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2016 ; 81
(ä): 257-267
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A Pipeline for Drug Target Identification and Validation
#MMPMID28057848
Manchado E
; Huang CH
; Tasdemir N
; Tschaharganeh DF
; Wilkinson JE
; Lowe SW
Cold Spring Harb Symp Quant Biol
2016[]; 81
(ä): 257-267
PMID28057848
show ga
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.
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