Abstract 1722: Effectiveness of predictive simulation in identifying potential patient-specific therapeutic targets in multiple myeloma-a pilot study

Abstract

Abstract Targeting specific constellation of molecular abnormalities through predictive simulation modeling may provide a practical therapeutic approach to this complex disease. Cellworks provides a simulation approach that comprehensively models signal transduction, epigenetic regulation, metabolic, and other regulatory networks in cancer cells. This approach is able to identify a patient's dominant characteristics and enable design of a personalized treatment incorporating the patient's genomic signature. We validated this in patients with glioblastoma1, multiple myeloma2 and polycythemia vera3. In this feasibility study we test personalization methodology by modeling MM patients based on genomic information derived from patient marrow and predict therapeutic targets. The modeling analysis for two MM patients is presented. Cytogenetic analyses indicated massive chromosome aberrations and changes in gene copy numbers (CNV) in both patients. Using this information, 557 and 816 gene perturbations (low and high CNV), respectively, were included to model the patients’ simulation avatar. In the first patient, analysis of the simulation network predicted elevated NFkB levels due to high copy number of NFkB, TRAF1, MYD88, TLR2, TLR6. High levels of ERK, AP1 and beta catenin (CTNNB1) were also detected. In the second patient, a similar analysis predicted increased activation of STAT3/5 signaling due to high CNV of IL6 and IL6ST, JAK3 and JAK2; and low CNV of ETV6 that negatively regulates STAT3/5 signaling. Data also indicated amplification of PI3K/Akt and mToR signaling pathways in both cases. Most importantly, modeling predicted sensitivity to a combination of ERK inhibitor Trematinib with mTOR inhibitor Everolimus and Cyclooxygenase 2 inhibitor Celecoxib in the first patient and sensitivity to a combination of JAK inhibitor Tofacitinib with Everolimus and Celecoxib in the second patient. Based on these actionable insights, 5 MM patients to be profiled for cytogenetic and molecular abnormalities in a pilot study (IRB under review), and thereafter modeled to create patient simulation avatars. A library of FDA-approved drugs from across indications will be simulated against the predicted deregulated pathways to generate predictive drugs with therapeutic potential. In parallel, CD138+ plasma cells will be sorted from the aspirated samples for ex vivo clinical validations with the predicted therapeutic drugs. 1.Pingle S. et al. Journal of Translational Medicine 2014; 12:128; 3. Sayeski, P. et al. ASH 2014 Abstract:3212; 2.Doudican, N. et al. ASH 2014 Abstract: 2232. Citation Format: Sathish Kumar, Shireen Vali, Kabya Basu, Saji Gera, Neeraj Singh, Ansu Kumar, Taher Abbasi, Shazib Pervaiz. Effectiveness of predictive simulation in identifying potential patient-specific therapeutic targets in multiple myeloma-a pilot study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1722. doi:10.1158/1538-7445.AM2015-1722