A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma

Amaravadi, Ravi K.; Schilder, Russell J.; Martin, Lainie P.; Levin, Myron J.; Graham, Martin A.; Weng, David E.; Adjei, Alex A.

doi:10.1158/1535-7163.mct-15-0475

Cited by 99 publications

(78 citation statements)

References 30 publications

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“…21,22 Moreover, there are several ongoing clinical studies to prove the antitumor efficacy of SMAC mimetics either alone or in combination with chemotherapy in different tumor types. 23,24 One of the recently developed SMAC mimetics is BV6, which binds to BIR domains of IAPs leading to their ubiquitination, followed by proteosomal degradation and inhibition of XIAP-mediated inhibition of caspases. 25,26 In the present study, we sought to explore the cytotoxic effects of BV6 in numerous human cancer cells.…”

Section: Introductionmentioning

confidence: 99%

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

El-Mesery

Shaker

Elgaml

2016

Exp Biol Med (Maywood)

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The inhibitors of apoptosis proteins are implicated in promoting cancer cells survival and resistance toward immune surveillance and chemotherapy. Second mitochondria-derived activator of caspases (SMAC) mimetics are novel compounds developed to mimic the inhibitory effect of the endogenous SMAC/DIABLO on these IAPs. Here, we examined the potential effects of the novel SMAC mimetic BV6 on different human cancer cell lines. Our results indicated that BV6 was able to induce cell death in different human cancer cell lines. Mechanistically, BV6 dose dependently induced degradation of IAPs, including cIAP1 and cIAP2. This was coincided with activating the non-canonical NF-kappa B (NF-kB) pathway, as indicated by stabilizing NF-kB-inducing kinase (NIK) for p100 processing to p52. More interestingly, BV6 was able to sensitize some of the resistant cancer cell lines to apoptosis induced by the death ligands tumor necrosis factor-a (TNF-a) and TNF-related apoptosis-inducing ligand (TRAIL) that are produced by different cells of the immune system. Such cell death enhancement was mediated by inducing an additional cleavage of caspase-9 to augment that of caspase-8 induced by death ligands. This eventually led to more processing of the executioner caspase-3 and poly (ADP-ribose) polymerase (PARP). In conclusion, therapeutic targeting of IAPs by BV6 might be an effective approach to enhance cancer regression induced by immune system. Our data also open up the future possibility of using BV6 in combination with other antitumor therapies to overcome cancer drug resistance.

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Section: Introductionmentioning

confidence: 99%

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

El-Mesery

Shaker

Elgaml

2016

Exp Biol Med (Maywood)

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“…Birinapant is a SMAC mimetic that demonstrated activity in FADD and IAP amplified tumor models in combination with death factors TNF and TRAIL, and radiation 52. Seven patients with HNSCC out of a cohort of 50 patients were treated with the bivalent SMAC mimetic with dose range of 0.18 to 63 mg/m3 in a 3 + 3 dose escalation design once weekly, defining a phase II dose 53. Debio 1143 is SMAC mimetic that antagonizes IAP activity (XIAP, cIAP‐1, 2, and ML‐IAP) and promotes apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Genomics and advances towards precision medicine for head and neck squamous cell carcinoma

Waes

Musbahi

2017

Laryngoscope Investig Oto

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ObjectiveTo provide a review of emerging knowledge from genomics and related basic science, preclinical, and clinical precision medicine studies in head and neck squamous cell carcinoma (HNSCC).Data SourcesThe Cancer Genome Atlas Network (TCGA) publications, PubMed‐based literature review, and ClinicalTrials.gov.Review MethodsTCGA publications, PubMed, and ClinicalTrials.gov were queried for genomics and related basic science, preclinical, and developmental clinical precision medicine studies in HNSCC.ResultsTCGA reported comprehensive genomic analyses of 279 HNSCC, defining the landscape and frequency of chromosomal copy number alterations, mutations, and expressed genes that contribute to pathogenesis, prognosis, and resistance to therapy. This provides a road map for basic science and preclinical studies to identify key pathways in cancer and cells of the tumor microenvironment affected by these alterations, and candidate targets for new small molecule and biologic therapies.ConclusionRecurrent chromosomal abnormalities, mutations, and expression of genes affecting HNSCC subsets are associated with differences in prognosis, and define molecules, pathways, and deregulated immune responses as candidates for therapy. Activity of molecularly targeted agents appears to be enhanced by rational combinations of these agents and standard therapies targeting the complex alterations that affect multiple pathways and mechanisms in HNSCC.Level of EvidenceNA.

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“…Following binding to the corresponding IAPs, a pro-apoptotic effect is caused by the degradation of proteins by proteasomes (22,23). Thus far, several monovalent and bivalent SMAC mimetics have entered clinical testing for dose escalation, mono therapy or combination therapy with chemotherapy and/or radiation (12,(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis-sensitizing activity of birinapant in head and neck squamous cell carcinoma cell lines

et al. 2018

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Abstract. Inhibitor of apoptosis proteins, which are overexpressed in head and neck squamous cell carcinoma (HNSCC), may cause therapeutic resistance. Using SMAC mimetic compounds, including birinapant, to degrade and/or inhibit these proteins and sensitize apoptosis may enhance therapies in HNSCC. Fas expression was analyzed in nine HNSCC cell lines and one keratinocyte cell line via flow cytometry. These cell lines were treated with Fas ligand-Fc (FasL) and birinapant, a bivalent SMAC mimetic, in mono and combination therapies. Cytotoxicity was measured using a crystal violet assay. Annexin V assay was performed for detection of apoptosis. The treatment efficacy of mono and combination therapies was statistically analyzed. Nonlinear regression analysis was performed to determine the inhibitory concentration (IC 10 ) of birinapant. Fas expression was detected in each cell line tested. Mono treatment with FasL revealed minor to no apoptotic effects in the majority of the cell lines. Crystal violet and Annexin V staining revealed increased apoptosis rates for all cell lines following incubation with birinapant in mono treatment. Combination treatment with FasL and birinapant (IC 10 ) revealed additional and synergistic effects in eight out of the ten cell lines. To the best of our knowledge, the present study provided the first evidence of the apoptosis-sensitizing activity of combination treatment with FasL and birinapant in HNSCC cell lines.

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A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma

Cited by 99 publications

References 30 publications

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

Genomics and advances towards precision medicine for head and neck squamous cell carcinoma

Apoptosis-sensitizing activity of birinapant in head and neck squamous cell carcinoma cell lines

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