Anti-cancer therapy has typically been targeted on neoplastic cells. Inhibitors of the enzyme thymidylate synthase (TS), particularly fluoropyrimidines, have been used for many years in the clinical management of a variety of cancers. In spite of the extensive research on the genetic and molecular factors governing tumor response to TS inhibitors, its clinical efficacy remains limited. In this project, we propose a novel approach to increase tumor response to these agents. Tumors are infiltrated with a heterogeneous population of non-neoplastic cells. These include host-derived cells such as fibroblasts, macrophages, lymphocytes, endothelial cells, etc. Together with extracellular matrix, make up the tumor stroma or microenvironment. By secreting an array of cytokines, growth factors, hormones, etc., they play a critical role in tumor growth and progression, as well as response to therapeutic agents. In this proposal, we will test the hypothesis that tumor response to TS inhibitors is governed by the chemosensitivity of infiltrating stromal cells. We will utilize the ApcMin/+ mouse which is predisposed to the development of adenomatous tumors of the small intestine and the colon. By bone marrow transplantation we will generate chimeric mice wherein the chemosensitivity of stromal cells is distinct from that of the tumor. We predict that tumors in these mice will show a drug response that reflects the chemosensitivity of stromal cells. Based on preliminary results, Aim 1 will determine the impact of TS inhibitors on cells in the stromal compartment to identify stromal mediators of response to TS inhibitors.
Aim 2, will examine the effect of TS down regulation in stromal cells on tumor response to TS inhibitors.
In Aim 3, we will direct sensitization to TS inhibitors specifically to tumor associated stromal cells. In all, the hypothesis being tested in this project will pave the way for development of new treatment modalities using stromal cells to improve therapies targeted at tumor cells to ensure drug induced cancer cell death.

Public Health Relevance

The anticancer efficacy of chemotherapeutic agents targeting the enzyme thymidylate synthase (TS) has been enhanced by their combined administration with other metabolites;however, their clinical use continues to be limited by acquired resistance and drug-induced toxicity due to their lack of selectivity, targeting both cancer and normal cells alike. In this proposal, we will use mouse models to develop a novel strategy to specifically sensitize tumors to TS inhibitors while protecting normal cells from their toxicity by targeting stromal cells in the tumor microenvironment. The results of these studies can be extended to other chemotherapeutic agents resulting in more effective clinical management of a wide variety of cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA154731-03S1
Application #
8668358
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Ogunbiyi, Peter
Project Start
2011-07-25
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$42,125
Indirect Cost
$10,594
Name
University of South Carolina at Columbia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Peña, Edsel A; Wu, Wensong; Piegorsch, Walter et al. (2016) Model Selection and Estimation with Quantal-Response Data in Benchmark Risk Assessment. Risk Anal :
Kindo, Bereket P; Wang, Hao; Peña, Edsel A (2016) Multinomial probit Bayesian additive regression trees. Stat (Int Stat Inst) 5:119-131
Watson, Shana R; Liu, Piaomu; Peña, Edsel A et al. (2016) Comparison of Aortic Collagen Fiber Angle Distribution in Mouse Models of Atherosclerosis Using Second-Harmonic Generation (SHG) Microscopy. Microsc Microanal 22:55-62
Jung, Joo-Yong; Gleave Parson, Madeline; Kraft, Jennifer D et al. (2016) Elevated interleukin-27 levels in human neonatal macrophages regulate indoleamine dioxygenase in a STAT-1 and STAT-3-dependent manner. Immunology 149:35-47
Mlotshwa, Sizolwenkosi; Pruss, Gail J; MacArthur, John L et al. (2015) A novel chemopreventive strategy based on therapeutic microRNAs produced in plants. Cell Res 25:521-4
Peña, Edsel A; Habiger, Joshua D; Wu, Wensong (2015) Classes of Multiple Decision Functions Strongly Controlling FWER and FDR. Metrika 78:563-595
Habiger, Joshua D; Peña, Edsel A (2014) Compound p-value statistics for multiple testing procedures. J Multivar Anal 126:153-166
Xu, Hanwen; Zhang, Yu; Altomare, Diego et al. (2014) Six1 promotes epithelial-mesenchymal transition and malignant conversion in human papillomavirus type 16-immortalized human keratinocytes. Carcinogenesis 35:1379-88
Shi, Y; Ou, L; Han, S et al. (2014) Deficiency of Kruppel-like factor KLF4 in myeloid-derived suppressor cells inhibits tumor pulmonary metastasis in mice accompanied by decreased fibrocytes. Oncogenesis 3:e129
Mahoney, Sara E; Davis, J Mark; Murphy, E Angela et al. (2014) Dietary quercetin reduces chemotherapy-induced fatigue in mice. Integr Cancer Ther 13:417-24

Showing the most recent 10 out of 21 publications