Abstract

Our studies to date have demonstrated that inhibiting RAS reduces the radiation survival of tumor cells in which RAS is activated by mutation or epidermal growth factor receptor (EGFR) signaling. We have used a pharmacological approach to inhibit RAS post-translational processing. This processing is required for RAS membrane binding and activity. We have shown that farnesyltransferase inhibitor (FTI) treatment radiosensitizes tumor cells with H-ras mutations without altering the radiation sensitivity of normal cells. While the effect was significant in tissue culture, animal experiments led us to examine whether FTI treatment had additional effects in vivo. Subsequent studies revealed that FTI treatment led to increased oxygenation in tumors xenografts expressing oncogenic H-ras. We propose to further explore the ability of FTIs to alter the tumor microenvironment by determining whether mutant RAS is the target for this action of FTIs. We will investigate the mechanism through which FTIs alter the oxygenation of tumors and whether it involves changes in tumor vasculature. We have also shown, using a genetic approach, that oncogenic H-, K-, and N-RAS all contribute to radiation resistance. Signaling from the three RAS isoforms to down-stream effectors has been reported to differ. This raises the question of which pathways downstream of RAS contribute to the observed radiation resistance. We propose to explore the contribution of each RAS isoform to intrinsic radiation resistance and to investigate downstream pathways using both pharmacologic inhibitors as well as novel genetic reagents. Small interfering RNA (siRNA) will be used to specifically target expression of the different RAS isoforms as well as to specifically target oncogenic RAS expression. The results of these studies could be valuable in developing new molecular targets to improve the efficacy of radiotherapy. They may also provide a rationale for the application of FTIs in the treatment of tumors with RAS activation that is due to EGFR signaling. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073820-06
Application #
6706284
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1997-12-12
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
6
Fiscal Year
2004
Total Cost
$277,375
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Qayum, Naseer; Im, Jaehong; Stratford, Michael R et al. (2012) Modulation of the tumor microvasculature by phosphoinositide-3 kinase inhibition increases doxorubicin delivery in vivo. Clin Cancer Res 18:161-9
Maity, Amit; Bernhard, Eric J (2010) Modulating tumor vasculature through signaling inhibition to improve cytotoxic therapy. Cancer Res 70:2141-5
Hamilton, Julie; Higgins, Geoff; Bernhard, Eric J (2009) Conventional radiotherapy or hypofractionation? A study of molecular changes resulting from different radiation fractionation schemes. Cancer Biol Ther 8:774-6
Qayum, Naseer; Muschel, Ruth J; Im, Jae Hong et al. (2009) Tumor vascular changes mediated by inhibition of oncogenic signaling. Cancer Res 69:6347-54
Cordes, N; Frick, S; Brunner, T B et al. (2007) Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1. Oncogene 26:6851-62
Cengel, Keith A; Voong, K Rahn; Chandrasekaran, Sanjay et al. (2007) Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells. Neoplasia 9:341-8
Jiang, Zibin; Pore, Nabendu; Cerniglia, George J et al. (2007) Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. Cancer Res 67:4467-73
Kim, In-Ah; Bae, Sun-Sik; Fernandes, Annemarie et al. (2005) Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res 65:7902-10
Brunner, Thomas B; Cengel, Keith A; Hahn, Stephen M et al. (2005) Pancreatic cancer cell radiation survival and prenyltransferase inhibition: the role of K-Ras. Cancer Res 65:8433-41
Martin, Neil E; Brunner, Thomas B; Kiel, Krystina D et al. (2004) A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clin Cancer Res 10:5447-54

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