TY - JOUR
T1 - A transcriptomics approach to expand therapeutic options and optimize clinical trials in oncology
AU - Lazar, Vladimir
AU - Zhang, Baolin
AU - Magidi, Shai
AU - Le Tourneau, Christophe
AU - Raymond, Eric
AU - Ducreux, Michel
AU - Bresson, Catherine
AU - Raynaud, Jacques
AU - Wunder, Fanny
AU - Onn, Amir
AU - Felip, Enriqueta
AU - Tabernero, Josep
AU - Batist, Gerald
AU - Kurzrock, Razelle
AU - Rubin, Eitan
AU - Schilsky, Richard L.
N1 - Publisher Copyright:
© The Author(s), 2023.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Background: The current model of clinical drug development in oncology displays major limitations due to a high attrition rate in patient enrollment in early phase trials and a high failure rate of drugs in phase III studies. Objective: Integrating transcriptomics for selection of patients has the potential to achieve enhanced speed and efficacy of precision oncology trials for any targeted therapies or immunotherapies. Methods: Relative gene expression level in the metastasis and normal organ-matched tissues from the WINTHER database was used to estimate in silico the potential clinical benefit of specific treatments in a variety of metastatic solid tumors. Results: As example, high mRNA expression in tumor tissue compared to analogous normal tissue of c-MET and its ligand HGF correlated in silico with shorter overall survival (OS; p < 0.0001) and may constitute an independent prognostic marker for outcome of patients with metastatic solid tumors, suggesting a strategy to identify patients most likely to benefit from MET-targeted treatments. The prognostic value of gene expression of several immune therapy targets (PD-L1, CTLA4, TIM3, TIGIT, LAG3, TLR4) was investigated in non-small-cell lung cancers and colorectal cancers (CRCs) and may be useful to optimize the development of their inhibitors, and opening new avenues such as use of anti-TLR4 in treatment of patients with metastatic CRC. Conclusion: This in silico approach is expected to dramatically decrease the attrition of patient enrollment and to simultaneously increase the speed and detection of early signs of efficacy. The model may significantly contribute to lower toxicities. Altogether, our model aims to overcome the limits of current approaches.
AB - Background: The current model of clinical drug development in oncology displays major limitations due to a high attrition rate in patient enrollment in early phase trials and a high failure rate of drugs in phase III studies. Objective: Integrating transcriptomics for selection of patients has the potential to achieve enhanced speed and efficacy of precision oncology trials for any targeted therapies or immunotherapies. Methods: Relative gene expression level in the metastasis and normal organ-matched tissues from the WINTHER database was used to estimate in silico the potential clinical benefit of specific treatments in a variety of metastatic solid tumors. Results: As example, high mRNA expression in tumor tissue compared to analogous normal tissue of c-MET and its ligand HGF correlated in silico with shorter overall survival (OS; p < 0.0001) and may constitute an independent prognostic marker for outcome of patients with metastatic solid tumors, suggesting a strategy to identify patients most likely to benefit from MET-targeted treatments. The prognostic value of gene expression of several immune therapy targets (PD-L1, CTLA4, TIM3, TIGIT, LAG3, TLR4) was investigated in non-small-cell lung cancers and colorectal cancers (CRCs) and may be useful to optimize the development of their inhibitors, and opening new avenues such as use of anti-TLR4 in treatment of patients with metastatic CRC. Conclusion: This in silico approach is expected to dramatically decrease the attrition of patient enrollment and to simultaneously increase the speed and detection of early signs of efficacy. The model may significantly contribute to lower toxicities. Altogether, our model aims to overcome the limits of current approaches.
KW - analogous normal tissue biopsies
KW - clinical trials
KW - oncology
KW - transcriptomics
KW - tumor biopsies
UR - http://www.scopus.com/inward/record.url?scp=85152061053&partnerID=8YFLogxK
U2 - 10.1177/17588359231156382
DO - 10.1177/17588359231156382
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 37025260
AN - SCOPUS:85152061053
SN - 1758-8340
VL - 15
JO - Therapeutic Advances in Medical Oncology
JF - Therapeutic Advances in Medical Oncology
ER -