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Crizotinib

Crizotinib is an orally bioavailable agent belonging to the class of c-met/hepatocyte growth factor receptor (HGFR) tyrosine kinase inhibitors with potential antineoplastic activity. Crizotinib was approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and childre. Crizotinib inhibits the membrane receptor MET and activation of the MET signaling pathway, which may block tumor cell growth, migration and invasion, and tumor angiogenesis in susceptible tumor cell populations. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

Current developer:    Pfizer.

Crizotinib (also known as PF-02341066 or 1066), is an ALK (anaplastic lymphoma kinase) inhibitor of the aminopyridine chemical series that is being developed by Pfizer Incorporated.  In August 2011, FDA approved XALKORI® (crizotinib) capsules, the first-ever therapy targeting anaplastic lymphoma kinase (ALK), for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by an FDA-approved test. The effectiveness of XALKORI is based on objective response rates (ORR) and, as XALKORI received accelerated approval from the FDA, Pfizer is conducting post-marketing clinical trials to further evaluate its clinical benefit. XALKORI represents a new chapter in personalized therapy for lung cancer, enabling physicians to provide the right treatment for the right patient.

Mechanism of action

Crizotinib is an ALK (anaplastic lymphoma kinase) inhibitor under study in patients with advanced NSCLC carrying the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene. The protein product of this fusion has constitutive kinase activity that is carcinogenic. Crizotinib competes with ATP for the ALK kinase domain of this fusion protein. The ELM4-ALK fusion transcript was first described in a 2007 study published in Nature. Not all patients with lung cancer or NSCLC carry the ELM4-ALK fusion. Patients with this gene inversion are typically non-smokers who do not have mutations in the epidermal growth factor receptor gene (EGFR) or in the KRAS gene. Approximately 4% of the 220,000 Americans diagnosed with lung cancer each year have the ALK fusion gene, and 45,000 newly diagnosed NSCLC patients are ALK positive worldwide. ALK gene mutations are also thought to be important in driving the malignant phenotype in a significant percentage (15%) of cases of neuroblastoma, a rare form of nervous system cancer that occurs almost exclusively in very young children. Crizotinib is also an inhibitor of the c-Met/Hepatocyte Growth Factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of cancer. Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies suggest that Crizotinib may also act via inhibition of angiogenesis in malignant tumors. (source:http://en.wikipedia.org/wiki/Crizotinib.)

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2: Shaw AT, Solomon B, Kenudson MM. Crizotinib and Testing for ALK. J Natl Compr Canc Netw. 2011 Dec 1;9(12):1335-41. PubMed PMID: 22157554.

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8: Christensen JG. Proof of Principle for Crizotinib in Anaplastic Lymphoma Kinase-Positive Malignancies Was Achieved in ALK-Positive Nonclinical Models. Mol Cancer Ther. 2011 Nov;10(11):2024. PubMed PMID: 22072808.

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27: Ou SH, Bazhenova L, Camidge DR, Solomon BJ, Herman J, Kain T, Bang YJ, Kwak EL, Shaw AT, Salgia R, Maki RG, Clark JW, Wilner KD, Iafrate AJ. Rapid and dramatic radiographic and clinical response to an ALK inhibitor (crizotinib, PF02341066) in an ALK translocation-positive patient with non-small cell lung cancer. J Thorac Oncol. 2010 Dec;5(12):2044-6. PubMed PMID: 21102269.

28: Hallberg B, Palmer RH. Crizotinib--latest champion in the cancer wars? N Engl J Med. 2010 Oct 28;363(18):1760-2. PubMed PMID: 20979477.

29: Butrynski JE, D'Adamo DR, Hornick JL, Dal Cin P, Antonescu CR, Jhanwar SC, Ladanyi M, Capelletti M, Rodig SJ, Ramaiya N, Kwak EL, Clark JW, Wilner KD, Christensen JG, Jänne PA, Maki RG, Demetri GD, Shapiro GI. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010 Oct 28;363(18):1727-33. PubMed PMID: 20979472; PubMed Central PMCID: PMC3014292.