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

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.

Large-scale assessment of pros and cons of autopsy-derived or tumor-matched tissues as the norms for gene expression analysis in cancers

“…For instance, transcriptomic profiling, compared to DNA mutation-based approach, was reported to substantially extend the cohort of patients who could receive benefit from personalized molecular diagnostics, and prescription of the corresponding targeted therapies. This could increase median overall survival, as well as the speed and efficiency of clinical trials [67] , [68] , [69] .…”

The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors

“…An objective response rate is the primary endpoint in both studies and preliminary results from subcohorts consisting of TGCT patients are eagerly awaited. Interestingly, preclinical evidence suggests an interplay and direct interaction between Nectin-4 and TIGIT as well as an upregulation of TIGIT and other immune-suppressive signals in metastatic compared to primary sites [69,70]. These observations could be applicable in TGCT biology as well and merit further investigation in the clinical setting.…”