Berlow, N. E., Rikhi, R., Geltzeiler, M., Abraham, J., Svalina, M. N., Davis, L. E., Wise, E., Mancini, M., Noujaim, J., Mansoor, A., Quist, M. J., Matlock, K. L., Goros, M. W., Hernandez, B. S., Doung, Y. C., Thway, K., Tsukahara, T., Nishio, J., Huang, E. T., Airhart, S., Bult, C. J., Gandour-Edwards, R., Maki, R. G., Jones, R. L., Michalek, J. E., Milovancev, M., Ghosh, S., Pal, R., Keller, C. (June 2019) Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma. BMC Cancer, 19 (1). p. 593. ISSN 1471-2407 (Public Dataset)
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Abstract
BACKGROUND: Cancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments. METHODS: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the primary murine tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient's epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient's primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. RESULTS: Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model). CONCLUSIONS: These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.
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