There is a pressing need for new classes of antitumor drugs, particularly drugs with activity against the common solid human tumors, most of which remain refractory to effective chemotherapy. This need argues for novel, rationally based approaches to drug development, combined with appropriate and effective models for evaluating antitumor activity. A fundamental event in neoplastic transformation, and one that distinguishes a normal cell from a tumor cell, is the inappropriate or faulty expression in a tumor cell of growth regulatory genes (oncogenes). A major function of oncogenes is to code for components of intracellular signal transduction pathways that medicate the processes that occur between binding growth factors to cell surface receptors and events in the cell nucleus leading to cell proliferation. The constitutive activation of these signal transduction pathways by oncogenes is a major factor leading to transformed cell growth. Thus, signal transduction pathways offer rational and novel biochemical targets for new anticancer drug development, and offers the promise of selective control of cancer cell growth by exploiting a basic biological difference between normal and tumor cells. The goals of the project are to 1) use novel chemical structures with activity against signal transduction pathways as candidate drugs for preclinical development and eventual clinical trial in cancer patients; 2) to conduct mechanistic studies of selected inhibitors of signal transduction; 3) to identify peptide inhibitors of the signal transducing enzyme phosphatidylinositol phospholipase C; and, 4) to identify clinically relevant mechanisms of drug resistance due to altered levels of intracellular signaling or reductive enzymes. The ultimate objective of the studies is to find novel and improved agents and strategies for treating cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA017094-18A1
Application #
3749212
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Landowski, Terry H; Guntle, Gerald P; Zhao, Dezheng et al. (2016) Magnetic Resonance Imaging Identifies Differential Response to Pro-Oxidant Chemotherapy in a Xenograft Model. Transl Oncol 9:228-35
Barrett, Harrison H; Alberts, David S; Woolfenden, James M et al. (2016) Therapy operating characteristic curves: tools for precision chemotherapy. J Med Imaging (Bellingham) 3:023502
Chang, Hae Ryung; Nam, Seungyoon; Kook, Myeong-Cherl et al. (2016) HNF4? is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer. Gut 65:19-32
Samulitis, Betty K; Pond, Kelvin W; Pond, Erika et al. (2015) Gemcitabine resistant pancreatic cancer cell lines acquire an invasive phenotype with collateral hypersensitivity to histone deacetylase inhibitors. Cancer Biol Ther 16:43-51
Malm, Scott W; Hanke, Neale T; Gill, Alexander et al. (2015) The anti-tumor efficacy of 2-deoxyglucose and D-allose are enhanced with p38 inhibition in pancreatic and ovarian cell lines. J Exp Clin Cancer Res 34:31
Landowski, Terry H; Gard, Jaime; Pond, Erika et al. (2014) Targeting integrin ?6 stimulates curative-type bone metastasis lesions in a xenograft model. Mol Cancer Ther 13:1558-66
Nam, S; Chang, H R; Kim, K-T et al. (2014) PATHOME: an algorithm for accurately detecting differentially expressed subpathways. Oncogene 33:4941-51
Dragovich, T; Laheru, D; Dayyani, F et al. (2014) Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother Pharmacol 74:379-87
Exley, Mark A; Hand, Laura; O'Shea, Donal et al. (2014) Interplay between the immune system and adipose tissue in obesity. J Endocrinol 223:R41-8
Zhang, Xiaomeng; Pagel, Mark D; Baker, Amanda F et al. (2014) Reproducibility of magnetic resonance perfusion imaging. PLoS One 9:e89797

Showing the most recent 10 out of 314 publications