Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma.

Autor: Berlow NE; Children's Cancer Therapy Development Institute, 12655 SW Beaverdam Road-West, Beaverton, OR, 97005, USA. noah@cc-tdi.org.; Electrical and Computer Engineering, Texas Tech University, Lubbock, TX, 79409, USA. noah@cc-tdi.org., Rikhi R; Children's Cancer Therapy Development Institute, 12655 SW Beaverdam Road-West, Beaverton, OR, 97005, USA., Geltzeiler M; Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA.; Department of Otolaryngology - Head and Neck Surgery, Oregon Health & Science University, Portland, OR, 97239, USA., Abraham J; Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA., Svalina MN; Children's Cancer Therapy Development Institute, 12655 SW Beaverdam Road-West, Beaverton, OR, 97005, USA., Davis LE; Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA.; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA., Wise E; Champions Oncology, Baltimore, MD, 21205, USA., Mancini M; Champions Oncology, Baltimore, MD, 21205, USA., Noujaim J; Royal Marsden Hospital and Institute of Cancer Research, London, SW3 6JJ, UK.; Hôpital Maisonneuve-Rosemont, Montreal, H1T 2M4, Canada., Mansoor A; Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA., Quist MJ; Center for Spatial Systems Biomedicine Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA., Matlock KL; Electrical and Computer Engineering, Texas Tech University, Lubbock, TX, 79409, USA.; Omics Data Automation, 12655 SW Beaverdam Road, Beaverton, OR 97005, USA., Goros MW; Department of Epidemiology and Biostatistics, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA., Hernandez BS; Department of Epidemiology and Biostatistics, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA., Doung YC; Department of Orthopedic Surgery, Oregon Health & Science University, Portland, OR, 97239, USA., Thway K; Royal Marsden Hospital and Institute of Cancer Research, London, SW3 6JJ, UK., Tsukahara T; Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan., Nishio J; Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan., Huang ET; Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA., Airhart S; The Jackson Laboratory, Bar Harbor, ME, 04609, USA., Bult CJ; The Jackson Laboratory, Bar Harbor, ME, 04609, USA., Gandour-Edwards R; Department of Pathology & Laboratory Medicine, UC Davis Health System, Sacramento, CA, 95817, USA., Maki RG; Sarcoma Program, Zucker School of Medicine at Hofstra/Northwell & Cold Spring Harbor Laboratory, Long Island, NY, 10142, USA., Jones RL; Royal Marsden Hospital and Institute of Cancer Research, London, SW3 6JJ, UK., Michalek JE; Department of Epidemiology and Biostatistics, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA., Milovancev M; Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR, 97331, USA., Ghosh S; Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX, 79409, USA., Pal R; Electrical and Computer Engineering, Texas Tech University, Lubbock, TX, 79409, USA. ranadip.pal@ttu.edu., Keller C; Children's Cancer Therapy Development Institute, 12655 SW Beaverdam Road-West, Beaverton, OR, 97005, USA. charles@cc-tdi.org.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2019 Jun 17; Vol. 19 (1), pp. 593. Date of Electronic Publication: 2019 Jun 17.
DOI: 10.1186/s12885-019-5681-6
Abstrakt: 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.
Databáze: MEDLINE
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