Prediction of cancer response to drugs
Drugs that target VEGF and mTOR signalling, namely sunitinib and everolimus, have been successfully developed for the treatment of renal cell carcinoma. However, in many cases, renal cancer patients develop resistance and tumours metastasise to distant sites. It would be beneficial if clinicians could predict patient response to these drugs. Towards this goal, the EU-funded PREDICT (Predicting individual response and resistance to VEGFR/mTOR pathway therapeutic intervention using biomarkers discovered through tumour functional genomics) project set out to identify biomarkers predictive of the therapeutic response to novel interventions in cancer. For this purpose, they performed molecular analysis on tumour biopsies with powerful technologies such as next generation sequencing and siRNA interference. Results demonstrated the presence of intra-tumour heterogeneity in renal cancer with most known cancer-driver events being subclonal. This clearly suggested that biomarkers based on the oncogenic mechanisms would not be representative of the entire tumour. In addition, scientists observed the evolution of minor subclones into lethal drug-resistant and metastatic clones, further supporting the intra-tumour heterogeneity of renal cancer. To address this issue, the consortium performed analytical profiling on multiple regions of the same tumour. Multi-region whole exome sequencing allowed scientists to resolve the genetic architecture and evolutionary histories of renal cancer. To address one of the main problems in translational oncology, the consortium established a large number of in vivo xenograft models and in vitro cell cultures from patient material. siRNA screens led to the identification of 13 candidate genes whose expression correlated with drug sensitivity, while an additional 17 genes sensitised renal cancer cells to everolimus treatment and could act as new drug targets. Furthermore, the consortium discovered replication stress as a mechanism for intra-tumour heterogeneity that led to structural chromosome aberrations and mis-segregation. Intra-tumour heterogeneity has been identified as a key factor in the emergence of drug resistance. Despite the great implications of this heterogeneity on cancer evolution and treatment, PREDICT researchers offered strategies for the development of therapeutic interventions and the identification of clinical biomarkers for renal cancer.
Keywords
Renal cell carcinoma, biomarker, VEGF, mTOR signalling, intra-tumour heterogeneity, xenograft
