pathway in disease. Nat Rev Drug Discov 11:790-811
Durinck, Steffen; Ho, Christine; Wang, Nicholas J et al. (2011) Temporal dissection of tumorigenesis in primary cancers. Cancer Discov 1:137-43
Connolly, Erin C; Saunier, Elise F; Quigley, David et al. (2011) Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term T?RI/II kinase inhibition with LY2109761. Cancer Res 71:2339-49
Bouquet, Fanny; Pal, Anupama; Pilones, Karsten A et al. (2011) TGFýý1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res 17:6754-65
de Feraudy, Sebastien; Ridd, Katie; Richards, Lauren M et al. (2010) The DNA damage-binding protein XPC is a frequent target for inactivation in squamous cell carcinomas. Am J Pathol 177:555-62
de Feraudy, Sebastien; Revet, Ingrid; Bezrookove, Vladimir et al. (2010) A minority of foci or pan-nuclear apoptotic staining of gammaH2AX in the S phase after UV damage contain DNA double-strand breaks. Proc Natl Acad Sci U S A 107:6870-5
Ridd, Katie; Bastian, Boris C (2010) Somatic mutation of epidermal growth factor receptor in a small subset of cutaneous squamous cell carcinoma. J Invest Dermatol 130:901-3

Showing the most recent 10 out of 27 publications