Revolution in Understanding Genetic Contributions to the Research Paper

Excerpt from Research Paper :

revolution in understanding genetic contributions to the susceptibility for developing particular diseases and disorders has been the development of the notion of "personalized medicine." The "personalized" connotation of this growing facet in the practice does not refer to individualized treatments as much as it refers to a personalizing of treatments targeted at a specific subset of patients, for example the development of certain drugs that can target specific cancer-causing genes found in patients' tumors. A drug currently being reviewed by the FDA for release is crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor. ALK is believed to be active in several different types of tumors, including about five percent of non-small-cell lung carcinomas (NSCLC). In patients with advanced NSCLC it has been found that those carrying the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene possess a protein product of this fusion that contains a constitutive kinase activity that is carcinogenic (Christensen et al., 2007). EML4-ALK is a fusion oncogene. It was first discovered in 2007 and is found predominantly in people who do not smoke or in light smokers with a 10 pack or less history of tobacco use. It is also found in younger patients and those with adenocarcinoma histology (Ku & Lima Jopes Jr., 2011). Crizotinib is a direct inhibitor of the enzyme produced by the mutated gene.

Treatment with crizotinib offers two main advantages: 1) it is vastly superior to chemotherapy which only is effective in about 10% of such advanced cancers, and 2) because the targeted gene is not found in healthy cells treatment with crizotinib results in far fewer serious side effects than chemotherapy. Trials of crizotinib for use in the treatment of NSCLC have been underway since 2006. About 10,000 of the 222,000 Americans diagnosed with non-small-cell lung cancer each year could be expected to have the genetic abnormality and it is estimated that 50,000 people worldwide have it (Christensen et al., 2007). The medication was shifted to the fast track category by the Food and Drug Administration (FDA) so that Pfizer Inc., the drug's manufacturer, could submit efficacy data to the FDA without waiting for studies to be completed. The empirical evidence supporting crizotinib is impressive.

In Phase II clinical trial of 82 patients with ALK-rearranged advanced non-small-cell lung cancer oral crizotinib was administered on a continuous daily schedule. The overall response rate at a mean treatment duration of 6.4 months was 57%, an unheard of response rate for refractory lung cancer (Kwak et al., 2010). The researchers expected to see results in only about 10% of the 82 initial patients in the study, all of whom were in advanced stages of the disease. Instead, there were reports of tumor shrinkage in over 90% of the cases (Bang et al., 2010). A total of 63 of the 82 patients continued to receive crizotinib at the time of data cutoff with an estimated probability of 6-month progression-free survival of 72%. Crizotinib produced few side effects; in this study the drug produced mild gastrointestinal side effects and mild visual symptoms that wore off over time (Bang et al., 2010; Kwak et al., 2010).

Dr. Alice Shaw of the Massachusetts General Hospital Cancer Center reported the results of 119 patients with ALK-positive lung cancer treated with crizotinib. At a one year follow-up 74% of the patients were still alive; after a two-year follow-up 54% were still living. Treatment with the drug led to shrinkage in a majority of tumors in the patients and a dramatic response in more than 60% of the sample lasting about 48 weeks. This study did not have a control group, but studies following similar patients treated with chemotherapy have found a 44% survival after one year follow-up and a 12% survival rate after two years (Shaw & Solomon, 2011).

Phase III trials appear to be nearing completion at the time of this writing and it appears that Pfizer will have the go ahead to release the drug later this year. NSCLC is one of the most frustrating cancers…

Sources Used in Document:


Bang, Y., Kwak, E.L., Shaw, A.T. et al. (2010). Clinical activity of the oral ALK inhibitor PF- 02341066 in ALK-positive patients with nonsmall cell lung cancer (NSCLC). Journal of Clinical Oncology, 28 (18S), 3.

Christensen, J.G., Zou, H.Y., Arango, M.E., Li, Q., Lee, J.H., McDonnell, S.R., Yamazaki, S., Alton, G.R., Mroczkowski, B., & Los G. (2007). Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Molecular Cancer Therapy, 6, 3314-3322.

Ku, G.Y. & Lima Jopes Jr., G. (2011). EML4-ALK in non-small-cell lung cancer: the breathtaking progress from benchtop to Phase III clinical trial. Therapy, 8(1)55-61.

Kwak, E.L., Bang, Y.J., Camidge, D.R. et al. (2010). Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine, 263(18), 1693- 1703.

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