Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time
Shumei Chia, Joo-Leng Low, Xiaoqian Zhang, Xue-Lin Kwang, Fui-Teen Chong, Ankur Sharma, Denis Bertrand, Shen Yon Toh, Hui-Sun Leong, Matan T Thangavelu, Jacqueline S G Hwang, Kok-Hing Lim, Thakshayeni Skanthakumar, Hiang-Khoon Tan, Yan Su, Siang Hui Choo, Hannes Hentze, Iain B H Tan, Alexander Lezhava, Patrick Tan, Daniel S W Tan, Giridharan Periyasamy, Judice L Y Koh, N Gopalakrishna Iyer, Ramanuj DasGupta, Shumei Chia, Joo-Leng Low, Xiaoqian Zhang, Xue-Lin Kwang, Fui-Teen Chong, Ankur Sharma, Denis Bertrand, Shen Yon Toh, Hui-Sun Leong, Matan T Thangavelu, Jacqueline S G Hwang, Kok-Hing Lim, Thakshayeni Skanthakumar, Hiang-Khoon Tan, Yan Su, Siang Hui Choo, Hannes Hentze, Iain B H Tan, Alexander Lezhava, Patrick Tan, Daniel S W Tan, Giridharan Periyasamy, Judice L Y Koh, N Gopalakrishna Iyer, Ramanuj DasGupta
Abstract
Genomics-driven cancer therapeutics has gained prominence in personalized cancer treatment. However, its utility in indications lacking biomarker-driven treatment strategies remains limited. Here we present a "phenotype-driven precision-oncology" approach, based on the notion that biological response to perturbations, chemical or genetic, in ex vivo patient-individualized models can serve as predictive biomarkers for therapeutic response in the clinic. We generated a library of "screenable" patient-derived primary cultures (PDCs) for head and neck squamous cell carcinomas that reproducibly predicted treatment response in matched patient-derived-xenograft models. Importantly, PDCs could guide clinical practice and predict tumour progression in two n = 1 co-clinical trials. Comprehensive "-omics" interrogation of PDCs derived from one of these models revealed YAP1 as a putative biomarker for treatment response and survival in ~24% of oral squamous cell carcinoma. We envision that scaling of the proposed PDC approach could uncover biomarkers for therapeutic stratification and guide real-time therapeutic decisions in the future.Treatment response in patient-derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs.
Trial registration: ClinicalTrials.gov NCT02806388.
Conflict of interest statement
The authors declare no competing financial interests.
Figures
References
- Meric-Bernstam, F. et al. A decision support framework for genomically informed investigational cancer therapy. J. Natl Cancer Inst. 107, djv098 (2015).
- Garraway LA. Genomics-driven oncology: framework for an emerging paradigm. J. Clin. Oncol. 2013;31:1806–1814. doi: 10.1200/JCO.2012.46.8934.
- Uzilov AV, et al. Development and clinical application of an integrative genomic approach to personalized cancer therapy. Genome Med. 2016;8:62. doi: 10.1186/s13073-016-0313-0.
- Jones S, et al. Personalized genomic analyses for cancer mutation discovery and interpretation. Sci. Transl. Med. 2015;7:283ra253. doi: 10.1126/scitranslmed.aaa7161.
- Xue Y, Wilcox WR. Changing paradigm of cancer therapy: precision medicine by next-generation sequencing. Cancer Biol. Med. 2016;13:12–18. doi: 10.20892/j.issn.2095-3941.2016.0003.
- Johnson A, et al. The right drugs at the right time for the right patient: the MD Anderson precision oncology decision support platform. Drug Discov. Today. 2015;20:1433–1438. doi: 10.1016/j.drudis.2015.05.013.
- Arrowsmith J. Trial watch: phase II failures: 2008-2010. Nat. Rev. Drug Discov. 2011;10:328–329. doi: 10.1038/nrd3439.
- Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug Discov. 2013;12:569. doi: 10.1038/nrd4090.
- DiMasi JA, Reichert JM, Feldman L, Malins A. Clinical approval success rates for investigational cancer drugs. Clin. Pharmacol. Ther. 2013;94:329–335. doi: 10.1038/clpt.2013.117.
- Gao H, et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat. Med. 2015;21:1318–1325. doi: 10.1038/nm.3954.
- Vettore AL, et al. Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance. Genome Med. 2015;7:98. doi: 10.1186/s13073-015-0219-2.
- Wang W, et al. An eleven gene molecular signature for extra-capsular spread in oral squamous cell carcinoma serves as a prognosticator of outcome in patients without nodal metastases. Oral. Oncol. 2015;51:355–362. doi: 10.1016/j.oraloncology.2014.12.012.
- Carr TH, et al. Defining actionable mutations for oncology therapeutic development. Nat. Rev. Cancer. 2016;16:319–329. doi: 10.1038/nrc.2016.35.
- Nakahara T, et al. YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res. 2007;67:8014–8021. doi: 10.1158/0008-5472.CAN-07-1343.
- Yamauchi T, et al. Sepantronium bromide (YM155) induces disruption of the ILF3/p54(nrb) complex, which is required for survivin expression. Biochem. Biophys. Res. Commun. 2012;425:711–716. doi: 10.1016/j.bbrc.2012.07.103.
- Nakamura N, et al. Interleukin enhancer-binding factor 3/NF110 is a target of YM155, a suppressant of survivin. Mol. Cell. Proteomics. 2012;11:013243. doi: 10.1074/mcp.M111.013243.
- Cheng Q, et al. Suppression of survivin promoter activity by YM155 involves disruption of Sp1-DNA interaction in the survivin core promoter. Int. J. Biochem. Mol. Biol. 2012;3:179–197.
- Tan, et al. EGFR-AS1 long non-coding RNA mediates Epidermal Growth Factor Receptor addiction in squamous cell carcinoma. Nat. Med. (in the press).
- Rosenbluh J, et al. beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell. 2012;151:1457–1473. doi: 10.1016/j.cell.2012.11.026.
- Ota M, Sasaki H. Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling. Development. 2008;135:4059–4069. doi: 10.1242/dev.027151.
- Iyer NG, et al. Randomized trial comparing surgery and adjuvant radiotherapy versus concurrent chemoradiotherapy in patients with advanced, nonmetastatic squamous cell carcinoma of the head and neck: 10-year update and subset analysis. Cancer. 2015;121:1599–1607. doi: 10.1002/cncr.29251.
- Tannock IF, Hickman JA. Limits to personalized cancer medicine. N. Engl. J. Med. 2016;375:1289–1294. doi: 10.1056/NEJMsb1607705.
- Hunter DJ. Uncertainty in the era of precision medicine. N. Engl. J. Med. 2016;375:711–713. doi: 10.1056/NEJMp1608282.
- Prasad V, Fojo T, Brada M. Precision oncology: origins, optimism, and potential. Lancet Oncol. 2016;17:e81–e86. doi: 10.1016/S1470-2045(15)00620-8.
- Crystal AS, et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science. 2014;346:1480–1486. doi: 10.1126/science.1254721.
- Marangoni E, Poupon MF. Patient-derived tumour xenografts as models for breast cancer drug development. Curr. Opin. Oncol. 2014;26:556–561. doi: 10.1097/CCO.0000000000000133.
- Noll EM, et al. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nat. Med. 2016;22:278–287. doi: 10.1038/nm.4038.
- Bruna A, et al. A biobank of breast cancer explants with preserved intra-tumor heterogeneity to screen anticancer compounds. Cell. 2016;167:260–274. doi: 10.1016/j.cell.2016.08.041.
- van de Wetering M, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015;161:933–945. doi: 10.1016/j.cell.2015.03.053.
- Zhai W, et al. The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat. Commun. 2017;8:4565. doi: 10.1038/ncomms14565.
- Ricci F, et al. Patient-derived ovarian tumor xenografts recapitulate human clinicopathology and genetic alterations. Cancer Res. 2014;74:6980–6990. doi: 10.1158/0008-5472.CAN-14-0274.
- Choi SY, et al. Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv. Drug Deliv. Rev. 2014;79-80:222–237. doi: 10.1016/j.addr.2014.09.009.
- Cancer Genome Atlas Network Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576–582. doi: 10.1038/nature14129.
- Jerhammar F, et al. YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. Oral. Oncol. 2014;50:832–839. doi: 10.1016/j.oraloncology.2014.06.003.
- Mason KA, Hunter NR, Milas M, Abbruzzese JL, Milas L. Docetaxel enhances tumor radioresponse in vivo. Clin. Cancer Res. 1997;3:2431–2438.
- Hass MR, et al. SpDamID: marking DNA bound by protein complexes identifies notch-dimer responsive enhancers. Mol. Cell. 2015;59:685–697. doi: 10.1016/j.molcel.2015.07.008.
- Kumar V, et al. Uniform, optimal signal processing of mapped deep-sequencing data. Nat. Biotechnol. 2013;31:615–622. doi: 10.1038/nbt.2596.
- Subramanian A, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA. 2005;102:15545–15550. doi: 10.1073/pnas.0506580102.
- Benjamini Y, Yekutieli D. The control of the false discovery rate in multiple testing under dependency. Ann. Stat. 2001;29:1165–1188. doi: 10.1214/aos/1013699998.
- Krzywinski M, et al. Circos: an information aesthetic for comparative genomics. Genome Res. 2009;19:1639–1645. doi: 10.1101/gr.092759.109.
- Shannon P, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–2504. doi: 10.1101/gr.1239303.
- Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Preprint at (2013).
- Li H, et al. The sequence alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–2079. doi: 10.1093/bioinformatics/btp352.
- McKenna A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–1303. doi: 10.1101/gr.107524.110.
- Cibulskis K, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 2013;31:213–219. doi: 10.1038/nbt.2514.
- Wilm A, et al. LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets. Nucleic Acids Res. 2012;40:11189–11201. doi: 10.1093/nar/gks918.
- McLaren W, et al. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics. 2010;26:2069–2070. doi: 10.1093/bioinformatics/btq330.
Source: PubMed