Abstract

The objective of this application is to determine whether let-7 miRNA can be used as a therapy to enhance radiosensitivity in lung cancer treatment.
Specific Aim 1 : To test the hypothesis that over-expression of let-7 can alter the radiation response in Radelegans and cell lines. a. We will test the effect of let-7 manipulation in Radelegans, a model of reproductive cell death, the primary form of cell death in solid tumors. We will further use Radelegans to understand the genetic basis of the let-7 effects. b. We will evaluate the effect of let-7 manipulation in lung cancer cell lines in standard clonogenic radiosensitivity assays.
Specific Aim 2 : To test the hypothesis that let-7 over-expression can radiosensitize established invasive KRAS-mediated lung tumors in vivo in an inducible K-Ras mutant mouse model. a. We will test the effect of let-7 over-expression on early K-Ras mediated mouse lung tumors. b. We will test the effect of let-7 over-expression on advanced K-Ras mediated mouse lung tumors. Mice will be intranasally infected with the Ad-cre virus to activate the K-Ras gene to allow tumor progression. After 14 weeks, we will infect the mice with the Ad-let-7 virus, and subject one lung to irradiation and observe for radiosensitization effect. Lung cancer is the major cause of cancer deaths in the US, and existing therapies, including radiotherapy, fail to treat this disease successfully in the overwhelming majority of cases. This work Proposes to use the let-7 microRNA as a therapy to radiosensitize lung cancer. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA130376-01
Application #
7332547
Study Section
Special Emphasis Panel (ZRG1-F09-W (20))
Program Officer
Jakowlew, Sonia B
Project Start
2007-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$51,278
Indirect Cost

  Institution

Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Trang, Phong; Wiggins, Jason F; Daige, Christopher L et al. (2011) Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther 19:1116-22
Trang, P; Medina, P P; Wiggins, J F et al. (2010) Regression of murine lung tumors by the let-7 microRNA. Oncogene 29:1580-7
Esquela-Kerscher, Aurora; Trang, Phong; Wiggins, Jason F et al. (2008) The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 7:759-64