Lung cancer is the most common cause of cancer death for women and men. Given this, there is a pressing need to improve lung cancer prevention and treatment. This is the subject of this competing renewal of NIH R01-CA087546-10 that takes advantage of a previously unrecognized chemoprevention pathway uncovered during the prior funding period. This is constituted by the E1- like ubiquitin-activating enzyme (UBE1L), which partners with the ubiquitin-related interferon stimulated gene 15 (ISG15) that can destabilize cyclin D1 and other complexed proteins. The consequence is G1 checkpoint arrest that permits repair of carcinogenic DNA damage. Notably, the specific UBE1L-ISG15 deconjugase UBP43/USP18 is a key regulator of this pathway. We propose this as target for chemoprevention and hypothesize that targeting UPB43 destabilizes cyclin D1 and other ISG15 complexed proteins. This confers therapeutic and chemopreventive effects in the lung. This hypothesis will be pursued through these Specific Aims: (1) to learn whether UBP43 is a key regulator of the G1-S transition;(2) to establish whether UBP43 knock-down represses lung cancer growth, tumorigenicity, or affects response to chemotherapy and chemoprevention agents;and (3) to validate the biological and clinical relevance of this pathway using novel transgenic mouse models that we engineered to mimic key features of clinical lung cancer. We will cross these mice with those that have lung-specific loss of UBP43 and interrogate a paired normal-malignant lung tissue bank and a lung cancer tissue array that permits clinical associations. Intriguingly, our proof of principle trial platform at Dartmouth found this pathway is engaged in lung cancers of patients treated with the rexinoid bexarotene, a candidate chemopreventive agent. Unique cellular, biochemical, experimental and clinically-predictive transgenic mouse models as well as paired normal-malignant lung tissue banks will be used by our highly collaborative and interdisciplinary team. Successful completion of this proposal should have substantial translational impact. This would uncover a novel pharmacologic target to combat lung cancer, a major cancer problem that we must confront.

Public Health Relevance

Lung cancer is the most common cause of cancer death for both men and women. Given this, there is a pressing need to find better ways to treat and prevent lung cancer. This is the subject of this NIH R0-1 competing renewal application that seeks to investigate whether the deconjugase UBP43 is a target for lung cancer prevention or therapy by conferring anti-neoplastic effects via induced degradation of cyclin D1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
Other Domestic Higher Education
United States
Zip Code
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
Ma, Tian; Dong, Jessica P; Sekula, David J et al. (2013) Repression of exogenous gene expression by the retinoic acid target gene G0S2. Int J Oncol 42:1743-53
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

Showing the most recent 10 out of 51 publications