Hedgehog (Hh) signaling has emerged as a key growth pathway in human carcinogenesis and inappropriate Hh target gene activation drives the growth of tumors such as skin basal cell carcinomas (BCCs). Experimental support from 5ARO54780 facilitated approval by the FDA of the first therapy aimed at the Smoothened (Smo) receptor. While na?ve tumors responded, resistance appears to be common, reiterating the need for developing new therapies targeting the Gli transcription factors downstream of Smo. 5ARO54780 in the prior funding period focused on factors that regulate Gli activity and showed the importance of the primary cilium and the basal body-associated Missing-in- Metastasis. Moreover, a proteomics screen to identify druggable components isolated the oncogenic polarity kinase aPKC-?/? and demonstrated that aPKC-?/? plays a key role in hedgehog signaling, BCC tumor growth, and Smo inhibitor resistance. In tumors, aPKC-?/? phosphorylates and activates Gli1 within the regulatory region of the DNA binding domain at residue Gli T304. By contrast, phosphorylation within the linker region of the DNA binding domain appears to inhibit function, revealing a gap in our understanding how DNA binding domain modifications affect activity. Studies in the next funding period will test the hypothesis that aPKC-?/?-mediated DNA binding domain phosphorylation regulates Gli activity and Smo inhibitor resistance by: Determining the consequences of Gli DNA binding domain phosphorylation;Determining how aPKC phosphorylation affects the Gli- DNA interaction;and by 3) Determining the functional consequences of resistant human BCC tumor variants on BCC growth. Completion of the above aims will provide needed information about the pivotal Gli transcription factor and provide insights to help diagnose and treat na?ve and resistant hedgehog-dependent tumors.

Public Health Relevance

Hedgehog pathway targeted therapy to block Smo has been recently approved, but resistance appears to be common, reiterating the need for new therapies targeting the Gli transcription factors downstream of Smo. 5ARO54780 in the prior funding period focused on Gli regulation, and although the oncogenic kinase aPKC-?/? was shown to play a key role in hedgehog signaling, skin basal cell carcinoma tumor growth, and Smo inhibitor resistance by phosphorylating and activating Gli1 within the DNA binding domain, the extent of phosphorylation and how it affects Gli function remain poorly understood. Studies in the next funding period will test the hypothesis that aPKC-?/?-mediated DNA binding domain phosphorylation regulates Gli activity and Smo inhibitor resistance, providing needed information to help diagnose and treat naive and resistant hedgehog-dependent tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054780-07
Application #
8735060
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Baker, Carl
Project Start
2007-05-07
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Dermatology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Danial, Christina; Sarin, Kavita Y; Oro, Anthony E et al. (2016) An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib. Clin Cancer Res 22:1325-9
Ally, Mina S; Ransohoff, Katherine; Sarin, Kavita et al. (2016) Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma. JAMA Dermatol 152:452-6
Zhao, Xuesong; Ponomaryov, Tatyana; Ornell, Kimberly J et al. (2015) RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer Res 75:3623-35
Jaju, Prajakta D; Nguyen, Christie B; Nguyen, Christine B et al. (2015) Mutations in the Kinetochore Gene KNSTRN in Basal Cell Carcinoma. J Invest Dermatol 135:3197-200
Atwood, Scott X; Sarin, Kavita Y; Li, Jiang R et al. (2015) Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma. J Invest Dermatol 135:2138-41
Atwood, Scott X; Sarin, Kavita Y; Whitson, Ramon J et al. (2015) Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell 27:342-53
Yucel, Gozde; Van Arnam, John; Means, Paula Casey et al. (2014) Partial proteasome inhibitors induce hair follicle growth by stabilizing *-catenin. Stem Cells 32:85-92
Atwood, Scott X; Oro, Anthony E (2014) ""Atypical"" regulation of Hedgehog-dependent cancers. Cancer Cell 25:133-4
Atwood, Scott X; Whitson, Ramon J; Oro, Anthony E (2014) Advanced treatment for basal cell carcinomas. Cold Spring Harb Perspect Med 4:a013581
Atwood, Scott X; Whitson, Ramon J; Oro, Anthony E (2013) ""Patch""ing up our tumor signaling knowledge. J Invest Dermatol 133:1131-3

Showing the most recent 10 out of 22 publications