MYC transcription factors are frequently dysregulated in cancer. Chromatin-associated protein complexes link MYC to increased histone lysine acetylation in the epigenome. Bromodomain and extraterminal domain (BET) proteins, which bind to these acetylated histone lysines and recruit MYC protein, have therefore emerged as compelling targets in cancer, with inhibitors entering clinical trials. Neuroblastoma is the most common extracranial solid tumor of childhood, with high-risk disease frequently showing Amplification of MYCN. We performed an unbiased screen of diverse cancer cell lines for sensitivity to BET bromodomain inhibitors (BETi). We validated the activity of both BRD4-directed shRNA and BETi against MYCN-amplified neuroblastoma cells, extending these studies in vivo both to patient derived xenografts (PDX) and to genetically engineered mouse (GEM) models of MYCN-driven neuroblastoma. Importantly, while BETi showed remarkable efficacy in vivo, they were not curative, suggesting the need for combination therapies. We hypothesize tat BETi block interactions of MYCN with the epigenetic machinery, and that combination therapies incorporating BETi represent a robust, translatable approach to enhance efficacy, and block emergent resistance in MYCN-driven NB. Our proposal identifies A) Mechanisms through which blockade of MYCN interferes with transformation, B) Mechanisms by which tumors develop resistance to BETi, and C) Translatable combination therapies to block emergent resistance. Successful completion guides effective clinical translation of BETi as pathway-specific inhibitors of MYCN.
Aim 1 : To clarify a role for EZH2 as a mediator of response to BETi, in MYCN-driven neuroblastoma.
Aim 2 : To test BETi with EZH2i, and with other translatable combination therapies in preclinical trials in neuroblastoma.
Aim 3 : To guide development of additional effective combination therapies, by identifying emergent mechanisms for resistance.
Neuroblastoma is the most common extracrnial solid tumor of children, and is often resistant to therapy. We present published and unpublished data suggesting that an emerging class of BET bromodomain inhibitors (BETi) drugs is effective in high-risk, MYCN-amplified neuroblastoma. Our long-term objective is to guide effective clinical translation of BETi as pathway-specific inhibitors of MYCN in neuroblastoma.
| Chen, Liying; Alexe, Gabriela; Dharia, Neekesh V et al. (2018) CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2. J Clin Invest 128:446-462 |
| Witwicki, Robert M; Ekram, Muhammad B; Qiu, Xintao et al. (2018) TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer. Cell Rep 25:1255-1267.e5 |
| Fan, Qi Wen; Nicolaides, Theodore P; Weiss, William A (2018) Inhibiting 4EBP1 in Glioblastoma. Clin Cancer Res 24:14-21 |
| Iniguez, Amanda Balboni; Alexe, Gabriela; Wang, Emily Jue et al. (2018) Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling. Cancer Cell 34:922-938.e7 |
| An, Zhenyi; Aksoy, Ozlem; Zheng, Tina et al. (2018) Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene 37:1561-1575 |
| Zheng, Tina; Ménard, Marie; Weiss, William A (2017) Neuroblastoma Metastases: Leveraging the Avian Neural Crest. Cancer Cell 32:395-397 |
| Malone, Clare F; Stegmaier, Kimberly (2017) Scratching the Surface of Immunotherapeutic Targets in Neuroblastoma. Cancer Cell 32:271-273 |
| Huang, Miller; Miller, Matthew L; McHenry, Lauren K et al. (2016) Generating trunk neural crest from human pluripotent stem cells. Sci Rep 6:19727 |
