Human tumors have numerous genetic and epigenetic alterations that produce complex downstream changes in the expression levels of many genes. While some of these changes are necessary for the maintenance of the malignant phenotype, many others are sporadic or non-essential. One of the main challenges in new drug development for cancer is the identification of relevant therapeutic targets among a substantial number of these spurious background changes. Ideally, such a target would be tumor specific, present in a majority of tumors and necessary for tumor cell survival. The central hypothesis in this proposal is that tumors that appear different based on genetic changes alone, share converging downstream tumor specific pathways. The short-term objective of this proposal is to develop laboratory tools that are necessary to find these convergent pathways. The long-term objective is to validate our laboratory findings in primary human tumor samples and a broad cell line panel.
The specific aims of the project are: 1.) Establishing a panel of human tumor cell lines by ectopic expression of different transforming gene sets. 2.) Identification of the mRNAs expression pattern changes common to multiple transformation pathways and cellular backgrounds. 3.) Organization of the individual tumor specific changes into common pathways. The significance of this project is that the tools that are developed in the short-term will have broad applications for all human tumor types, and in the long-term, the results will have the potential to lead to new cancer treatment strategies. The experimental design will take advantage of unique tumorigenic human cell lines expressing defined transforming genes. These cells were recently developed by the laboratory in which these studies will be performed. Suppression subtractive hybridization (SSH) will be used to compare cell lines with different genetic backgrounds, in order to progressively eliminate all the genes that are non-essential for the tumorigenic phenotype. This tumor restricted gene panel will be used to profile primary human tumor samples. The pre-selection process will simplify data collection and interpretation. The priority of this project will be the development of the tumor restricted gene panel as a tool, rather than large scale expression profiling. The candidate, Dr. Tan A. Ince, will work at the Whitehead Institute for Biomedical Research, under the mentorship of Dr. Robert Weinberg and with the long-term goal of establishing an independent research career.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA092013-02
Application #
6515157
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2001-08-13
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2002-12-31
Support Year
2
Fiscal Year
2002
Total Cost
$69,660
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Petrocca, Fabio; Altschuler, Gabriel; Tan, Shen Mynn et al. (2013) A genome-wide siRNA screen identifies proteasome addiction as a vulnerability of basal-like triple-negative breast cancer cells. Cancer Cell 24:182-96
Godar, Samuel; Ince, Tan A; Bell, George W et al. (2008) Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 134:62-73
Ince, Tan A; Richardson, Andrea L; Bell, George W et al. (2007) Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12:160-70
Dinulescu, Daniela M; Ince, Tan A; Quade, Bradley J et al. (2005) Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11:63-70
Moore, Steven D P; Herrick, Steven R; Ince, Tan A et al. (2004) Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Cancer Res 64:5570-7
Ince, Tan A; Crum, Christopher P (2004) Telomerase: promise and challenge. Hum Pathol 35:393-5
Ince, Tan A; Cviko, Aida P; Quade, Bradley J et al. (2002) p63 Coordinates anogenital modeling and epithelial cell differentiation in the developing female urogenital tract. Am J Pathol 161:1111-7