A transcriptomics approach to expand therapeutic options and optimize clinical trials in oncology

Vladimir Lazar*, Baolin Zhang, Shai Magidi, Christophe Le Tourneau, Eric Raymond, Michel Ducreux, Catherine Bresson, Jacques Raynaud, Fanny Wunder, Amir Onn, Enriqueta Felip, Josep Tabernero, Gerald Batist, Razelle Kurzrock, Eitan Rubin, Richard L. Schilsky

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalTherapeutic Advances in Medical Oncology
Volume15
DOIs
StatePublished - 1 Jan 2023
Externally publishedYes

Keywords

  • analogous normal tissue biopsies
  • clinical trials
  • oncology
  • transcriptomics
  • tumor biopsies

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