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|Ref Type||Journal Article|
|Authors||Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS|
|Title||PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2011 May 01|
|Abstract Text||Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1(Met) (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1(Met) to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations.The therapeutic effect of PRIMA-1(Met)/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1(Met)/APR-246 was further evaluated in two different SCLC xenograft models.PRIMA-1(Met)/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1(Met)/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1(Met)/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1(Met) after i.v. injection in SCLC mouse models with no apparent toxicity.This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1(Met)/APR-246 for the treatment of SCLC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|TP53 inact mut||lung small cell carcinoma||sensitive||APR-246||Preclinical - Cell line xenograft||Actionable||In a preclinical study, APR-246 induced apoptosis in small-cell lung cancer (SCLC) cell lines and decreased tumor growth in SCLC cell line xenograft models harboring Tp53 inactivating mutations (PMID: 21415220).||21415220|
|TP53 S241F||lung small cell carcinoma||sensitive||APR-246||Preclinical - Cell line xenograft||Actionable||In a preclinical study, APR-246 demonstrated efficacy in xenograft models of small cell lung cancer harboring TP53 S241F (PMID: 21415220).||21415220|
|TP53 R273L||lung small cell carcinoma||sensitive||APR-246||Preclinical - Cell line xenograft||Actionable||In a preclinical study, APR-246 demonstrated efficacy in cell line xenograft models of small cell lung cancer harboring TP53 R273L (PMID: 21415220).||21415220|