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From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma.

ABSTRACT: Although tumor molecular-profile-directed therapy appears promising in early clinical studies, there are many practical challenges to its successful clinical application in non-small-cell lung cancer (NSCLC). These challenges may be broadly classified as those relating to tumor (heterogeneity), tissue (acquisition and processing), testing (assays for molecular profiling) and trials (clinical evaluation of molecular markers and drugs). Strategies to overcome these challenges include (i) understanding the biological basis of tumor heterogeneity and of carcinogenesis in the large subset of patients with no currently evident driver events; (ii) technological advances in minimally invasive acquisition of tumor and next-generation sequencing (NGS) which would enable single-platform analysis of molecular alterations in limited tissue at a reasonable turnaround time (TAT); (iii) deliberation in early stages of drug development as well as clinical trial design to identify, validate and assess the clinical utility of biomarkers in conjunction with drugs and (iv) collaboration to improve understanding of and accrual to trials enrolling patients with rare molecular alterations.

SUBMITTER: Thomas A

PROVIDER: S-EPMC3574546 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma.

Thomas A A Rajan A A Lopez-Chavez A A Wang Y Y Giaccone G G

Annals of oncology : official journal of the European Society for Medical Oncology 20121106 3

Although tumor molecular-profile-directed therapy appears promising in early clinical studies, there are many practical challenges to its successful clinical application in non-small-cell lung cancer (NSCLC). These challenges may be broadly classified as those relating to tumor (heterogeneity), tissue (acquisition and processing), testing (assays for molecular profiling) and trials (clinical evaluation of molecular markers and drugs). Strategies to overcome these challenges include (i) understan ...[more]

PMID: 23131389

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Project description:The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and advantageous in overcoming treatment resistance compared with monotherapy approaches. Understanding the role of the tumor microenvironment in the development and maintenance of the malignant phenotype provided additional therapeutic approaches as well. More recently, improved knowledge on tumor immunology has set the stage for promising immunotherapies in NSCLC. This review will focus on the rationale for the development of targeted therapies in NSCLC and the various strategies employed in preventing or overcoming the inevitable occurrence of treatment resistance.

Dataset Information

From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma.

Publications

From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma.

Similar Datasets

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