Missing content? – Request curation!
Request curation for specific Genes, variants, or PubMed publications.
Have questions, comments or suggestions? - Let us know!
Email us at : firstname.lastname@example.org
|Ref Type||Journal Article|
|Authors||Tonsing-Carter E, Bailey BJ, Saadatzadeh MR, Ding J, Wang H, Sinn AL, Peterman KM, Spragins TK, Silver JM, Sprouse AA, Georgiadis TM, Gunter TZ, Long EC, Minto RE, Marchal CC, Batuello CN, Safa AR, Hanenberg H, Territo PR, Sandusky GE, Mayo LD, Eischen CM, Shannon HE, Pollok KE|
|Title||Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC.|
|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 mutant||triple-receptor negative breast cancer||predicted - sensitive||Carboplatin + Nutlin-3a||Preclinical - Cell culture||Actionable||In a preclinical study, Nutlin-3 and Paraplatin (carboplatin) synergistically inhibited growth in TP53 mutated triple-receptor negative breast cancer cell lines in culture and in cell line xenograft models (PMID: 26494859).||26494859|