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Academic literature on the topic 'Birinapant'

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Published: 10 December 2022
Last updated: 28 January 2023

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Journal articles on the topic "Birinapant"

1

Fetterly, Gerald J., Biao Liu, Neil N. Senzer, Ravi K. Amaravadi, Russell J. Schilder, Lainie P. Martin, Patricia LoRusso, et al. "Clinical pharmacokinetics of the Smac-mimetic birinapant (TL32711) as a single agent and in combination with multiple chemotherapy regimens." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3029. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3029.

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3029 Background: Birinapant is a novel small molecule Smac-mimetic that targets members of the inhibitor of apoptosis proteins (cIAP1, cIAP2 and XIAP) involved in the blockade of apoptosis. A population PK model was developed to characterize the interpatient variability in birinapant PK and to evaluate the effect of multiple combination regimens on birinapant disposition and safety. Methods: Birinapant was administered alone or in combination to 114 patients (55M/59F; 89% Caucasian) with advanced malignancies. Birinapant was administrated by a 30 min IV infusion QW alone (30 pats), or approx. 30 min. after chemotherapy with irinotecan (19 pats), docetaxel (20 pats), gemcitabine (17 pats), liposomal doxorubicin (13 pats), or paclitaxel/carboplatin (15 pats). Birinapant dose levels ranged from 0.18 to 35 mg/m2. Population PK modeling was performed to investigate the effect of the following patient covariates: [BW (38.5-127.5 kg), age (27.5-86.0 yrs), CrCL (36.4-219.2 ml/min), ALT (6-121 IU/L), and TBIL (0.1-1.7 mg/dL)]. Results: A 3-compartment PK model described the time course of birinapant disposition with predicted values for T1/2, CL, and Vd of 40 h, 21 L/h and 10.2 L, respectively. Birinapant displayed linear PK across the dose range with no significant accumulation in plasma following weekly dosing. Goodness of fit plots supported the model fit, with residual variability of 23%. The PK of birinapant remained unchanged when combined with irinotecan, docetaxel, gemcitabine and liposomal doxorubicin. Concomitant administration with paclitaxel/carboplatin resulted in a 2-fold increase in birinapant AUC possibly due to reduced OATP1B3 mediated tissue uptake. Conclusions: These data show that birinapant possesses an excellent PK profile with dose proportional kinetics, a long terminal half-life for target coverage, low/moderate interpatient variability in CL and no significant accumulation following weekly dosing. Importantly, the PK of birinapant remained unchanged when combined with multiple chemotherapy regimens and the increased exposure with paclitaxel/carboplatin was not associated with any change in birinapant tolerability.
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Noonan, Anne M., Amanda Cousins, David Anderson, Kristen P. Zeligs, Kristen Bunch, Lidia Hernandez, Yusuke Shibuya, et al. "Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer." Cancers 12, no. 12 (December 15, 2020): 3784. http://dx.doi.org/10.3390/cancers12123784.

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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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Carter, Bing Z., Po Yee Mak, Duncan H. Mak, Vivian Ruvolo, Rodrigo Jacamo, Steven M. Kornblau, and Michael Andreeff. "Apoptosis Repressor with Caspase Recruitment Domain Is Regulated by the cIAP1-NIK Axis and Confers Resistance to SMAC Mimetic Birinapant-Induced Cell Death in AML." Blood 120, no. 21 (November 16, 2012): 534. http://dx.doi.org/10.1182/blood.v120.21.534.534.

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Abstract Abstract 534 The inhibitors of apoptosis (IAPs), including cIAP1, cIAP2, and XIAP are a family of anti-apoptotic proteins that play important roles in regulating cell survival. SMAC, a mitochondrial protein, is a natural cellular inhibitor of IAPs. SMAC mimetics, mimicking the IAP-binding site in the N-terminal AVPI peptide sequence of SMAC, are a new class of anticancer agents that degrade cIAPs and suppress XIAP activity. ARC (Apoptosis repressor with caspase recruitment domain) is an anti-apoptotic protein that inhibits the activation of caspase-8. We previously reported that the SMAC mimetic birinapant (TL32711; Tetralogic Pharmaceuticals, Malvern, PA) degrades cIAP1 and promotes apoptosis via the death receptor/caspase-8-mediated extrinsic pathway in primary AML cells and in AML cell lines in the presence of death receptor ligands (Carter BZ et al., ASH 2011). High ARC levels also predict adverse outcome in patients with AML (Carter BZ et al., Blood 2011). Here we report that birinapant-induced reduction in cIAP1 is accompanied by increased ARC levels. cIAPs are known E3 ligases for NF-κB-inducing kinase (NIK), an upstream kinase of non-canonical NF-κB. SMAC mimetics, including birinapant cleave cIAPs, leading to stabilization of NIK and activation of non-canonical NF-κB signaling and its downstream targets. To determine whether ARC is regulated via the cIAP1-NIK axis, we knocked down NIK in OCI-AML3 and Molm13 cells by siRNAs and found that inhibition of NIK decreased ARC RNA and protein levels in these cells and suppressed birinapant-induced increases of ARC, suggesting that ARC is regulated via the cIAP1/NIK/NF-κB cascade. We determined levels of ARC and cIAP1 by reverse-phase protein array in 511 samples obtained from patients with newly diagnosed AML and found that cIAP1 and ARC were inversely correlated (R = −0.225, P< 0.0001) further supporting the negative regulation of ARC by cIAP1 in primary AML samples. Data indicate that birinapant induces caspase-8-mediated cell death, but increases levels of ARC in AML cells which inhibits caspase-8 activation, suggesting that ARC is a resistance factor for birinapant-induced cell death. To further investigate this mechanism, we generated stable ARC-knock down (K/D) OCI-AML3 and Molm13 cells and stable ARC-overexpressing (O/E) KG-1 cells and treated these cells with birinapant or birinapant plus TNFα. We found what ARC-K/D OCI-AML3 and Molm13 cells were more sensitive and ARC-O/E KG-1 cells were more resistant to birinapant- or birinapant plus TNFα-induced apoptosis than their control cells. We reported previously that demethylating agents can enhance birinapant-induced apoptosis induction in AML cells. Examination of NIK and ARC levels in decitabine or 5-azacytidine treated AML cells showed that the demethylating agents indeed decreased NIK and ARC protein levels. Leukemia cells are in close contact with the bone marrow (BM) microenvironment in vivo that protects them from cell death induced by various therapeutic agents. Leukemia cells were co-cultured with BM-derived mesenchymal stromal cells (MSCs) in vitro to mimic in vivo conditions. We found that birinapant decreased cIAP1 and increased ARC levels also in MSCs co-cultured with AML cells. We generated stable ARC-K/D MSCs and treated KG-1, OCI-AML3, and Molm13 cells co-cultured with ARC-K/D or vector control MSCs with birinapant plus TNFα and primary AML patient samples co-cultured with ARC-K/D or vector control MSCs with birinapant. ARC-K/D MSCs provided AML cells with less protection than control MSCs against birinapant plus TNFα- or birinapant-induced apoptosis. Collectively, data demonstrate that ARC is regulated via the cIAP1/NIK signaling pathway and is a resistance factor for SMAC mimetic birinapant-induced cell death. ARC K/D sensitizes AML cells to SMAC mimetic-induced cell death and also suppresses MSC-mediated protection of AML cells against drug-induced apoptosis. Disclosures: No relevant conflicts of interest to declare.
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Smith, Malcolm A., Hernan Carol, Kathryn Evans, Jennifer Richmond, Min Kang, C. Patrick Reynolds, Srinivas Chunduru, et al. "Birinapant (TL32711), a Small Molecule Smac Mimetic, Induces Regressions in Childhood Acute Lymphoblastic Leukemia (ALL) Xenografts That Express TNFα and Synergizes with TNFα in Vitro – A Report From the Pediatric Preclinical Testing Program (PPTP)." Blood 120, no. 21 (November 16, 2012): 3565. http://dx.doi.org/10.1182/blood.v120.21.3565.3565.

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Abstract Abstract 3565 Introduction: Birinapant is a small molecule mimetic of Smac that potently and specifically antagonizes multiple inhibitors of apoptosis proteins (IAPs). Birinapant rapidly degrades cIAPs and enables cytokines (TNFα, TRAIL) to activate the extrinsic apoptosis pathway, while it rapidly turns off the canonical NF-κB survival pathway, causing cancer cell death. Preclinical studies using adult cancer models have shown that birinapant causes tumor regressions as a single agent in selected models and that it has potent antitumor activity when combined with chemotherapies and death receptor ligands. Methods: Birinapant was evaluated against the 23 cell lines of the PPTP in vitro panel (including 1 AML and 5 ALL lines) using 96 hour exposure at concentrations from 1.0 nM to 3.0 μM, both as a single agent and in combination with TNFα (10 ng/mL) or TRAIL (10 ng/mL). Birinapant was tested against 2 PPTP solid tumor xenografts (rhabdomyosarcoma, Rh30; Ewing, CHLA-258), an anaplastic large cell lymphoma (ALCL) xenograft (Karpas-299), and 3 B-precursor ALL xenografts (ALL-2, ALL-17, & ALL-19) at a dose of 30 mg/kg administered by the intraperitoneal route using a Q3 day × 5 schedule. Gene expression data for the PPTP cell lines and xenografts was available using both Affymetrix U133 Plus 2.0 and Agilent SurePrint G3 arrays. Results: Birinapant demonstrated limited single agent activity (median relative IC50 (rIC50) > 3 μM), with only the AML cell line Kasumi-1 showing Relative In/Out% (Rel I/O%) values < 0% with rIC50 of 37 nM. Marked potentiation of birinapant was observed for a subset of cell lines with the addition of TNFα or TRAIL. The 5 ALL cell lines showed a median rIC50 value of 3.6 nM for birinapant in combination with TNFα, with Rel I/O% values between −50% and −100% (indicative of a profound cytotoxic effect). Four of 5 ALL cell lines showed little or no potentiation of birinapant effect with the addition of TRAIL. Among solid tumor cell lines, potentiation of birinapant effect was observed for selected rhabdomyosarcoma, rhabdoid tumor, Ewing sarcoma, and neuroblastoma cell lines with the addition of either TNFα or TRAIL. Birinapant was well tolerated in vivo. Birinapant induced significant differences in event-free survival (EFS) distribution compared to control in 3 of 3 (100%) of the B-precursor ALL xenografts, but in none of the solid tumor or ALCL xenografts. Objective responses were not observed for the solid tumor and ALCL xenografts, whereas for the ALL panel one xenograft (ALL-17) achieved a complete response (CR) and another (ALL-2) achieved a maintained CR, with treated animals remaining in remission at day 42, approximately 30 days after their last treatment with birinapant. Given the mechanism of action of Smac mimetics, TNFα expression was examined. TNFα expression was significantly higher for the PPTP ALL xenografts compared to the PPTP solid tumor xenografts and to 15 normal tissues. TNFα expression in ALL clinical specimens was examined using publicly available datasets, with the observation that its expression is significantly higher for high-risk B-precursor ALL compared to a set of normal tissues, but with a wide range of TNFα expression among ALL cases. Lymphotoxin A and B also show significantly elevated expression in ALL compared to normal tissues. Among the ALL xenografts tested with birinapant, the best responding xenograft (ALL-2) showed the highest TNFα expression. Karpas-299 also showed high TNFα expression, but the two solid tumor xenografts did not. Unlike the ALL cell lines for which exogenous TNFα potentiated birinapant in vitro activity, exogenous TNFα did not potentiate birinapant in vitro activity against Karpas-299. Conclusion: Birinapant showed little single agent in vitro activity against ALL cell lines, though it markedly potentiated the activity of exogenously added TNFα for these cell lines. In vivo, birinapant showed remission-inducing activity against 2 of 3 ALL xenografts, with one of these showing a maintained CR. TNFα is mechanistically associated with the activity of Smac mimetics, and the initial PPTP in vivo data for ALL xenografts are consistent with a relationship between TNFα expression and responsiveness to birinapant. The PPTP results suggest that birinapant may show high level activity against a subset of childhood ALL, and additional in vivo testing is ongoing to better identify predictive markers that can reliably select responsive cases. Disclosures: Chunduru: TetraLogic Pharmaceuticals: Employment, Equity Ownership. Graham:TetraLogic Pharmaceuticals: Employment, Equity Ownership. Geier:TetraLogic Pharmaceuticals: Honoraria. Houghton:TetraLogic Pharmaceuticals: Honoraria.
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Wang, Beatrice T., Melanie Desbois, Susan E. Calhoun, Thomas J. Matthew, Poonam Yakkundi, Ling Wang, Xingjie Chen, et al. "Abstract 1068: Anti-DR5 agonist IgM antibody IGM-8444 combined with SMAC mimetic birinapant induces strong synergistic tumor cytotoxicity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1068. http://dx.doi.org/10.1158/1538-7445.am2022-1068.

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Abstract Apoptosis is induced through extrinsic and intrinsic signaling pathways. Extrinsic apoptosis can be activated through multimerization of death receptor 5 (DR5), a tumor necrosis factor (TNF) receptor family member highly expressed in many cancers. However, cellular resistance mechanisms within the intrinsic pathway may limit DR5 activity, including inhibitor of apoptosis proteins (IAPs) that block caspase activity or promote pro-survival NFκB signaling. Second mitochondria-derived activator of caspases (SMAC) is an endogenous bivalent IAP antagonist. Birinapant, a bivalent SMAC mimetic that binds and degrades IAPs, has been evaluated through Phase 2, demonstrating good safety and on target activity but minimal efficacy as a monotherapy. We hypothesized that simultaneously targeting the extrinsic apoptotic pathway with IGM-8444, an anti-DR5 multivalent IgM agonist, and the intrinsic apoptotic pathway with birinapant could enhance tumor cell apoptosis. Human cancer cell lines including triple negative breast cancer (TNBC), head and neck, ovarian, colorectal, lung, and sarcomas, were screened for sensitivity to IGM-8444 and birinapant combination. Strong synergistic cytotoxicity was observed in vitro in 36/45 (80%) cancer cell lines, as measured by both Bliss synergy score and maximal killing. IGM-8444 and birinapant combination also induced synergistic cytotoxicity in cells with acquired resistance to DR5 agonist antibodies. By contrast, IGM-8444 and birinapant did not kill primary human hepatocytes in vitro, demonstrating the potential clinical safety for this combination. In vivo, the IGM-8444 and birinapant combination dose-dependently reduced tumor growth in a MDA-MB-231 TNBC model, with 8/10 tumor-free mice at the highest dose of birinapant tested. By comparison, birinapant combination with an anti-DR5 IgG agonist showed a modest response. IGM-8444 and birinapant also showed significant anti-tumor responses in additional cell line and patient-derived xenograft models, including 7/9 tumor-free animals in a HT-1080 fibrosarcoma model and 9/10 complete responses in a EBC-1 lung squamous cell lung carcinoma model. Lastly, pharmacodynamic biomarkers including cIAP1 degradation, caspase activation, and caspase-cleaved cytokeratin 18 in tumor and serum correlated with anti-tumor response. In summary, combined targeting of the extrinsic and intrinsic apoptotic pathways with IGM-8444 and birinapant respectively enhances tumor cytotoxicity in multiple preclinical models. The combination of IGM-8444 with birinapant is currently under evaluation in a Phase 1 study in patients with relapsed and/or refractory solid cancers (NCT04553692). Citation Format: Beatrice T. Wang, Melanie Desbois, Susan E. Calhoun, Thomas J. Matthew, Poonam Yakkundi, Ling Wang, Xingjie Chen, Tasnim Kothambawala, Miho Oyasu, Maya F. Kotturi, Genevive Hernandez, Xiaohan Liu, Marvin S. Peterson, Eric W. Humke, Bruce A. Keyt, Angus M. Sinclair. Anti-DR5 agonist IgM antibody IGM-8444 combined with SMAC mimetic birinapant induces strong synergistic tumor cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1068.
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Joshi, Indira D., and Mitchell R. Smith. "Birinapant Enhances Bendamustine-Induced Apoptosis In Activated B Cell-Diffuse Large Cell Lymphoma Cells." Blood 122, no. 21 (November 15, 2013): 5150. http://dx.doi.org/10.1182/blood.v122.21.5150.5150.

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Abstract Birinapant (TL32711), a Smac mimetic in clinical testing, potently targets Inhibitor of Apoptosis Proteins (IAPs, including cIAPs and XIAP) to unblock intrinsic and extrinsic pathways, enabling caspase-dependent apoptosis via multiple signals. Birinapant also inactivates canonical NF-kB signaling through cIAPs. We investigated the pro-apoptotic effects of birinapant, alone and in combination with bendamustine (BDM), an active lymphoma therapeutic agent, in a panel of B cell lymphoma cell lines representing germinal center/follicular (GC) vs. activated B cell (ABC) subtypes. We hypothesized that the efficacy of this potential combination therapeutic strategy might differ between GC and ABC lymphoma types, as ABC are reported to be NF-kB-dependent. We used the following EBV negative cell lines: WSU-FSCCL t(14:18)+ follicular lymphoma (FL), FC-TxFL2 t(14:18)+ transformed FL, and SU-DHL4 GC-type diffuse large B cell lymphoma (DLBCL) as examples of GC origin lymphomas. U2932 and TMD8 cell lines represent ABC-type DLBCL. Apoptosis was determined by annexin V staining and confirmed by caspase-3 activation, each assessed by flow cytometric methods following 48 h incubation. Birinapant had little effect (<5% annexin V+ cells) as a single agent on any of these B cell lymphoma cell lines at ≤ 100 nM, though a low level of apoptosis (7-12% annexin V+ cells) was detectable at 10-20 µM in GC types. Addition of birinapant 30-60 minutes prior to BDM did not further enhance the already high level (>50% annexin V+) of apoptosis induced by 10 uM BDM in WSU-FSCCL and FC-TxFL2, and only slightly enhanced the low level of BDM-induced apoptosis in the GC DLBCL cell line DHL-4 (to 10-15%). In the ABC DLBCL cell lines, however, whereas 10uM BDM induced <5% annexin V+ cells for U2932 and 10-15% for TMD8, addition of 100 nM birinapant 30-60 minutes prior to 10 uM BDM induced 35-40% annexin V+ cells in each of these ABC-DLBCL cell lines. This enhancement was schedule-dependent, not observed when birinapant was added after BDM. Thus, the cell lines representing FL and transformed FL are sensitive to BDM at clinically-achievable concentrations, without further enhancement by birinapant. The 3 DLBCL lines were relatively insensitive to BDM compared with FL cells, but BDM-induced apoptosis was markedly enhanced when birinapant was added before (but not after) BDM in the 2 ABC type DLBCL lines. Further explorations into the mechanism of birinapant sensitization of ABC-DLBCL to BDM, issues of dose and schedule, and role of NF-kB-dependency are ongoing. These data suggest that therapeutic trials of BDM plus birinapant would be of interest in ABC type DLBCL. Disclosures: No relevant conflicts of interest to declare.
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Morrish, Emma, Liana Mackiewicz, Natasha Silke, Marc Pellegrini, John Silke, Gabriela Brumatti, and Gregor Ebert. "Combinatorial Treatment of Birinapant and Zosuquidar Enhances Effective Control of HBV Replication In Vivo." Viruses 12, no. 8 (August 17, 2020): 901. http://dx.doi.org/10.3390/v12080901.

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Chronic hepatitis B virus (HBV) infection remains a global health threat and affects hundreds of millions worldwide. Small molecule compounds that mimic natural antagonists of inhibitor of apoptosis (IAP) proteins, known as Smac-mimetics (second mitochondria-derived activator of caspases-mimetics), can promote the death of HBV-replicating liver cells and promote clearance of infection in preclinical models of HBV infection. The Smac-mimetic birinapant is a substrate of the multidrug resistance protein 1 (MDR1) efflux pump, and therefore inhibitors of MDR1 increase intracellular concentration of birinapant in MDR1 expressing cells. Liver cells are known to express MDR1 and other drug pump proteins. In this study, we investigated whether combining the clinical drugs, birinapant and the MDR1 inhibitor zosuquidar, increases the efficacy of birinapant in killing HBV expressing liver cells. We showed that this combination treatment is well tolerated and, compared to birinapant single agent, was more efficient at inducing death of HBV-positive liver cells and improving HBV-DNA and HBV surface antigen (HBsAg) control kinetics in an immunocompetent mouse model of HBV infection. Thus, this study identifies a novel and safe combinatorial treatment strategy to potentiate substantial reduction of HBV replication using an IAP antagonist.
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Morrish, Emma, Anthony Copeland, Donia M. Moujalled, Jason A. Powell, Natasha Silke, Ann Lin, Kate E. Jarman, et al. "Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models." Blood Advances 4, no. 20 (October 20, 2020): 5062–77. http://dx.doi.org/10.1182/bloodadvances.2020001576.

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Abstract The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML samples to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.
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Schilder, Russell J., Mark Albertella, James Fredric Strauss, Malin Sydvander, Dung T. Le, Stefan Norin, Monica M. Mita, et al. "Determination of the recommended phase II dose of birinapant in combination with pembrolizumab: Results from the dose-escalation phase of BPT-201." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2506. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2506.

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2506 Background: Birinapant is a bivalent SMAC mimetic targeting cIAP1. Synergistic effects of combining birinapant with immune checkpoint inhibitors have been demonstrated in preclinical models. Based on these observations, a clinical trial with birinapant and pembrolizumab was initiated (NCT02587962). Methods: Patients ≥18 years with advanced solid tumors without further suitable standard therapeutic options were eligible for inclusion. Birinapant (5.6-22 mg/m2) was administered IV on day 1 and 8 in addition to pembrolizumab 200 mg on day 1 in a 21-day cycle until disease progression using standard 3+3 dose-escalation. The primary objective was to determine the safety and tolerability of the recommended phase 2 dose (RP2D) of birinapant in combination with pembrolizumab. Secondary and exploratory objectives included antitumor activity assessed by RECIST 1.1 and iRECIST, pharmacokinetics and assessment of biomarkers including serum cytokines, cIAP1, PD-L1 expression and tumor infiltrating lymphocytes. Results: Nineteen patients were enrolled at 4 dose levels of 5.6 (n = 3), 11 (n = 3), 17 (n = 6) and 22 (n = 7) mg/m2. Most common tumors were pancreatic (n = 5), colorectal (n = 4), ovarian (n = 3) and sarcoma (n = 3). Median prior therapies were 4 (0-12). The most common AE related to any of the study drugs was rash occurring in 3 patients. Ten patients had 17 SAE's of which only one (stomatitis) was judged related to birinapant. Increased ALT/AST (G3/G2) leading to missed day 8 dose constituted a DLT at 22 mg/m2. Grade 2 lipase increases were seen in 2 patients. No cases of Bell’s palsy were detected. ORR by RECIST 1.1 was 5.6% (n = 1) in 18 evaluable patients. The responding patient had microsatellite stable colorectal carcinoma (MSS-CRC)) and remains on therapy 13+ months after first dose. By iRECIST, ORR was 11.1%. CBR (PR+SD) by RECIST was 22.2%. The exposure to birinapant generally increased with dose. The RP2D was determined to be 22 mg/m2. Conclusions: Birinapant and pembrolizumab is a safe and tolerable combination that has shown encouraging signals of efficacy. A phase 2 study evaluating efficacy of this combination in MSS-CRC is ongoing. Clinical trial information: NCT02587962.
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Lalaoui, Najoua, Delphine Merino, Goknur Giner, François Vaillant, Diep Chau, Lin Liu, Tobias Kratina, et al. "Targeting triple-negative breast cancers with the Smac-mimetic birinapant." Cell Death & Differentiation 27, no. 10 (April 27, 2020): 2768–80. http://dx.doi.org/10.1038/s41418-020-0541-0.

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Abstract Smac mimetics target inhibitor of apoptosis (IAP) proteins, thereby suppressing their function to facilitate tumor cell death. Here we have evaluated the efficacy of the preclinical Smac-mimetic compound A and the clinical lead birinapant on breast cancer cells. Both exhibited potent in vitro activity in triple-negative breast cancer (TNBC) cells, including those from patient-derived xenograft (PDX) models. Birinapant was further studied using in vivo PDX models of TNBC and estrogen receptor-positive (ER+) breast cancer. Birinapant exhibited single agent activity in all TNBC PDX models and augmented response to docetaxel, the latter through induction of TNF. Transcriptomic analysis of TCGA datasets revealed that genes encoding mediators of Smac-mimetic-induced cell death were expressed at higher levels in TNBC compared with ER+ breast cancer, resulting in a molecular signature associated with responsiveness to Smac mimetics. In addition, the cell death complex was preferentially formed in TNBCs versus ER+ cells in response to Smac mimetics. Taken together, our findings provide a rationale for prospectively selecting patients whose breast tumors contain a competent death receptor signaling pathway for the further evaluation of birinapant in the clinic.
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Dissertations / Theses on the topic "Birinapant"

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Zhu, Xu. "Pharmacokinetic and Pharmacodynamic Analysis of Gemcitabine and Birinapant Combinations in Pancreatic Cancer." Thesis, State University of New York at Buffalo, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10263448.

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Pancreatic cancer is the one of the leading causes of cancer-related deaths in the United States and is characterized with low survival rate and high drug resistance. Because of the redundant and highly mutated signaling pathways in pancreatic cancer, numerous combinational therapies have been sought. Currently the selection of drug combinations is largely empirical and methods of evaluating and optimizing drug combinations have not been standardized. An important reason for this is the lack of comprehensive characterization of drug mechanisms of action and causes for drug resistance.

The purposes of this dissertation are: first, to set up a paradigm for evaluating drug combinations mathematically and translating the evaluation methods from in vitro to in vivo preclinical systems; second, to serve as an example for characterizing the biological signaling pathways and drug pharmacology comprehensively with systems modeling approaches, supported with “big data” from advanced techniques such as proteomic analysis; and third, using such systems models, further selecting and optimizing drug combinations to reverse drug resistance and enhance efficacy.

The two drugs selected are gemcitabine, a major component in the therapies for pancreatic cancer treatment, and birinapant, an antagonist of inhibitor of apoptosis proteins (IAP). In Chapter 1, the efficacy of this drug combination was evaluated in PANC-1 cells. A basic pharmacodynamic (PD) model was developed to characterize the temporal changes in the numbers of attached and floating cells after treatments, and synergistic effects were observed for both proliferation inhibition and death induction. Measurements of cell cycle distributions and apoptosis were then obtained and a mechanism-based PD model was developed to reveal more details and capture the major features of the beneficial interactions. From the mechanism-based PD model, different exposure schedules were tested and an optimal one to achieve maximal efficacy was proposed.

Assumptions were made in developing the mechanism-based PD model in Chapter 1. In Chapter 2, a proteomic approach was utilized for a comprehensive, unbiased study of proteins perturbed by gemcitabine and birinapant to test previous hypotheses. The mechanisms of action for both drugs were characterized more intensively, and additional details were incorporated into the interaction knowledge described previously. Based on the proteomics data, reasons for gemcitabine resistance were discussed, and regulators of DNA damage responses involving DNA repair, anti-apoptosis, and pro-migration and invasion proteins were proposed as promising candidates for therapeutic targeting.

With the rich quantitative proteomics data, a network modeling approach was attempted in Chapter 3. Quantitative relationships were developed for selected signaling pathways of cell cycle regulation, DNA damage responses, DNA repair, apoptosis, NF-κB, and MAPK-p38, which were then linked to describe the cell cycle progression and apoptosis, and finally to changes in cell numbers. Based on the developed network model, simulations were made under different conditions and compared with observations, serving as a validation process. The impact of p53 mutation and p53 silencing on the efficacy of gemcitabine was tested with this model. Sobol Sensitivity Analysis was applied to select promising targets to be combined with gemcitabine. In addition, the efficacy of curcumin combined with gemcitabine was evaluated based on the model simulation.

With extensive evaluation and comprehensive characterization of the mechanisms of this drug combination in cell culture, efforts were continued to investigate the effects of the combination in a mice xenograft model. In Chapter 4, pharmacokinetic information for gemcitabine and birinapant was gathered from the literature and full physiologically-based pharmacokinetic models (PBPK) were developed to characterize drug distribution in the body and into the pancreatic tumor. The tumor concentrations then were used to drive inhibition in tumor growth and a semi-mechanistic PBPK/PD model was developed to evaluate the efficacy of the drug combination in vivo. Their joint effects were revealed as merely additive. The network model developed in Chapter 3 was introduced to bridge the PBPK and PD models, and reasons for the discrepancies in vitro and in vivo were explored. Model predictions showed that simultaneous dosing was preferable to sequential dosing in vivo with stronger suppression of the DNA repair signaling.

In summary, this dissertation proposed a paradigm for evaluating drug combinations quantitatively in preclinical systems of cell lines and xenograft models. Comprehensive characterization of drug mechanisms of action and biological systems through network modeling can facilitate the selection and optimization of candidates for anti-cancer combination therapy. The bridging of knowledge in different scales with mathematical models in different complexity helps to minimize the gap of translating from in vitro to in vivo or even from preclinical to clinical research.

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Schüßler, Lion Maximilian [Verfasser], and Urs [Gutachter] Müller-Richter. "Analyse der Wirksamkeit der SMAC Mimetics Birinapant, BV6 und LCL161 und der Zytostatika Docetaxel und Paclitaxel auf Zellen des Multiplen Myeloms / Lion Maximilian Schüßler ; Gutachter: Urs Müller-Richter." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1215033931/34.

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Schüßler, Lion Maximilian. "Analyse der Wirksamkeit der SMAC Mimetics Birinapant, BV6 und LCL161 und der Zytostatika Docetaxel und Paclitaxel auf Zellen des Multiplen Myeloms." Doctoral thesis, 2020. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-208974.

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Die Zellen des Multiplen Myeloms (MM) zeichnen sich durch eine klonale Heterogenität aus, die eine kurative Therapie erschwert und zu Resistenzen gegenüber Medikamenten führt. Neue Substanzen, wie die Smac Mimetics Birinapant, BV6 und LCL161, sollen durch Nachahmung des in der Krebszelle reduziert vorkommenden Gegenspielers (SMAC/Diablo) der Apoptose-Inhibitoren (IAPs) die Apoptose der entarteten Zellen induzieren. In der vorliegenden Arbeit wurde die Wirksamkeit der Smac Mimetics Birinapant, BV6 und LCL161 und der Zytostatika Docetaxel und Paclitaxel auf 10 humane MM-Zellen in vitro untersucht. Es konnte bei einigen Zelllinien ein synergetischer Effekt auf die Reduktion der Zellzahl in einer Kombinationstherapie mit den Smac Mimetics und den Zytostatika nachgewiesen und teilweise Resistenzen überwunden werden. Weitere Forschungsarbeit zu Kombinationstherapien mit Smac Mimetics sollen deren Rolle und klinischen Nutzen in einer Therapiemöglichkeit bei rezidivierenden und refraktären MM-Patienten untersuchen
In multiple myeloma malignant plasma cells show a high level of clonal heterogeneity which leads to resistance to current medication and furthermore bad prognosis of treatment. New developed substances like Smac Mimetics Birinapant, BV6 and LCL161 shall induce apoptosis in multiple myeloma cells in imitating of the cellular protein SMAC/Diablo which is an antagonist of apoptosis inhibitors. This study investigates the in vitro effectiviness of the SMAC Mimetics Birinapant, BV6 and LCL161 and of the cytostatics Docetaxel and Paclitaxel on 10 human multiple myeloma cells. Some celllines showed in a combination treatement with Smac Mimetics and zytostatics a synergetic effect on cell viability and an overcoming of drug resistance. Further studies shall investigate the benefits and clinical use of combination treatment with Smac Mimetics for patients with recurrent and refractory multiple myeloma
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Conference papers on the topic "Birinapant"

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Papaevangelou, Efthymia, Gilberto S. Almeida, Yann Jamin, Simon P. Robinson, and Nandita M. deSouza. "Abstract 2930: Differential tumour response to birinapant and irinotecan revealed by non-invasive MRI." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2930.

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Neiman, Eric M., Christopher A. Benetatos, Gurpreet S. Kapoor, Yasuhiro Mitsuuchi, Mark A. McKinlay, Martin E. Seipel, Guangyao Yu, Stephen M. Condon, and Srinivas K. Chunduru. "Abstract 5302: Characterization of tumor cell lines resistant to birinapant, a novel bivalent smac mimetic." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-5302.

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La, Vincent, Rachel Fujikawa, Deanna Janzen, Liat Bainvoll, and Sanaz Memarzadeh. "Abstract LB-131: Birinapant and carboplatin co-therapy can effectively target platinum resistant ovarian cancer initiating cells." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-lb-131.

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Derakhshan, Adeeb, Danielle Eytan, Grace Snow, Sophie Carlson, Anthony Saleh, Hui Cheng, Stephen Schiltz, et al. "Abstract 3821: Targeted therapy for head and neck squamous cell carcinoma using the novel SMAC-mimetic birinapant." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-3821.

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Fichtner, Michael, Emir Bozkurt, Katherine McAllister, Christopher McCann, Daniel Longley, and Jochen H. Prehn. "Abstract 3907: Birinapant co-treatments of colon cancer cell lines show consensus molecular subtype-specific synergistic effects." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-3907.

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Kapoor, Gurpreet Singh, Christopher A. Benetatos, Yasuhiro Mitsuuchi, Eric M. Neiman, Guangyao Yu, Mark A. Mckinlay, Jennifer Burns, John Silke, Stephen M. Condon, and Srinivas K. Chunduru. "Abstract 2278: The SMAC-mimetic birinapant regulates autocrine TNF production by caspase-8:RIPK1 complex via p38MAPK pathway." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-2278.

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Benetatos, Christopher A., Jennifer M. Burns, Ernest C. Borden, Daniel Lindner, Yasuhiro Mitsuuchi, Mark A. Mckinlay, Gurpreet Singh Kapoor, et al. "Abstract 3336: The Smac Mimetic Birinapant Synergistically Induces Apoptosis in Combination with Type I Interferons and GM-CSF." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3336.

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Xie, Xuemei, Jangsoon Lee, Troy Pearson, Alexander Y. Lu, Debu Tripathy, Gayathri R. Devi, Chandra Bartholomeusz, and Naoto T. Ueno. "Abstract 548: Birinapant enhances gemcitabine's anti-tumor efficacy in triple-negative breast cancer by inducing intrinsic pathway-dependent apoptosis." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-548.

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Richmond, Jennifer, Kathryn Evans, Alissa Robbins, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, and Richard B. Lock. "Abstract 1620: In vivo and in vitro efficacy of birinapant in preclinical models of Ph-like pediatric acute lymphoblastic leukemia." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1620.

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An, Yi, Jun W. Jeon, Lillian Sun, Adeeb Derakhshan, Jianhong Chen, Hui Cheng, Xinping Yang, Christopher Silvin, Carter Van Waes, and Zhong Chen. "Abstract 5175: Birinapant enhances death agonist antibody against TRAILR2 anti-tumor activity in HPV-positive head and neck squamous cell carcinomas." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-5175.

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