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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES030481&format=word)
| Principal Investigator: Bickers, David Rinsey | |
|---|---|
| Institute Receiving Award | Columbia University Health Sciences |
| Location | New York, NY |
| Grant Number | R01ES030481 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 07 Apr 2020 to 31 Jan 2025 |
| DESCRIPTION (provided by applicant): | SUMMARY BCCs are the most common type of human malignancy in the US, affecting more than 3 million Americans annually. Defective regulation of Hedgehog (Hh) signaling, typically through loss of function of the tumor suppressor Patched (PTCH) leading to oncogenic activation of SMO, are thought to be the primary drivers of BCC growth. Ligand binding to PTCH relieves SMO repression, triggering its migration to the primary cilium with activation of GLI transcription factors that drive cell proliferation/tumor growth. Aberrant HH signaling underlies the Gorlin-Goltz syndrome, also known as basal cell nevus syndrome(BCNS), a dominantly inherited disorder in which affected individuals are born with one functional PTCH allele and during life acquire mutations in the second allele that accelerate HH signaling and drive the growth of BCCs in these patients whose inordinate tumor burden necessitates multiple costly mutilating surgical procedures over their lifetime. Furthermore, Hh inhibitors (HHi) are associated with intolerable side-effects in treated individuals such that half the patients discontinue treatment despite substantial anti-tumor efficacy. Our group and others around the world have fostered bench-to-bedside clinical trials with drugs that target HH signaling and in 2012 these efforts resulted in FDA approval of vismodegib, a potent orally administered SMO inhibitor for the treatment of locally advanced, surgically inoperable and potentially fatal BCCs. Despite their undeniable efficacy, the utility of currently available HH signaling inhibitors is hampered by rapid development of tumor resistance and tumor recurrence. While uninhibited Hh signaling clearly drives BCC resistance and recurrence, many BCCs do not manifest SMO mutations indicating involvement of additional tumorigenic mechanisms. We have discovered that vismodegib resistance involves dysregulation of the bromodomain-containing proteins BRD7 and BRD9 of the SWItch/Sucrose NonFermentable (SWI/SNF) nucleosome remodeling complexes. Utilizing genetically well- defined in vitro and in vivo murine models of BCC, and patient-derived human BCC cells, our preliminary data compellingly demonstrate that (i) HHi resistance is associated with global decreases in histone acetylation and chromatin accessibility, and (ii) genetic ablation of BRD7 renders drug-naïve BCC cells resistant to HHi. Based on our preliminary data, this application will test the hypothesis that the BRD7-BRD9 nexus drives HHi resistance and that the BRD9 blockade prevents the emergence of HHi resistance. Aim 1 will probe the chromatin modifications and gene expression signatures associated with HHi resistance, and their relevance to the BRD7- BRD9 axis. Aim 2 will test in vivo consequences of genetic manipulation of the BRD7 and BRD9 nexus in genetically-defined models (i.e., epidermis-specific deletions in BRD7 [Brd7 KO] or Akt1 [Akt1+/-]. Aim 3 will test the potential utility of select BRD9 and Akt inhibitors for overcoming/preventing HHi resistance using an in vivo BCC model system developed in the PI’s laboratory that faithfully mimics human BCNS and previously was used to verify the efficacy and safety of HHi. |
| Science Code(s)/Area of Science(s) |
Primary: 58 - Skin Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | See publications associated with this Grant. |
| Program Officer | Michael Humble |