23IN - Targets, targets everywhere but not a drug to give

Date 28 September 2014
Event ESMO 2014
Session Molecular profiling: Challenges and perspectives
Topics Clinical research
Pathology/Molecular Biology
Basic Scientific Principles
Presenter Udai Banerji
Citation Annals of Oncology (2014) 25 (suppl_4): iv9-iv10. 10.1093/annonc/mdu294
Authors U. Banerji
  • Cr-uk Cancer Therapeutics Unit, Drug Development Unit, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, SM2 5NG - London/GB

Abstract

Body

Abstract:

In the era of precision medicine, enabled by affordable next generation sequencing oncologists are often faced with patients requiring treatment and reports describing mutations, amplifications or deletions of oncogenes and tumour suppressor genes. The challenge can be broadly classified into four areas: Drug directly targeting genomic abnormality available: Identifying activating mutations in genes (KIT, EGFR) can lead to the recommendation of drugs targeting those oncogenes however, there are exceptions e.g., BRAF mutations predict for BRAF inhibitor responses in melanoma but not colorectal cancer. Also, not all mutations in oncogenes are activating and reports often do not specify this. The presence of amplifications have been successfully exploited for use of HER-2 targeting drugs, however, the answer is less certain for MET and FGFR amplifications predicting responses to MET and FGFR inhibitors. Drug directly targeting genomic abnormality not available: Loss of function of tumour suppressor genes like PTEN and P53 are increasingly used to enrich trials with patients with PI3Kb and CHK inhibitors respectively. There are multiple validated oncogenes where activating mutations (KRAS) and amplification (MYC) are known drivers but are currently considered not directly druggable. Combining signal transduction inhibitors (MEK + AKT inhibitors for KRAS mutations) or targeting proteins regulating the targets (bromodomain inhibitors for MYC amplifications) are some approaches that could be considered. Drugs targeting broad oncogenic processes available but genomic abnormalities not always clearly defined: Drugs such as HDAC, proteasome, VEGFR, HSP90 and CDK4 inhibitors fall in this category. Drugs that do no target genetic abnormalities in tumour available: Trials of immune check point inhibitors that target T cells (PD-1 and CTLA4 inhibitors) are not currently helped by gene mutation and copy number data. Emerging technological advances in proteomics and transcriptomics requiring complex bioinformatics approaches in the future will pose further challenges and exciting opportunities.

Disclosure:

U. Banerji: The author is an employee of The Institute of Cancer Research which has commercial interests in Androgen regulating drugs, HSP90, PI3K, AKT, HDAC and BRAF inhibitors.