مقالات پذیرفته شده در سومین کنگره بین المللی زیست پزشکی
pharmacogenetics and non-small cell Lung Cancer
pharmacogenetics and non-small cell Lung Cancer
Fereshteh Moheb Afzali ,1,*
1. Department of Molecular and Cellular Biology , Faculty of Advanced Sciences and Technology , Tehran Medical Sciences Branch , Islamic Azad University , Tehran, Iran.
Introduction: Lung cancer is the leading cause of cancer-related death world wide. Non-small cell lung cancer (NSCLC) is aprevalent and rapidly-expanding challenge to modern medicine.
While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, the cornerstone of personalized medicine using genetic profiling to direct treatment has exalted the successes seen in the field and raised the standard for patient treatment in lung and other cancers.
In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity.
Methods: In this a review study, was initially conducted computer search in electronic data bases: PubMed, Embase, Cochrane Library, SCOPUS, OVID, Springer.
Studies eligible for this analysis were updated using the search terms, NSCLC, chemotherapy, patents, polymorphism, pharmacogenomics analysis and ELM4-ALK, EGFR, AKT, HER2, ABCG2,CYP.The inclusion criteria were as follows: (i) Only patients with advanced NSCLC were considered; (ii) All trials had to include a treatment of platinum-based agent, i.e. Cetuximab, Gefitinib, Erlotinib ,Ceritinib, Crizotinib , Afatinib (iii) Patents were downloaded from: http://www.delphion.com/fcgibin/ patsearch, www.google.com/patents, www.uspto.gov, www.freepatentsonline.com, and www.wipo.int/pctdb/en/search-simp.jsp, www.freshpatents.com.
Results: The epidermal growth factor receptor (EGFR) has been successfully targeted either by monoclonal antibodies or small molecules inhibiting the tyrosine kinase (TK) domain. The monoclonal antibody cetuximab blocks the extracellular domain of EGFR, there by competing with the ligands, and has been approved as first-line treatment combined with platinum-based chemotherapy in EGFR-positive non-small cell Lung Cancer (NSCLC) patients with good performance status . The EGFR tyrosine kinase inhibitor (TKI) gefitinib has been approved by FDA and EMEA as upfront therapy replacing chemotherapy in late-stage NSCLC patients harboring activating EGFR mutations . The manageable toxicity, along with its efficacy, make erlotinib an important option also as maintenance therapy, and erlotinib and gefitinib are the only drugs of proven efficacy in the third-line setting for NSCLC.
Another example of targeted therapy is the anaplastic lymphoma kinase (ALK) inhibitor crizotinib, which has been approved by FDA for the treatment of locally advanced or metastatic NSCLCs with the fusion-type protein kinase echinoderm microtubule-associated protein-like 4 (EML4)–ALK translocation. This traslocation occurs in up to 5% of NSCLC tumors as a result of a small inversion within the short arm of human chromosome 2.1.
Fusion of EML4 with ALK enables ALK to dimerize ligand independently, resulting in an aberrantly active protein. Aberrant expression of the EML4-ALK fusion protein activates several pathways important for cell survival and cell proliferation such as PI3K, JAK3/STAT, and Ras/Mek/Erk pathways .
The fast-tracked FDA approval of crizotinib, as well as of the second-generation ALK inhibitor ceritinib, which inhibits two of the most common ALK mutants that confer resistance to crizotinib, L1196M and G1202R, is due to the excellent clinical trial design and should set an example for future cancer drug development. The efficacy of these compounds in NSCLC patients is indeed based on well-researched mechanisms and proven to be a solid choice as therapy for NSCLC.
Conclusion: Personalized medicine has become indispensable to formulating effective treatment plans mainly due to the etiological diversity of lung cancer. However, resistance, both as a response to treatment and as an innate trait, is a complicating factor in personalized medicine as well as alasting bane for effective cancer treatment . Genetic determination for metabolic rate, proper target protein, and circumvention of natural resistance has become commonplace among the factors that physicians must consider when choosing the best line of therapy for their patients.
Advances into the knowledge of the genetics of lung cancer have recently identified key biological processes and molecular targets for antitumor treatment. Novel agents targeting these aberrant processes have revolutionized the management of specific molecular subsets of NSCLC and have greatly contributed to recent improvements in survival rates. For example, EGFR mutant and EML4-ALK fusion status, which are detected in approximately15% and 4% of lung adenocarcinomas, predict response to therapies with selective inhibitors. These results led to the approval of EGFR-TKIs and the ALK inhibitors as first-line treatments in molecularly selected NSCLC patients.