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Published on: January 22, 2011
Personal Mutanomes Meet Modern Oncology Drug Discovery and Precision Health
Feixiong Cheng1, Han Liang2, Atul J Butte2
1Genomic Medicine Institute, Lerner Research Institute (F.C., C.E.) and Taussig Cancer Institute (C.E.), Cleveland Clinic, Cleveland, Ohio; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio (F.C., C.E.); CASE Comprehensive Cancer Center (F.C., C.E.) and Department of Genetics and Genome Sciences (C.E.), Case Western Reserve University School of Medicine, Cleveland, Ohio; Departments of Bioinformatics and Computational Biology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.L.); Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, California (A.J.B.); Center for Data-Driven Insights and Innovation, University of California Health, Oakland, California (A.J.B.); Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland (R.N.); and Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (R.N.) chengf@ccf.org engc@ccf.org nussinor@mail.nih.gov.
None:
Recent remarkable advances in genome sequencing have enabled detailed maps of identified and interpreted genomic variation, dubbed "mutanomes." The availability of thousands of exome/genome sequencing data has prompted the emergence of new challenges in the identification of novel druggable targets and therapeutic strategies. Typically, mutanomes are viewed as one- or two-dimensional. The three-dimensional protein structural view of personal mutanomes sheds light on the functional consequences of clinically actionable mutations revealed in tumor diagnosis and followed up in personalized treatments, in a mutanome-informed manner. In this review, we describe the protein structural landscape of personal mutanomes and provide expert opinions on rational strategies for more streamlined oncological drug discovery and molecularly targeted therapies for each individual and each tumor. We provide the structural mechanism of orthosteric versus allosteric drugs at the atom-level via targeting specific somatic alterations for combating drug resistance and the "undruggable" challenges in solid and hematologic neoplasias. We discuss computational biophysics strategies for innovative mutanome-informed cancer immunotherapies and combination immunotherapies. Finally, we highlight a personal mutanome infrastructure for the emerging development of personalized cancer medicine using a breast cancer case study.
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