Prostate cancer is the second leading cause of cancer-related death among males in the United States. Beyond the burden in lives affected and lost, more than 192,280 new cases of prostate cancer are projected in 2014. The need to define the genetic basis of this disease is clear. One of the hallmarks of oncogenesis is the aberrant activation of various cellular kinases and growth promoting nuclear hormone receptor signaling. Sustained oncogenic activation requires coordinate inactivation of tumor suppressor genes, such as protein phosphatases, to allow propagation of signaling. Although the inhibition of oncogenic signaling through the development of nuclear hormone antagonists (such as MDV3100) or kinase inhibitors has resulted in some therapeutic success, most exhibit modest efficacy, leading to eventual tumor resistance. The therapeutic activation of tumor suppressor genes has remained largely unexplored. We have developed a series of novel drugs that uniquely target protein phosphatases and possess favorable pharmacokinetics and no significant toxicity. Characterization of these compounds revealed their ability to simultaneously inhibit both the MYC and AR effector pathways in prostate cancer cell lines and mouse models. Our studies represent a first step into that new territory and highlight the potential for the development of small molecule activators of other protein phosphatases and tumor suppressor proteins for the treatment of prostate cancer specifically and other cancers more generally.

Public Health Relevance

Prostate cancer is the second leading cause of cancer-related death among men in the United States. The experiments proposed in this application will focus on developing a novel small molecule series of PP2A activators for the treatment of both castrate resistant and androgen independent prostate cancer. We will use preclinical models of prostate cancer to test the therapeutic potential of targeting this pathway to treat prostate cancer, which might lead to the discovery of new treatment options for this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA181654-05
Application #
9829272
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Chen, Weiwei
Project Start
2015-06-01
Project End
2020-05-31
Budget Start
2019-01-16
Budget End
2019-05-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Narla, Goutham; Sangodkar, Jaya; Ryder, Christopher B (2018) The impact of phosphatases on proliferative and survival signaling in cancer. Cell Mol Life Sci 75:2695-2718
McClinch, Kimberly; Avelar, Rita A; Callejas, David et al. (2018) Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer. Cancer Res 78:2065-2080
O'Connor, Caitlin M; Perl, Abbey; Leonard, Daniel et al. (2018) Therapeutic targeting of PP2A. Int J Biochem Cell Biol 96:182-193
Sangodkar, Jaya; Perl, Abbey; Tohme, Rita et al. (2017) Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth. J Clin Invest 127:2081-2090
Sangodkar, Jaya; Farrington, Caroline C; McClinch, Kimberly et al. (2016) All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J 283:1004-24
Hatami, Raheleh; Sieuwerts, Anieta M; Izadmehr, Sudeh et al. (2013) KLF6-SV1 drives breast cancer metastasis and is associated with poor survival. Sci Transl Med 5:169ra12