title: A Pipeline for Drug Target Identification and Validation.
abstract: Rapid and affordable tumor profiling has led to an explosion of genomic data that is facilitating the development of new cancer therapies. The potential of therapeutic strategies aimed at inactivating the oncogenic lesions that contribute to the aberrant survival and proliferation of tumor cells has yielded remarkable success in some malignancies such as BRAF-mutant melanoma and BCR-ABL expressing chronic myeloid leukemia. However, the direct inhibition of several well-established oncoproteins in some of these cancers is not possible or produces only transient benefits. Functional genomics represents a powerful approach for the identification of vulnerabilities linked to specific genetic alterations and has provided substantial insights into cancer signaling networks. Still, as inhibition of gene function can have diverse effects on both tumor and normal tissues, information on the potency of target inhibition on tumor growth as well as the toxic side effects of target inhibition are also needed. Here, we discuss our RNA interference (RNAi) pipeline for cancer target discovery based on our optimized short-hairpin RNA (shRNA) tools for negative selection screens and inducible RNAi platform that, in combination with embryonic stem cell (ESC)-based genetically engineered mouse models (GEMMs), enable deep in vivo target validation.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Manchado
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065.|Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York 10065.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724.
authors.forename: Nilgun
authors.initials: N
authors.lastname: Tasdemir
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
authors.forename: Darjus F
authors.initials: DF
authors.lastname: Tschaharganeh
authors.affiliation: ULAM/Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109.
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065.|Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York 10065.|Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering