Abstract
The transcription factor MYC is associated with the regulation of over 15% of human gene expression. Deregulation of MYC is found in up to 70% of human cancers. As MYC is responsible for the reprogramming of cell metabolism, growth and survival, it is an attractive therapeutic target, yet effective drug development has been slow. As the Bromodomain/BET proteins epigenetically regulate MYC, BET inhibitors like JQ1 have been developed as MYC therapeutics. We used the Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) previously shown to correlate with response, time to progression and survival, to examine JQ1 activity in 46 human tumor specimens isolated from surgical biopsies.
Methods: Surgical biopsies were mechanically and enzymatically disaggregated, with micro spheroids of desired size isolated by density centrifugation. Five-Point dose response curves were interpolated to provide LC50 values for comparison by Z-score. Synergy was conducted by median-effect.
Results: JQ1 revealed activity in hematologic, breast, glial & gastrointestinal (GI) tumors. By rank order, JQ1 activity favored hematologic (AML & NHL) & breast tumors over Lung, Ovary and GI with inter-patient differences observed within tumor types. MYC association with histone acetylation and aurora kinase (AURK) activity, led to an exploration of JQ1 synergy with SAHA (HDACi), MLN 8054 & Tozasertib (both AURKi). JQ1 synergy analysis revealed SAHA > Tozasertib > MLN 8054.
Conclusions: Based upon JQ1 activity, several tumor types appear to be candidates for agents that target MYC-mediated cell survival, offering potential treatment options for patients with advanced malignancies. JQ1 synergy with HDACi & AURKi suggests novel drug combinations for future development. As MYC signaling influences thousands of gene targets, phenotypic analyses like the EVA/PCD platform can offer insights into cellular cell death events that serve as surrogate markers for clinical response to MYC inhibition. Supported in part by the Vanguard Cancer Foundation, the Nagourney Institute and the Malcolm C. Todd Cancer Institute.
Citation Format: Robert Alan Nagourney, Steven S. Evans, Alexander J. Nagourney, Paula J. Bernard, Federico R. Francisco, Milan Sheth, Nilesh Vora, Eknath Deo. MYC inhibition in human malignancy by BET-Bromodomain inhibitor JQ1, using a 3-D human tumor primary culture micro-spheroid platform to explore clinically relevant observations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4684. doi:10.1158/1538-7445.AM2017-4684
- ©2017 American Association for Cancer Research.
Volume 77, Issue 13 Supplement
