title: Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity.
abstract: Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine.
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Biswanath
authors.initials: B
authors.lastname: Majumder
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Ulaganathan
authors.initials: U
authors.lastname: Baraneedharan
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Thiyagarajan
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Padhma
authors.initials: P
authors.lastname: Radhakrishnan
authors.affiliation: Indian Institute of Science, Bangalore 560012, India.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Narasimhan
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Muthu
authors.initials: M
authors.lastname: Dhandapani
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Brijwani
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Dency D
authors.initials: DD
authors.lastname: Pinto
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Prasath
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Basavaraja U
authors.initials: BU
authors.lastname: Shanthappa
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Allen
authors.initials: A
authors.lastname: Thayakumar
authors.affiliation: Government Stanley Medical College, Chennai 600001, India.
authors.forename: Rajagopalan
authors.initials: R
authors.lastname: Surendran
authors.affiliation: Kidwai Memorial Institute of Oncology, Bangalore 560030, India.
authors.forename: Govind K
authors.initials: GK
authors.lastname: Babu
authors.affiliation: Kidwai Memorial Institute of Oncology, Bangalore 560030, India.
authors.forename: Ashok M
authors.initials: AM
authors.lastname: Shenoy
authors.affiliation: Mazumdar-Shaw Cancer Center, Bangalore 560099, India.
authors.forename: Moni A
authors.initials: MA
authors.lastname: Kuriakose
authors.affiliation: The Broad Institute of The Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bergthold
authors.affiliation: 1] The Broad Institute of The Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2] Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Peleg
authors.initials: P
authors.lastname: Horowitz
authors.affiliation: 1] The Broad Institute of The Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2] Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: 1] Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Indian Institute of Science, Bangalore 560012, India.
authors.forename: Shivani
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: 1] Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] India Innovation Research Center, New Delhi 110092, India [3] Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Mitra Biotech, Bangalore 560099, India.
authors.forename: Mallikarjun
authors.initials: M
authors.lastname: Sundaram
authors.affiliation: 1] Mitra Biotech, Bangalore 560099, India [2] India Innovation Research Center, New Delhi 110092, India.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Majumder
mesh_terms: D000465:Algorithms; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002853:Chromatography, Liquid; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D000069550:Machine Learning; D008855:Microscopy, Electron, Scanning; D057285:Precision Medicine / Q000379:methods*; D011237:Predictive Value of Tests; D053719:Tandem Mass Spectrometry; D023822:Tissue Engineering / Q000379:methods*; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins