Abstract SY43-02: Predicting solid tumor sensitivity to drug combinations using a multiplexed microinjection platform and prioritizing therapies for clinical development

Abstract

Abstract Functional testing of Voruciclib combinations using the CIVO precision medicine platform. Joyoti Dey, Joey Casalini, Marc Grenley, Sally Ditzler, Angela Merrell, Jason Frazier, Matt Biery, Derek Thirstrup, Bill Kerwin, Emily Beirne, Connor Burns, Kate Gillespie, Tom Deckwerth, James Olson, Richard Klinghoffer Genomics-driven precision oncology has been exceptionally powerful in certain instances where therapeutically actionable genetic mutations drive cancer progression at the time of treatment and when redundant pathways or anti-apoptotic mechanisms fail to limit the efficacy of the selected therapeutic. Unfortunately, these cases represent a minority of solid tumors and many effective cancer drugs have pleiotropic effects that are not easily aligned with genomics-based efficacy predictions. In vitro functional analyses address this to a certain degree but in the absence of intact tumor microenvironment and the patient's immune system, both of which are important determinants of drug responses. The CIVO platform was designed to assess chemosensitivity, chemoresistance and underlying molecular mechanisms in a multiplexed fashion, in vivo, in human patients’ cancer or nonclinical models. The first human trial with CIVO was recently reported1 (Klinghoffer et al (2015). As our team works with the FDA to expand human precision medicine, we used the CIVO platform in canine patients and patient-derived murine models to establish translational strategies to advance investigational CDK inhibitor, Voruciclib in human clinical trials as well as to distinguish Voruciclib from other approved agents belonging to the same class of drugs. Using both our platform and conventional systemic administration, a direct comparison of Bortezomib in combination with Voruciclib or Palbociclib in a triple-negative breast cancer model revealed synergistic activity when Bortezomib was combined with Voruciclib, but not when combined with Palbociclib (see Poster/Abstract #6264). Further studies revealed that this effect is potentially linked to the MCL1-dependent basal subtype of TNBC. In addition to suppression of MCL1 activity and upregulation of Noxa activity, at a transcriptional level Voruciclib inhibits generation of the cytoprotective XBP1-spliced variant involved in the unfolded protein response (UPR) resulting in increased apoptosis as measured by cleaved PARP. The MCL1 suppression caused by Voruciclib in TNBC prompted us to evaluate Voruciclib as a single agent in DLBCL lymphoma and in combination with the BCL2 inhibitor, ABT199 (Venetoclax). In murine DLBCL models, Voruciclib and ABT199 showed modest activity when locally injected as single agents, but demonstrated profound synergy when injected in combination. To assess whether the synergy is restricted to cancer cells vs normal tissue and hence to assess the potential therapeutic window, we are currently assessing the systemic efficacy of the aforementioned combination using DLBCL tumor bearing mice. 1. Klinghoffer, R. A. et al. A technology platform to assess multiple cancer agents simultaneously within a patient's tumor. Sci Transl Med 7, 284ra258, doi:10.1126/scitranslmed.aaa7489 (2015). Citation Format: James Olson. Predicting solid tumor sensitivity to drug combinations using a multiplexed microinjection platform and prioritizing therapies for clinical development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY43-02.