RETRACTED ARTICLE: Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy

La, Vincent; Fujikawa, R.; Janzen, Deanna M.; Nunez, M.; Bainvoll, Liat; Hwang, Lih Hwa; Faull, Kym F.; Lawson, Gregory; Memarzadeh, Sanaz

doi:10.1038/s41698-017-0008-z

Cited by 10 publications

(3 citation statements)

References 40 publications

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“…Progress has been made in nearly 50% of carboplatin-resistant HGSOC by co-therapy with carboplatin and birinapant, a potent cIAP inhibitor, which re-sensitizes cells to carboplatin [48]. As a cisplatin derivative, carboplatin shares a similar mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations

Liu

Jiang

Nowak

et al. 2017

Cancer Chemother Pharmacol

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Purpose The mechanism of action of CNDAC (2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosyl-cytosine) is unique among deoxycytidine analogs because upon incorporation into DNA it causes a single strand break which is converted to a double strand break after DNA replication. This lesion requires homologous recombination (HR) for repair. CNDAC, as the parent nucleoside, DFP10917, and as an oral prodrug, sapacitabine, are undergoing clinical trials for hematological malignancies and solid tumors. The purpose of this study is to investigate the potential of CNDAC for the therapy of ovarian cancer (OC). Methods Drug sensitivity was evaluated using a clonogenic survival assay. Drug combination effects were quantified by median effect analysis. Results OC cells lacking function of the key HR genes, BRCA1 or BRCA2, were more sensitive to CNDAC than corresponding HR proficient cells. The sensitization was associated with greater levels of DNA damage in response to CNDAC at clinically achievable concentrations, manifested as chromosomal aberrations. Three classes of CNDAC-based drug combinations were investigated. First, the PARP1 inhibitors, rucaparib and talazoparib, were selectively synergistic with CNDAC in BRCA1/2 deficient OC cells (combination index < 1) at a relatively low concentration range. Second, cisplatin and oxaliplatin had additive combination effects with CNDAC (combination index ~ 1). Finally, paclitaxel and docetaxel achieved additive cell-killing effects with CNDAC at concentration ranges of the taxanes similar for both BRCA1/2 deficient and proficient OC cells. Conclusions This study provides mechanistic rationales for combining CNDAC with PARP inhibitors, platinum compounds and taxanes in ovarian cancer lacking BRCA1/2 function.

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Section: Discussionmentioning

confidence: 99%

Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations

Liu

Jiang

Nowak

et al. 2017

Cancer Chemother Pharmacol

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“…Therefore, birinapant is a promising candidate and has entered clinical trials (ClinicalTrial.gov identifiers: NCT01681368 and NCT01940172) for advanced platinum-resistant or relapsed epithelial ovarian cancer (EOC) (Table 1). More recent data suggest that birinapant is suitable for improving carboplatin sensitivity in platinum-resistant tumors with high levels of cellular IAP (cIAP) [52]. These observations further suggest that it is possible to promote apoptosis in platinum-resistant settings.…”

Section: Direct Targets In Apoptotic Pathwaysmentioning

confidence: 99%

Therapeutic Inducers of Apoptosis in Ovarian Cancer

Binju

Amaya-Padilla

Wan

et al. 2019

Cancers

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Ovarian cancers remain one of the most common causes of gynecologic cancer-related death in women worldwide. The standard treatment comprises platinum-based chemotherapy, and most tumors develop resistance to therapeutic drugs. One mechanism of developing drug resistance is alterations of molecules involved in apoptosis, ultimately assisting in the cells’ capability to evade death. Thus, there is a need to focus on identifying potential drugs that restore apoptosis in cancer cells. Here, we discuss the major inducers of apoptosis mediated through various mechanisms and their usefulness as potential future treatment options for ovarian cancer. Broadly, they can target the apoptotic pathways directly or affect apoptosis indirectly through major cancer-pathways in cells. The direct apoptotic targets include the Bcl-2 family of proteins and the inhibitor of apoptotic proteins (IAPs). However, indirect targets include processes related to homologous recombination DNA repair, micro-RNA, and p53 mutation. Besides, apoptosis inducers may also disturb major pathways converging into apoptotic signals including janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), wingless-related integration site (Wnt)/β-Catenin, mesenchymal-epithelial transition factor (MET)/hepatocyte growth factor (HGF), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homologue (AKT)/mammalian target of rapamycin (mTOR) pathways. Several drugs in our review are undergoing clinical trials, for example, birinapant, DEBIO-1143, Alisertib, and other small molecules are in preclinical investigations showing promising results in combination with chemotherapy. Molecules that exhibit better efficacy in the treatment of chemo-resistant cancer cells are of interest but require more extensive preclinical and clinical evaluation.

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“…Despite on-target activity and good tolerability, birinapant demonstrated minimal single-agent activity in recurrent ovarian cancer [ 11 ]. When combined with other cytotoxic therapies, however, synergistic cooperation occurred with greater sensitization of tumor cells to cytotoxic treatment [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer

Noonan

Cousins

Anderson

et al. 2020

Cancers

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Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.

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RETRACTED ARTICLE: Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy

Cited by 10 publications

References 40 publications

Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations

Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations

Therapeutic Inducers of Apoptosis in Ovarian Cancer

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer

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