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|Ref Type||Journal Article|
|Authors||Hansen JB, Fisker N, Westergaard M, Kjaerulff LS, Hansen HF, Thrue CA, Rosenbohm C, Wissenbach M, Orum H, Koch T|
|Title||SPC3042: a proapoptotic survivin inhibitor.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||The ability to regulate the cellular homeostasis of a higher organism through tight control of apoptosis and cell division is crucial for life. Dysregulation of these mechanisms is often associated with cancerous phenotypes in cells. Optimal cancer therapy is a fine balance between effective cancer cell killing and at the same time minimizing, or avoiding, damage to the surrounding healthy tissue. To obtain this, it is necessary to identify and inhibit molecular targets on which the cancer cells are strongly dependent. Survivin represents such a target, and it has been published previously that peptide vaccines, the small-molecule YM155, and the antisense molecule LY2181308/ISIS23722, via different mechanisms, have been used as survivin inhibitors. In this article, a new potent antisense inhibitor of survivin, SPC3042, is presented, and the properties of SPC3042 are compared with the previously published antisense drug, LY2181308/ISIS23722. SPC3042 is a 16-mer locked nucleic acid (LNA) oligonucleotide and designed as a fully phosphorothiolated gapmer containing 7 LNA nucleotides in the flanks. The LNA nucleotides in SPC3042 provide nuclease stability and higher potency for survivin mRNA inhibition compared with earlier generations of antisense reagents. It is shown that the down-regulation of survivin with SPC3042 leads to cell cycle arrest, pronounced cellular apoptosis, and down-regulation of Bcl-2. It is also shown that SPC3042 is a sensitizer of prostate cancer cells to Taxol treatment in vitro and in vivo.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|SPC3042||SPC-3042||SPC3042 is an antisense oligonuecliotide that targets Survivin leading to decreased Survivin expression, which may result in increased tumor cell apoptosis and increased sensitivity to chemotherapeutics (PMID: 18790754, PMID: 20024838).|
|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|
|Unknown unknown||prostate cancer||not applicable||SPC3042||Preclinical||Actionable||In a preclinical study, SPC3042 decreased Survivin expression and induced apoptosis of prostate cancer cells in culture (PMID: 18790754).||18790754|
|Unknown unknown||prostate cancer||not applicable||Paclitaxel + SPC3042||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of SPC3042 and Taxol (paclitaxel) worked synergistically to inhibit tumor growth in prostate cancer cell line xenograft models, with increased activity over either agent alone (PMID: 18790754).||18790754|