This revised competing renewal application of NIH RO1-CA111422: "Cyclin D as a Retinoid Differentiation Molecular Target" continues in depth studies of the important role of cyclin D1 as a major target of all-trans- retinoic acid (RA, retinoid) response by now examining how this is also a target of the hedgehog (Hh) pathway, also retinoid regulated, but in a previously unrecognized manner critical for differentiation and self- renewal of germ cell tumors (GCTs), the malignant counterparts of human embryonal stem (ES) cells. Intriguingly, our studies uncovered a unique retinoid response: induction of the Patched-1 (Ptch1) receptor which drives loss of self-renewal and regulates differentiation. Ptch1 is a target gene of the Hh pathway and is used as a read-out of Hh activation. The hypothesis explored is RA represses Hh signaling by a novel mechanism, Ptch1 induction, independent of smoothened (Smo), the only recognized target of Hh inhibitors, such as cyclopamine. Recognizing importance of this came from mining gene profiling studies successfully used by our team to identify unique retinoid targets in embryonal cancers (ECs). This proposal explores a distinct pharmacologic mechanism regulating self-renewal of ECs and likely other tumors. We are eager to pursue the Specific Aims that: (1) discover whether RA induction of Ptch1 is a general mechanism engaged by EC cells independent of Smo and if this is a common pathway of agents that trigger terminal differentiation of pluripotent EC cells;(2) probe the functional importance of this pathway by gain and loss of Ptch1 expression studies that affect Hh targets and regulate apoptosis, self-renewal or differentiation response;and (3) elucidate in vivo and clinical relevancy by learning whether RA induces Ptch1 in ES cells (or other cancer or stem cells) as well as in Ptch1 reporter mice and by confirming Ptch1 and its targets are differentially expressed in a unique tumor bank enabling comprehensive analyses of differentiated (mature teratoma) versus undifferentiated (EC) GCTs. This has successfully uncovered D-type cyclins as key regulators of human EC growth, chemotherapy response and differentiation. These unique in vitro, in vivo, and clinical resources with pharmacologic, cell and molecular biologic approaches will provide critical insights into the Hh pathway in regulating apoptosis, self-renewal or differentiation of GCT or other tumors.

Public Health Relevance

This project studies how all-trans-retinoic acid, an FDA approved Vitamin A derivative, causes repression of the hedgehog pathway through a previously unrecognized mechanism that induces its receptor, Patched. This mechanism is active in embryonal cancers and stem cells. This project is relevant to embryonal cancer cells, the malignant counterpart of normal stem cells and successful conclusion of this project will provide insights into the retinoid role of targeting the hedgehog pathway in cancer to suppress self-renewal or growth and induce apoptosis or differentiation in these cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111422-09
Application #
8588248
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2004-12-01
Project End
2014-11-30
Budget Start
2013-12-10
Budget End
2014-11-30
Support Year
9
Fiscal Year
2014
Total Cost
$266,052
Indirect Cost
$97,665
Name
Dartmouth College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Busch, Alexander M; Galimberti, Fabrizio; Nehls, Kristen E et al. (2014) All-trans-retinoic acid antagonizes the Hedgehog pathway by inducing patched. Cancer Biol Ther 15:463-72
Ma, Tian; Lopez-Aguiar, Alexandra G N; Li, Aihua et al. (2014) Mice lacking G0S2 are lean and cold-tolerant. Cancer Biol Ther 15:643-50
Ma, Tian; Galimberti, Fabrizio; Erkmen, Cherie P et al. (2013) Comparing histone deacetylase inhibitor responses in genetically engineered mouse lung cancer models and a window of opportunity trial in patients with lung cancer. Mol Cancer Ther 12:1545-55
Busch, Alexander M; Johnson, Kevin C; Stan, Radu V et al. (2013) Evidence for tankyrases as antineoplastic targets in lung cancer. BMC Cancer 13:211
Rodriguez-Blanco, J; Schilling, N S; Tokhunts, R et al. (2013) The hedgehog processing pathway is required for NSCLC growth and survival. Oncogene 32:2335-45
Galimberti, Fabrizio; Thompson, Sarah L; Ravi, Saranya et al. (2011) Anaphase catastrophe is a target for cancer therapy. Clin Cancer Res 17:1218-22
Singh, Samer; Wang, Zhiqiang; Liang Fei, Dennis et al. (2011) Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity. Cancer Res 71:4454-63
Liu, Xi; Sempere, Lorenzo F; Guo, Yongli et al. (2011) Involvement of microRNAs in lung cancer biology and therapy. Transl Res 157:200-8
Dragnev, Konstantin H; Ma, Tian; Cyrus, Jobin et al. (2011) Bexarotene plus erlotinib suppress lung carcinogenesis independent of KRAS mutations in two clinical trials and transgenic models. Cancer Prev Res (Phila) 4:818-28
Galimberti, Fabrizio; Thompson, Sarah L; Liu, Xi et al. (2010) Targeting the cyclin E-Cdk-2 complex represses lung cancer growth by triggering anaphase catastrophe. Clin Cancer Res 16:109-20

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