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Published: 10 December 2022
Last updated: 28 January 2023

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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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2

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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3

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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4

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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5

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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6

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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Kandeel, Mahmoud, Jinsoo Kim, Mahmoud Fayez, Yukio Kitade, and Hyung-Joo Kwon. "Antiviral drug discovery by targeting the SARS-CoV-2 polyprotein processing by inhibition of the main protease." PeerJ 10 (February 8, 2022): e12929. http://dx.doi.org/10.7717/peerj.12929.

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The spread of SARS-CoV-2, the causative agent for COVID-19, has led to a global and deadly pandemic. To date, few drugs have been approved for treating SARS-CoV-2 infections. In this study, a structure-based approach was adopted using the SARS-CoV-2 main protease (Mpro) and a carefully selected dataset of 37,060 compounds comprising Mpro and antiviral protein-specific libraries. The compounds passed two-step docking filtration, starting with standard precision (SP) followed by extra precision (XP) runs. Fourteen compounds with the highest XP docking scores were examined by 20 ns molecular dynamics simulations (MDs). Based on backbone route mean square deviations (RMSD) and molecular mechanics/generalized Born surface area (MM/GBSA) binding energy, four drugs were selected for comprehensive MDs analysis at 100 ns. Results indicated that birinapant, atazanavir, and ritonavir potently bound and stabilized SARS-CoV-2 Mpro structure. Binding energies higher than −102 kcal/mol, RMSD values <0.22 nm, formation of several hydrogen bonds with Mpro, favourable electrostatic contributions, and low radii of gyration were among the estimated factors contributing to the strength of the binding of these three compounds with Mpro. The top two compounds, atazanavir and birinapant, were tested for their ability to prevent SARS-CoV-2 plaque formation. At 10 µM of birinapant concentration, antiviral tests against SARS-CoV-2 demonstrated a 37% reduction of virus multiplication. Antiviral assays demonstrated that birinapant has high anti-SARS-CoV-2 activity in the low micromolar range, with an IC50 value of 18 ± 3.6 µM. Therefore, birinapant is a candidate for further investigation to determine whether it is a feasible therapy option.
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Ritchie, Ellen K., Apurv Agrawal, Kashyap B. Patel, Seth Rosen, Amy Law, Jeffrey M. Skolnik, and Ashkan Lashkari. "A Phase 2 Study of Birinapant in Combination with 5-Azacitadine in Patients with Myelodysplastic Syndrome Who Are Naïve to 5-Azacitadine: A Preliminary Analysis of Phase 2a." Blood 126, no. 23 (December 3, 2015): 2904. http://dx.doi.org/10.1182/blood.v126.23.2904.2904.

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Abstract Background: The Inhibitors of Apoptosis (IAP) proteins are a family of molecules that suppress apoptotic cell death. Expression of IAPs is dysregulated in Myelodysplastic Syndrome (MDS) and is a potential path for therapeutic intervention. SMAC (second mitochondrial-derived activator of caspases) is an IAP antagonist, resulting in caspase activation, inhibition of NF-k B and increased apoptosis. Birinapant is a potent bivalent SMAC mimetic under clinical investigation for several cancer types. Pre-clinical data support its investigation in myeloid malignancies, including MDS, and a previous phase 1b study demonstrated promising clinical activity in patients with higher-risk MDS who were naïve or had relapsed or were refractory to prior therapy. In this trial birinapant is combined with 5-azacitidine (5-AZA) in high-risk MDS patients who have not yet been treated with a hypomethylating agent. Methods: This phase 2 ongoing study of birinapant plus 5-AZA in patients with MDS or CMMoL recently completed enrollment to the unblinded portion, in which 9 patients were dosed with birinapant 13 mg/m2 IV twice weekly for 3 weeks of a 28-day cycle plus 5-AZA 75 mg/m2 by IV infusion daily for 7 days of a 28-day cycle. The primary objective of this study is to determine the objective response rate by International Working Group criteria of birinapant plus 5-AZA in patients with high-risk MDS or CMMoL who are naïve to hypomethylating agents. Secondary objectives include assessing the tolerability of this regimen, and determining the pharmacokinetics and exploratory pharmacodynamics of the combination. Results: Of the 9 patients enrolled, 6 patients had high or very high risk MDS; no patients had CMMoL. 8 patients were age ≥60 years. All patients were naïve to 5-AZA. Of the 9 patients enrolled, 6 completed up to four cycles of chemotherapy and were considered evaluable for response; three discontinued therapy prior to Cycle 4 (patient or investigator decision, or occurrence of adverse events (AEs)). Of the 6 evaluable patients, 3 had a complete response (CR), one had a marrow CR, and one had a partial response (PR). A sixth patient had a best response of stable disease at Cycle 4. Of these six patients evaluable, one (PR) was able to proceed to stem cell transplantation. The median duration of response (range) in these patients has not yet been assessed. Adverse events were consistent with the disease under investigation or the known profile of birinapant or 5-AZA. The most common ≥Grade 3 AEs seen in ≥2 patients were neutropenia and thrombocytopenia (5 patients each); fatigue, anemia, increased lipase and syncope (2 patients each). One patient developed a Grade 1 VIth cranial nerve palsy. No serious adverse events were reported in more than one patient, and one fatal event (sepsis) was reported. No patients developed infusion site reaction. Data showing inhibition of NF-k B, a downstream pro-survival molecule activated by IAPs, in circulating blast cells, demonstrated evidence of a potential biomarker in this population. Conclusion: This ongoing phase 2 study provide data for an acceptable safety profile of the combination of birinapant administered with IV 5-AZA. Preliminary evidence of promising clinical activity in this non-randomized, open-label phase was observed. These results provide rationale for the continuation to the next phase of this global randomized, blinded phase 2 study comparing birinapant in combination with 5-AZA vs. 5-AZA alone in patients with high-risk MDS or CMMoL in the front-line setting. Disclosures Ritchie: Celgene: Speakers Bureau; Incyte: Speakers Bureau. Skolnik:TetraLogic Pharmaceuticals: Employment, Equity Ownership.
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Frey, Noelle V., Selina Luger, James Mangan, Alexis Zebrowski, Alison W. Loren, Hans Minderman, John Baird, et al. "A Phase I Study Using Single Agent Birinapant in Patients with Relapsed Myelodysplastic Syndrome and Acute Myelogenous Leukemia." Blood 124, no. 21 (December 6, 2014): 3758. http://dx.doi.org/10.1182/blood.v124.21.3758.3758.

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Abstract BACKGROUND: Effective and well tolerated treatment options for patients with relapsed acute myelogenous leukemia (AML) are limited. Birinapant is a small molecule, peptidomimetic of second mitochondrial-derived activator of caspases (SMAC) that selectively targets Inhibitor of Apotosis proteins (IAPs) resulting in tumor cell apoptosis and inactivation of NF-kB. SMAC mimetics represent a novel class of anti-tumor agents and birinapant has been explored as a single agent and in combination with chemotherapy in trials in solid tumors. Based on pre-clinical response observed in a mouse model with AML, we developed an investigator initiated Phase I clinical trial using single agent birinapant in pts with relapsed AML and high risk myelodysplastic syndrome (MDS). METHODS: Eligible pts were >18 years old with non-M3 relapsed or refractory AML or high risk MDS refractory to a hypomethylating agent. A standard 3+3 dose escalation was planned using single agent birinapant at increasing dose levels and frequency. Subjects who did not complete at least one cycle of therapy (4 wks) or experience a dose limiting toxicity (DLT) were replaced. The primary endpoint was safety and determination a maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetic (PK) and pharmacodynamics (PD) analysis as well as disease response. RESULTS: From 12/2011 to 05/2014, 20 subjects were enrolled at the Hospital of the University of Pennsylvania and received at least one dose of study drug, 1 had MDS, 19 had AML (9 with antecedent MDS). The median age was 75 (range 36 to 80). The median number of prior treatments was 2 (range 1 to 5) and 11 patients required hydroxyurea during study treatment. No other concurrent chemotherapy was permitted. Several dose levels were tested varying the dose (17mg/m2, 22mg/m2 and 26mg/m2) and frequency (weekly, twice weekly (BIW) and 3 times weekly (TIW)) for 3 out of 4 wk cycles. Evaluable subjects have stayed on study drug for <1 wk to 45wks. Two dose levels tested resulted in a DLT. DLTs of grade 3 and grade 4 serum amylase and lipase abnormalities were observed in the 26mg/m2 weekly dose level. Pancreatic enzyme abnormalities were clinically silent and reversible with dose reduction or cessation. A DLT of Bell’s palsy was observed at 22mg/m2 BIW dosing level. No dose limiting toxicities were observed at 17mg/m2 weekly nor thus far at 17mg/m2 BIW. One subject only was treated at 17mg/m2 TIW dosing level who withdrew due to flare of underlying Behcets during week 1 of study treatment. Further exploration of TIW dosing was abandoned due to feasibility concerns. Enrollment continues at the final expanded cohort of 17mg/m2 BIW. The best disease response observed to date is stable disease at one month, 3 months and 6 months for some pts: one pt had a decline in their bone marrow blast count from 60% to 10% with single-agent birinapant. PK and PD analysis were performed at specified time points. Feasibility of measuring cIAP1 and cIAP2 inhibition as well as NFkB activity as PD response parameters for birinapant was explored. cIAP1 and cIAP2 levels were evaluated via Western blot analysis of mononuclear cells from pts; NFkB activity was assessed by imaging flow cytometry prior to and during initiation of birinapant treatment. cIAP1/cIAP2 suppression as well as inhibition of NFkB were evident. PK levels in plasma and blasts were also assessed at the same specified time points. Based on analysis to date, birinapant has excellent drug exposure and target suppression of cIAP1/cIAP2 and inhibition of NF-kB activity during the BIW schedule of 17mg/m2 for 3 out of 4 wks. CONCLUSIONS: This is the first study evaluating the safety and role of birinapant in pts with MDS and AML and first study in humans evaluating administration of this drug on a BIW dosing schedule. Observed adverse events related to study drug in this pt population include exacerbation of underlying autoimmune disease, Bell’s palsy and reversible and clinically silent elevation of amylase and lipase. Feasibility of measuring NFkB and cIAP1/2 expression as pharmacodynamics markers is established. Our study supports the safety and on tumor targeting of BIW dosing of birinapant which is currently under evaluation in combination with other agents in MDS. Disclosures Frey: Tetralogic Pharmaceuticals: Research Funding. Minderman:Tetralogic Pharmaceuticals: Research Funding. Porter:Novartis: managed according to U Penn Policy Patents & Royalties, Research Funding. Carroll:Tetralogic: Research Funding.
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Borthakur, Gautam, James M. Foran, Eunice S. Wang, Amol Rakkar, Hans Minderman, Jennifer Burns, Michael Andreeff, and Raoul Tibes. "A Phase 1b Study of Birinapant in Combination with 5-Azacitadine in Patients with Myelodysplastic Syndrome Who Are Naïve, Refractory or Have Relapsed to 5-Azacitadine." Blood 126, no. 23 (December 3, 2015): 93. http://dx.doi.org/10.1182/blood.v126.23.93.93.

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Background: Although 5-azacitidine (5-AZA) is the standard of care for patients with higher-risk patients with Myelodysplastic Syndrome (MDS) almost all patients will fail 5-AZA therapy with the majority of patients progressing within 2 years. Two-year survival for MDS patients refractory to 5-AZA is only 15%. There is a need for more effective therapies for these patients with higher-risk MDS. The Inhibitors of Apoptosis (IAP) Proteins are a family of molecules that suppress apoptotic cell death. Expression of IAPs is dysregulated in MDS, supporting potential as therapeutic targets. SMAC (second mitochondrial activator of caspases) is an IAP antagonist, resulting in caspase activation, inhibition of the pro-survival transcription factor NF-kB and increased apoptosis leading to tumor cell death. Birinapant is a potent bivalent SMAC mimetic in clinical development for the treatment of several cancers. Pre-clinical data support its investigation in myeloid malignancies, specifically MDS. Methods: This Phase 1b study was designed to determine the MTD and recommended Phase 2 dose and schedule of birinapant in combination with 5-AZA in patients with higher-risk MDS who are naïve to or have relapsed or are refractory to 5-AZA. Secondary objectives included determining the clinical activity of the combination of birinapant plus 5-AZA, and assessing the pharmacokinetics (PK) and exploratory biomarkers. Results: Twenty-one patients were enrolled, of whom 15 had high/very high risk MDS, with median IPSS score of 3 (range, 1.5-8). Median age (range) was 73 years (48-84 years). Eight patients were therapy-naïve. All patients received 5-AZA, administered either intravenous (IV; 13 patients) or subcutaneous (SC; 8 of whom 4 later switched to IV), at 75 mg/m2 for 7 days of a 28-day cycle in combination with birinapant. Birinapant was administered IV twice weekly (Days 1 and 4) at 13 mg/m2 for either 3 of 4 weeks (15 patients; Cohort 1 and Expansion Cohort) or 4 of 4 weeks (6 patients; Cohort 2) in 28-day cycles. No cycle 1 dose-limiting toxicities were observed. Adverse events ≥Grade 3 observed in two or more patients were thrombocytopenia (9 patients); pneumonia (including fungal pneumonia; 8); anemia (8); leukopenia (7); febrile neutropenia (7) neutropenia (5); fatigue (4); respiratory failure (3); cellulitis or soft tissue necrosis (3); and nausea, vomiting, or hypoxia (2 patients each). SAEs seen in more than one patient included pneumonia (6 patients, including fungal pneumonia); febrile neutropenia (4); sepsis (3) and cellulitis or soft tissue necrosis (3). Grade 3 abdominal soft tissue necrosis occurred in the area of subcutaneous injections of 5-AZA, and two events of Grade 3 cellulitis were judged related to treatment. These local injection site reactions were more severe than expected with SC 5-AZA, and were not observed with subsequent IV administration. These events were not considered DLTs. Treatment-related suppression of NF-k B activity was evident in circulating blast cells from patients in Cohort 1 suggesting pharmacodynamic activity of birinapant at this dose and schedule. Based on this, the Phase 2 dosing regimen has been recommended as birinapant administered at 13 mg/m2 IV twice weekly for 3 weeks of a 28-day cycle in combination with 5-AZA at 75 mg/m2 IV daily for 7 days of a 28-day cycle. Although not a primary endpoint, evidence of clinical activity, as demonstrated by significant reduction in marrow blast percentages, was seen, including 3 patients considered relapsed or refractory to prior therapy. Nine patients of 20 evaluable (45%) demonstrated either a ≥50% decrease in marrow blast count, or a blast count of ≤5% at the end of Cycle 1 or 2. Two additional patients (10%) demonstrated hematological improvement in one or more peripheral cell lineages without transfusions. In addition, 2 patients, one of whom had previously received 5-AZA, could be bridged to stem cell transplant subsequent to response with birinapant plus 5-AZA. Several patients remain in active follow-up. Conclusion: This Phase 1b trial confirms the acceptable safety profile of the combination of birinapant administered with IV 5-AZA. Evidence of clinical activity in both 5-AZA naïve and refractory patients provide the rationale for an ongoing global randomized, blinded Phase 2 study comparing birinapant in combination with 5-AZA vs. 5-AZA alone in patients with higher-risk MDS in the front-line setting. Disclosures Wang: Immunogen: Research Funding. Rakkar:TetraLogic Pharmaceuticals: Research Funding. Minderman:TetraLogic Pharmaceuticals: Research Funding. Burns:TetraLogic Pharmaceuticals: Employment. Tibes:TetraLogic Pharmaceuticals: Research Funding.
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Ebert, Gregor, Cody Allison, Simon Preston, James Cooney, Jesse G. Toe, Michael D. Stutz, Samar Ojaimi, et al. "Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis." Proceedings of the National Academy of Sciences 112, no. 18 (April 20, 2015): 5803–8. http://dx.doi.org/10.1073/pnas.1502400112.

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We have shown that cellular inhibitor of apoptosis proteins (cIAPs) impair clearance of hepatitis B virus (HBV) infection by preventing TNF-mediated killing/death of infected cells. A key question, with profound therapeutic implications, is whether this finding can be translated to the development of drugs that promote elimination of infected cells. Drug inhibitors of cIAPs were developed as cancer therapeutics to promote TNF-mediated tumor killing. These drugs are also known as Smac mimetics, because they mimic the action of the endogenous protein Smac/Diablo that antagonizes cIAP function. Here, we show using an immunocompetent mouse model of chronic HBV infection that birinapant and other Smac mimetics are able to rapidly reduce serum HBV DNA and serum HBV surface antigen, and they promote the elimination of hepatocytes containing HBV core antigen. The efficacy of Smac mimetics in treating HBV infection is dependent on their chemistry, host CD4+ T cells, and TNF. Birinapant enhances the ability of entecavir, an antiviral nucleoside analog, to reduce viral DNA production in HBV-infected animals. These results indicate that birinapant and other Smac mimetics may have efficacy in treating HBV infection and perhaps, other intracellular infections.
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Borthakur, Gautam, James M. Foran, Eunice S. Wang, Amol Rakkar, Steven Hager, Noelle V. Frey, Michael Andreeff, et al. "A Phase 1b/2a Study of Birinapant in Combination with 5-Azacitadine in Patients with Myelodysplastic Syndrome Who Are Naïve, Refractory to or Have Relapsed on 5-Azacitadine: a Preliminary Analysis." Blood 124, no. 21 (December 6, 2014): 3263. http://dx.doi.org/10.1182/blood.v124.21.3263.3263.

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Abstract 5-azacitidine (5-AZA) is standard of care in the first-line setting for higher-risk patients with Myelodysplastic Syndrome (MDS). However, 40-50% of patients are refractory to 5-AZA and most responders ultimately demonstrate disease progression within 2 years, often progressing to AML. For patients refractory to 5-AZA, 2-year survival probability is low (15%). Thus, there is a need for more effective initial and second-line therapies for patients with higher-risk MDS. The Inhibitors of Apoptosis (IAP) Proteins are a family of molecules that suppress apoptotic cell death. Expression of IAPs is dysregulated in MDS, suggesting a potential path for therapeutic intervention. SMAC (second mitochondrial activator of caspases) is an IAP antagonist, resulting in caspase activation, inhibition of NF-kB and increased apoptosis. Birinapant is a potent bivalent SMAC mimetic with improved tolerability and therapeutic index compared to other SMAC mimetics. This Phase Ib/2a study was designed primarily to determine the MTD and recommended Phase 2 dose and schedule of birinapant in combination with 5-AZA in patients with higher-risk MDS who are naïve or have relapsed or are refractory to 5-AZA. To date, 11 patients have been enrolled in the Phase 1b portion of the study, including 7 with IPSS classification high-risk MDS (5 male, 2 female; median age 75, range 64-82) and 4 with intermediate-risk MDS (2 male, 2 female; median age 72.5, range 65-84). All patients received standard 5-AZA, administered via either intravenous (IV) or subcutaneous (SC) routes, at 75 mg/m2 for 7 days of a 28-day cycle in combination with birinapant. Birinapant was administered IV twice weekly (Days 1 and 4) for either 3 of 4 weeks or 4 of 4 weeks per 28-day cycle at a dose of 13 mg/m2. No cycle 1 dose-limiting toxicities have been observed. Adverse events ≥ Grade 2 observed in two or more patients and judged to be related to treatment were rash/pruritis (Grade 2, 2 patients), thrombocytopenia (Grade 4, 2 patients) and neutropenia (Grade 4, 1 patient; Grade 3, 1 patient). Two SAEs, Grade 3 abdominal soft tissue necrosis with abdominal pain in the area of subcutaneous injections of 5-AZA, and Grade 3 cellulitis were judged to be related to treatment. These local injection site reactions/cellulitis were more severe than usually expected with SC 5-AZA, suggesting an on target pharmacodynamic (TNF mediated) localized synergistic effect in skin, but were not observed with IV administration. Both occurred after cycle 1 and were not considered DLTs. Data showing inhibition of NF-kB, a downstream pro-survival molecule activated by IAPs, in circulating blast cells from patients treated with birinapant at a dose of 13 mg/m2 twice weekly for 3 weeks out of 4, suggests that birinapant is pharmacologically active at this dosing schedule. Based on these and other pharmacodynamic data, despite not determining the formal MTD, the Phase 2 dosing regimen has been established as birinapant administered at 13 mg/m2 IV twice weekly for 3 weeks of a 28-day cycle in combination with 5-AZA at 75 mg/m2 by IV infusion for 7 days of a 28-day cycle. Although not a primary endpoint, evidence of clinical activity in 5-AZA resistant/refractory patients was observed in 2 of 11 patients to date, with an additional good clinical response in a 5-AZA naive high-risk MDS/CMML patient. One patient with prior 5-AZA-refractory MDS (cytogenetics: hypodiploid and +11q) showed bone marrow (BM) blast count reduction from 25% to 2% after 1 cycle of 5-AZA/birinapant treatment. Another patient with MDS (cytogenetics: +X; +19; +21) refractory to single-agent 5-AZA showed BM blast count reduction from 21% to 7% after 2 cycles. A third patient with treatment-naïve MDS/CMML-2 (cytogenetics: 46, XY, inv(6)(p11.2q15), t(6;21)(q21;q22) ) who had received prior hydroxyurea demonstrated BM blast count reduction from 17% to 2% after 3 cycles and underwent hematopoietic stem cell transplant. Several patients remain on study and are in active follow-up. This Phase 1b trial provide data for an acceptable safety profile of the first combination of a SMAC mimetic (birinapant) administered with IV 5-AZA. Early signs of clinical activity including in 5-AZA naïve and refractory patients were observed. These results provide rationale for a randomized Phase 2 study comparing birinapant in combination with 5-AZA against 5-AZA alone in the first-line setting for patients with higher-risk MDS. Disclosures Borthakur: Tetralogic Pharmaceuticals: Research Funding. Foran:TetraLogic Pharmaceuticals: Research Funding. Wang:Tetralogic Pharmaceuticals: Research Funding. Rakkar:Tetralogic Pharmaceuticals: Research Funding. Hager:Tetralogic Pharmaceuticals: Research Funding. Frey:Tetralogic Pharmaceuticals: Research Funding. Andreeff:TetraLogic Pharmaceuticals: Research Funding. Carter:Tetralogic Pharmaceuticals: Research Funding. Minderman:Tetralogic Pharmaceuticals: Research Funding. Russell:Tetralogic Pharmaceuticals: Employment. Tibes:Tetralogic Pharmaceuticals: Research Funding.
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Toni, Tiffany, Ethan Morgan, Ramya Viswanathan, Xinping Yang, Hui Cheng, and Carter Van Waes. "Abstract 2997: Combination treatment with cIAP and WEE1 inhibitors exhibits synergism in HPV-positive and HPV-negative head and neck squamous carcinoma cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2997. http://dx.doi.org/10.1158/1538-7445.am2022-2997.

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Abstract Head and neck squamous cell carcinoma (HNSCC) remains a lethal and prevalent diagnosis with limited treatment options for recurrent metastatic cases, particularly in patients with sporadic, human papillomavirus (HPV) negative disease. Recently, the Human Cancer Genome Project identified cell death and NF-κB signaling alterations in a subset of HPV- and HPV+ HNSCC. Co-amplification of Fas-associated death domain (FADD) and cellular inhibitor of apoptosis protein 1 (cIAP1) was identified in HPV- HNSCC, whereas Tumor Necrosis Factor receptor-associated factor 3 (TRAF3) deletion was linked with HPV+ HNSCC. Birinapant, a cIAP inhibitor with primary affinity for cIAP1, functions as a SMAC mimetic to modulate downstream TNF death signaling and promote apoptosis. Clinical trials with Birinapant have demonstrated tolerability and favorable pharmacokinetics but limited activity as a single agent. Our lab recently demonstrated a key interaction between TNF-NF-κB signaling and the G2/M checkpoint kinase WEE1, providing a possible rationale for combination treatment targeting these pathways. We hypothesize that dual-antagonist therapy has the potential to synergistically inhibit TNF-induced canonical NF- κB pro-survival signaling, while enhancing sensitization to TNF-caspase and G2/M mitotic cell death. To investigate this, in vitro studies of Birinapant in combination with Adavosertib, a potent WEE1 inhibitor, were performed. Birinapant and Adavosertib demonstrated drug synergism to varying degrees in all HPV- and HPV+ cell lines tested, both in the presence and absence of tumor necrosis factor alpha (TNF-α), according to the Chou-Talalay method. In the majority of cell lines, synergistic drug activity, as indicated by a low combination index, was positively correlated with percent inhibition. These results were confirmed by increased levels of apoptosis as demonstrated by flow cytometry and both early and sustained cell growth inhibition over time in impedance assays. Ongoing studies include additional characterization of the downstream effects of these agents on NF-κB pro-survival signaling and the cell cycle, along with evaluation in a preclinical murine xenograft model with combined radiotherapy. Citation Format: Tiffany Toni, Ethan Morgan, Ramya Viswanathan, Xinping Yang, Hui Cheng, Carter Van Waes. Combination treatment with cIAP and WEE1 inhibitors exhibits synergism in HPV-positive and HPV-negative head and neck squamous carcinoma cells [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 2997.
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Murray, Susan E., Brittany Ligman, Ashley Burton, and Claire Kearney. "The effect of SMAC mimetics on human T cell activation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 246.13. http://dx.doi.org/10.4049/jimmunol.204.supp.246.13.

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Abstract Second mitochondria-derived activator of caspase (SMAC) mimetics are small molecule drugs currently in cancer clinical trials. They are thought to act by antagonizing inhibitors of apoptosis (IAPs), which are often overexpressed in malignancies. However, in leukocytes, IAPs inhibit cell activation via antagonizing non-canonical NF-κB. This suggests that, paradoxically, while SMAC mimetics can induce apoptosis in cancer cells, they may enhance activation in T cells. The aim of this project is to determine whether human T cell proliferation and effector function are affected by SMAC mimetics. We previously showed that non-canonical NF-κB plays an essential intrinsic role in T cell activation in mice. Here, we show that the SMAC mimetic TL32711 (Birinapant) activates non-canonical NF-κB in primary human T cells. Doses of SMAC mimetics that induce 100% apoptosis in the breast cancer cell line, MDA-MB-231, do not affect T cell viability. Birinapant dose-dependently increases IL-2 secretion, but the effects of SMAC mimetics on T cell proliferation and Th1 cytokine production are complex and depend on availability of costimulation and accessory cells. Endogenous T cells can combat cancer if properly stimulated, a fact underlined by the efficacy of checkpoint blockade. Thus, understanding the effect of SMAC mimetics on T cell responses is a critical consideration in using SMAC mimetics to treat cancer and for designing combination therapies.
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Deng, Yijun, Thomas Haimowitz, Matthew G. LaPorte, Susan R. Rippin, Matthew D. Alexander, Pavan Tirunahari Kumar, Mukta S. Hendi, Yu-Hua Lee, and Stephen M. Condon. "Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core of Birinapant." ACS Medicinal Chemistry Letters 7, no. 3 (January 13, 2016): 318–23. http://dx.doi.org/10.1021/acsmedchemlett.5b00461.

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Schilder, Russell J., Mark Albertella, James Strauss, Malin Sydvander, Santosh M. Nair, Kingsley Urakpo, Stefan Norin, and John Öhd. "A phase 1/2 study with birinapant in combination with pembrolizumab." Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018): TPS3131. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.tps3131.

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Gong, Tingting, Yujun Cai, Fengze Sun, Jiaxin Chen, Zhongzhen Su, Xintao Shuai, and Hong Shan. "A nanodrug incorporating siRNA PD-L1 and Birinapant for enhancing tumor immunotherapy." Biomaterials Science 9, no. 23 (2021): 8007–18. http://dx.doi.org/10.1039/d1bm01299a.

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Krepler, Clemens, Srinivas K. Chunduru, Molly B. Halloran, Xu He, Min Xiao, Adina Vultur, Jessie Villanueva, et al. "The Novel SMAC Mimetic Birinapant Exhibits Potent Activity against Human Melanoma Cells." Clinical Cancer Research 19, no. 7 (February 12, 2013): 1784–94. http://dx.doi.org/10.1158/1078-0432.ccr-12-2518.

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Werner, Thomas A., Inga Nolten, Levent Dizdar, Jasmin C. Riemer, Sina C. Schütte, Pablo E. Verde, Katharina Raba, Matthias Schott, Wolfram T. Knoefel, and Andreas Krieg. "IAPs cause resistance to TRAIL-dependent apoptosis in follicular thyroid cancer." Endocrine-Related Cancer 25, no. 3 (March 2018): 295–308. http://dx.doi.org/10.1530/erc-17-0479.

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Follicular thyroid cancer’s (FTC) excellent long-term prognosis is mainly dependent on postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes refractory, the 10-year disease-specific survival rate drops below 10%. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small-molecule-mediated antagonisation of inhibitor of apoptosis proteins (IAPs) on TRAIL sensitivity in vitro. Tissue microarrays were constructed from forty-four patients with histologically confirmed FTC. Expression levels of TRAIL and its receptors were correlated with clinicopathological data and overall as well as recurrence-free survival. Non-iodine-retaining FTC cell lines TT2609-bib2 and FTC133 were treated with recombinant human TRAIL alone and in combination with Smac mimetics GDC-0152 or Birinapant. TRAIL-R2/DR5 as well as TRAIL-R3/DcR1 and TRAIL-R4/DcR2 were significantly higher expressed in advanced tumour stages. Both decoy receptors were negatively associated with recurrence-free and overall survival. TRAIL-R4/DcR2 additionally proved to be an independent negative prognostic marker in FTC (HR = 1.446, 95% CI: 1.144–1.826; P < 0.001). In vitro, the co-incubation of Birinapant or GDC-0152 with rh-TRAIL-sensitised FTC cell lines for TRAIL-induced apoptosis, through degradation of cIAP1/2. The TRAIL system plays an important role in FTC tumour biology. Its decoy receptors are associated with poor prognosis as well as earlier recurrence. The specific degradation of cIAP1/2 sensitises FTC cells to TRAIL-induced apoptosis and might highlight a new point of attack in patients with RAI refractory disease.
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Richmond, Jennifer, Alissa Robbins, Kathryn Evans, Dominik Beck, Raushan T. Kurmasheva, Catherine A. Billups, Hernan Carol, et al. "Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant." Cancer Research 76, no. 15 (June 14, 2016): 4579–91. http://dx.doi.org/10.1158/0008-5472.can-16-0523.

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Zhu, Xu, Robert M. Straubinger, and William J. Jusko. "Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells." Journal of Pharmacokinetics and Pharmacodynamics 42, no. 5 (August 8, 2015): 477–96. http://dx.doi.org/10.1007/s10928-015-9429-x.

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La, V., R. Fujikawa, D. M. Janzen, L. Bainvoll, M. Nunez, and S. Memarzadeh. "Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy." Gynecologic Oncology 145 (June 2017): 20. http://dx.doi.org/10.1016/j.ygyno.2017.03.062.

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Shu, Xiaoming, Zhejiang Zhu, Dan Cao, Li Zheng, Fang Wang, Heying Pei, Jiaolin Wen, et al. "PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy." Colloids and Surfaces B: Biointerfaces 182 (October 2019): 110356. http://dx.doi.org/10.1016/j.colsurfb.2019.110356.

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Chang, Yung-Chieh, and Chun Hei Antonio Cheung. "An Updated Review of Smac Mimetics, LCL161, Birinapant, and GDC-0152 in Cancer Treatment." Applied Sciences 11, no. 1 (December 31, 2020): 335. http://dx.doi.org/10.3390/app11010335.

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Inhibitor of apoptosis proteins (IAPs) are suggested as therapeutic targets for cancer treatment. Smac/DIABLO is a natural IAP antagonist in cells; therefore, Smac mimetics have been developed for cancer treatment in the past decade. In this article, we review the anti-cancer potency and novel molecular targets of LCL161, birinapant, and GDC-0152. Preclinical studies demonstrated that Smac mimetics not only induce apoptosis but also arrest cell cycle, induce necroptosis, and induce immune storm in vitro and in vivo. The safety and tolerance of Smac mimetics are evaluated in phase 1 and phase 2 clinical trials. In addition, the combination of Smac mimetics and chemotherapeutic compounds was reported to improve anti-cancer effects. Interestingly, the novel anti-cancer molecular mechanism of action of Smac mimetics was reported in recent studies, suggesting that many unknown functions of Smac mimetics still need to be revealed. Exploring these currently unknown signaling pathways is important to provide hints for the modification and combination therapy of further compounds.
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Zhu, Xu, Sheryl Trueman, Robert M. Straubinger, and William J. Jusko. "Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts." Journal of Pharmacokinetics and Pharmacodynamics 45, no. 5 (August 1, 2018): 733–46. http://dx.doi.org/10.1007/s10928-018-9603-z.

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Gu, Shengqing, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, et al. "700 Increasing MHC-I expression to potentiate immune checkpoint blockade therapy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A728. http://dx.doi.org/10.1136/jitc-2021-sitc2021.700.

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BackgroundCancer immunotherapy, especially immune checkpoint blockade (ICB) therapy, is leading to a paradigm shift in cancer treatment, as a small percentage of cancer patients have obtained durable remission following ICB treatment. Successful ICB responses rely on cancer cells presenting antigens to the cell surface via the major histocompatibility complex (MHC), which activates antigen-specific T-lymphocytes to kill cancer cells. Type-I MHC (MHC-I) is wildly expressed in all cell types and mediates the interaction with cytotoxic CD8 T cells. However, over 65% of cancer patients are estimated to show defects in MHC-I-mediated antigen presentation, including downregulation of its expression that can lead to primary or acquired resistance to ICB therapy, and therapeutic strategies to effectively restore or boost MHC-I are limited.MethodsHere, we employed a CRISPR screening approach with dual-marker FACS sorting to identify factors that decouple the regulation of MHC-I and PD-L1. The experimentally validated target was used to generate a KO differential expression signature. Using this signature, we analyzed transcriptome data from drug perturbation studies to identify drugs that regulate MHC-I but not PD-L1. Finally, we validated the effect of the identified drug to enhance ICB response in a T-cell-dependent manner in vivo.ResultsCRISPR screens identified TRAF3, a suppressor of the NF-κB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and adds to ICB efficacy. However, in cancer cells with high NF-κB activity, the effect of birinapant on MHC-I is weak, indicating context-dependent MHC-I regulation.ConclusionsIn summary, Traf3 deletion specifically upregulates MHC-I without inducing PD-L1 in response to various cytokines and sensitizes cancer cells to T-cell-driven cytotoxicity. The SMAC mimetic birinapant phenocopies Traf3-knockout and sensitizes MHC-I-low melanoma to ICB therapy. Further studies are needed to elucidate the context-dependencies of MHC-I regulation. Our findings provide preclinical rationale for treating some tumors expressing low MHC-I with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.AcknowledgementsThis study was supported by grants from the NIH (R01CA234018 to XSL, R01AI137337 to BEG, P50CA101942-12 and P50CA206963 to GJF), Breast Cancer Research Foundation (BCRF-19-100 to XSL), Burroughs Wellcome Career Award in Medical Sciences (to BEG), and Sara Elizabeth O'Brien Trust Fellowship (to SG).We thank Drs. Kai Wucherpfennig and Deng Pan for their insightful suggestions on this study.Ethics ApprovalAll mice were housed in standard cage in Dana-Farber Cancer Institute Animal Resources Facility (ARF). All animal procedures were carried out under the ARF Institutional Animal Care and Use Committee (IACUC) protocol and were in accordance with the IACUC standards for the welfare of animals.
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Zhao, Li, Guoshan Yang, Hao Bai, Minghui Zhang, and Dongcheng Mou. "NCTD promotes Birinapant-mediated anticancer activity in breast cancer cells by downregulation of c-FLIP." Oncotarget 8, no. 16 (March 2, 2017): 26886–95. http://dx.doi.org/10.18632/oncotarget.15848.

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Anderson, D. M., K. P. Zeligs, K. P. Bunch, L. Hernandez, and C. M. Annunziata. "Mechanistic basis for synergy between SMAC-mimetic birinapant and chemotherapeutic agents: Insights for clinical development." Gynecologic Oncology 154 (June 2019): 87. http://dx.doi.org/10.1016/j.ygyno.2019.04.204.

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Song, E. Z., X. Wang, B. I. Philipson, Q. Zhang, R. Thokala, Z. A. Binder, D. O’Rourke, H. Song, and M. Milone. "Immunotherapy: THE IAP INHIBITOR BIRINAPANT ENHANCES CAR-T CELL THERAPY FOR GLIOBLASTOMA BY OVERCOMING ANTIGEN HETEROGENEITY." Cytotherapy 24, no. 5 (May 2022): S124. http://dx.doi.org/10.1016/s1465-3249(22)00334-6.

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Condon, Stephen M., Yasuhiro Mitsuuchi, Yijun Deng, Matthew G. LaPorte, Susan R. Rippin, Thomas Haimowitz, Matthew D. Alexander, et al. "Birinapant, a Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and Hematological Malignancies." Journal of Medicinal Chemistry 57, no. 9 (April 15, 2014): 3666–77. http://dx.doi.org/10.1021/jm500176w.

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Noonan, A. M., J. Chen, M. Herrmann, and C. M. Annunziata. "97 Birinapant, a Novel Smac Mimetic, Activates Apoptosis in NF-kappaB-dependent Gynecologic Cancer Cell Lines." European Journal of Cancer 48 (November 2012): 31. http://dx.doi.org/10.1016/s0959-8049(12)71895-6.

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36

Eytan, Danielle F., Grace E. Snow, Sophie G. Carlson, Stephen Schiltz, Zhong Chen, and Carter Van Waes. "Combination effects of SMAC mimetic birinapant with TNFα, TRAIL, and docetaxel in preclinical models of HNSCC." Laryngoscope 125, no. 3 (November 28, 2014): E118—E124. http://dx.doi.org/10.1002/lary.25056.

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37

Seong, Daehyeon, Manhyung Jeong, Jinho Seo, Ji-Yoon Lee, Chi Hyun Hwang, Ho-Chul Shin, Jeong Yoon Shin, et al. "Identification of MYC as an antinecroptotic protein that stifles RIPK1–RIPK3 complex formation." Proceedings of the National Academy of Sciences 117, no. 33 (August 4, 2020): 19982–93. http://dx.doi.org/10.1073/pnas.2000979117.

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The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1–RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1–RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.
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Amaravadi, Ravi K., Russell J. Schilder, Lainie P. Martin, Myron Levin, Martin A. Graham, David E. Weng, and Alex A. Adjei. "A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma." Molecular Cancer Therapeutics 14, no. 11 (September 2, 2015): 2569–75. http://dx.doi.org/10.1158/1535-7163.mct-15-0475.

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Zhu, D. L., and L. Y. Shuai. "The effects of birinapant on proliferation and invasion and its corresponding mechanism in MGC-803 gastric cancer cells." Bulletin of Experimental Biology and Medicine 171, no. 1 (2021): 73–79. http://dx.doi.org/10.47056/0365-9615-2021-171-1-73-79.

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40

Zakaria, Z., A. Tivnan, L. Flanagan, D. W. Murray, M. Salvucci, B. W. Stringer, B. W. Day, et al. "Patient-derived glioblastoma cells show significant heterogeneity in treatment responses to the inhibitor-of-apoptosis-protein antagonist birinapant." British Journal of Cancer 114, no. 2 (December 10, 2015): 188–98. http://dx.doi.org/10.1038/bjc.2015.420.

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Deng, Yijun, Qiuzhe Xie, Matthew G. LaPorte, Anna T. A. Chasnoff, Mark A. Mortensen, Debasis Patra, Seth A. Putrelo, et al. "Process Development and Synthesis of Birinapant: Large Scale Preparation and Acid-Mediated Dimerization of the Key Indole Intermediate." Organic Process Research & Development 20, no. 2 (January 15, 2016): 242–52. http://dx.doi.org/10.1021/acs.oprd.5b00390.

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Park, Eun Jung, Hae Dong Kim, Eun Kyoung Choi, Kwang-Lae Hoe, and Dong-Uk Kim. "Co-treatment of birinapant with TRAIL synergistically induces apoptosis by downregulating cFLIP(L) in MDA-MB-453 cell lines." Biochemical and Biophysical Research Communications 533, no. 3 (December 2020): 289–95. http://dx.doi.org/10.1016/j.bbrc.2020.09.031.

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Brumatti, Gabriela, Chunyan Ma, Najoua Lalaoui, Nhu-Y. Nguyen, Mario Navarro, Maria C. Tanzer, Jennifer Richmond, et al. "The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia." Science Translational Medicine 8, no. 339 (May 18, 2016): 339ra69. http://dx.doi.org/10.1126/scitranslmed.aad3099.

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Zhu, Xu, Xiaomeng Shen, Jun Qu, Robert M. Straubinger, and William J. Jusko. "Multi-Scale Network Model Supported by Proteomics for Analysis of Combined Gemcitabine and Birinapant Effects in Pancreatic Cancer Cells." CPT: Pharmacometrics & Systems Pharmacology 7, no. 9 (August 9, 2018): 549–61. http://dx.doi.org/10.1002/psp4.12320.

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45

Amaravadi, Ravi K., Neil N. Senzer, Lainie P. Martin, Russell J. Schilder, Patricia LoRusso, Kyriakos P. Papadopoulos, David Edward Weng, Martin Graham, and Alex A. Adjei. "A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2504. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2504.

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2504 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs with excellent tolerability, drug exposure, target suppression and apoptotic pathway activation in clinical studies. Preclinical studies demonstrate potent anti-tumor synergy when B is combined with TNFa-inducing chemotherapies (CT). Methods: Escalating doses of B were combined with CT in a 5-arm 3+3 phase 1 study for adults (pts) with relapsed/refractory solid tumors to determine maximum tolerated dose (MTD), pharmacokinetics (PK), and efficacy to identify indications for further studies. The arms included carboplatin/paclitaxel (CP), irinotecan (I), docetaxel (D), gemcitabine (G), and liposomal doxorubicin (LD). Results: 124 pts were treated with B at doses of 2.8 to 47 mg/m2. The MTD of B for each arm was CP (47 mg/m2); I (22 mg/m2); D (47 mg/m2). The proposed G regimen could not be administered in heavily pretreated pts and B could not be evaluated for dose escalation; this arm was discontinued and no dose-limiting toxicities (DLT) occurred. LD drug shortage prevented dose escalation for B > 35mg/m2 (MTD not reached). B did not limit CT administration for CP, I, D, LD, supporting tolerable combination of B with CT. B-associated toxicity of Bell’s palsy (Grade 2) was considered a DLT and noted at higher dose levels for I, D, and LD, but not CP. This unusual reversible toxicity occurred during cycle 1 in 7 pts. Six of these pts continued therapy without recurrence. PK studies demonstrated no effect of B on CT. Except for CP, CT did not change the PK of B. CP increased plasma PK for B, possibly due to OATP1B3 transporter effects, but without increased B toxicities. 11 pts had a partial response, 61 pts had stable disease (>2 cycles, median 4.6 mo) and 37 pts had progressive disease as their best response, with clinical benefit (CR+PR+SD) of 58%. Conclusions: B can be combined with excellent tolerability with multiple CT at standard dosing. B plus CT demonstrated clinical benefit in many tumor types. Notable clinical activity occurred with I + B in pts who had failed prior I. These results support planning for further clinical studies of the I + B, and support the hypothesis for TNFa-mediated I + B synergy. Clinical trial information: NCT01188499.
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Garitano-Trojaola, Andoni, Eva Teufel, Matteo Claudio Da Via', Ana Sancho, Nadine Rodhes, Thorsten Stuehmer, Santiago Barrio Garcia, et al. "The Role of NRAS G12D Mutations in the Response to Conventional Chemotherapy and 5-Azacitidine in Secondary AML." Blood 132, Supplement 1 (November 29, 2018): 5148. http://dx.doi.org/10.1182/blood-2018-99-118484.

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Abstract Secondary Acute Myeloid Leukemia (sAML) accounts for 10-30% of all AML. It arises from a preexisting clonal disorder of hematopoiesis, such as myelodysplastic syndromes (MDS) or chronic myeloproliferative neoplasia (cMPN) in most cases (60-70%) or from exposure to a leukemogenic agent e.g. chemotherapy. sAML is generally considered to be of unfavorable prognosis, as treatment sensitivity is reduced, compared to de novo AML (dnAML) and overall survival is shortened. The incidence of AML associated NRAS are similar between sAML and dnAML (10 to 15%, Jelena D. Milosevic et al.). Prognostic impact of such mutations have been controversially discussed, but have been linked to favorable response to high dose cytarabine treatment in dnAML patients (Andreas Neubauer et al.), thus providing the first example of an oncogenic mutation impacting drug response in dnAML. This effect, however, has not yet been shown in sAML, therefore the aim of this work is to study the role of mutated NRAS in the response to chemotherapy and the hypomethylating agent (HMA) 5-azacitidine in sAML. We utilized two sAML cell lines SET-2 and HEL (both NRAS wildtype) in which we stably introduced the NRAS WT and the known activating hotspot mutation NRAS G12D using the sleeping Beauty technology. The dose-response assays of conventional chemotherapy and 5-azacitidine were carried out in the parental cell lines (SET-2/HEL) compared to NRAS WT (SET-2 NRAS WT/HEL NRAS WT) and NRAS G12D (SET-2 NRAS G12D/HEL NRAS G12D). In contrast to our expectations, both NRAS G12D mutation harboring cell lines, SET-2 and HEL developed resistance to cytarabine, idarubicin and 5-azacytidine, whereas the ones with wildtype NRAS remained susceptible to the drugs. To reverse the resistance we tested the MEK inhibitors Binimetinib and Trametinib in our SET-2 NRAS G12D cell line model according to recent reports about preclinical efficacy of MEK inhibition in NRAS mutant dnAML cells (Michael R. Burgess et al.). And in fact, single agent Binetimib and Trametinib treatments reduced cell viability by 20% at 48 hours. Strikingly, in combination with 5-azacitidine, Binimetinib and Trametinib treatments led to a viability reduction by 90%. Next we induced necroptosis in our NRAS mutant cell line models through the combination of Birinapant (SMAC mimetics) and Emricasan (Inhibitor of Caspase 8), as recently described by Brumatti et al. and were, in addition, able to reduce the cell viability by 60 %. In summary, we provide first evidence, that in contrast to dnAML, activating NRAS mutations may promote resistance to conventional chemotherapy and 5-azacitidine in sAML cell lines. Furthermore we were able to demonstrate, that the combination of MEK inhibitors (Binimetinib and Trametinib) and 5-azacitidine as well as the induction of necroptosis such as the combination birinapant and emricasan, may provide a potential strategy to overcome the resistance. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Wang, Xue, Jin Niu, Jun Li, Xiaomeng Shen, Shichen Shen, Robert M. Straubinger, and Jun Qu. "Temporal Effects of Combined Birinapant and Paclitaxel on Pancreatic Cancer Cells Investigated via Large-Scale, Ion-Current-Based Quantitative Proteomics (IonStar)." Molecular & Cellular Proteomics 17, no. 4 (January 22, 2018): 655–71. http://dx.doi.org/10.1074/mcp.ra117.000519.

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Eytan, Danielle F., Grace E. Snow, Sophie Carlson, Adeeb Derakhshan, Anthony Saleh, Stephen Schiltz, Hui Cheng, et al. "SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2." Cancer Research 76, no. 18 (July 28, 2016): 5442–54. http://dx.doi.org/10.1158/0008-5472.can-15-3317.

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49

Crawford, Nyree, Manuela Salvucci, Christian T. Hellwig, Frank A. Lincoln, Ruth E. Mooney, Carla L. O’Connor, Jochen HM Prehn, Daniel B. Longley, and Markus Rehm. "Simulating and predicting cellular and in vivo responses of colon cancer to combined treatment with chemotherapy and IAP antagonist Birinapant/TL32711." Cell Death & Differentiation 25, no. 11 (March 2, 2018): 1952–66. http://dx.doi.org/10.1038/s41418-018-0082-y.

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50

Senzer, Neil N., Patricia LoRusso, Lainie P. Martin, Russell J. Schilder, Ravi K. Amaravadi, Kyriakos P. Papadopoulos, Zdenka E. Segota, David Edward Weng, Martin Graham, and Alex A. Adjei. "Phase II clinical activity and tolerability of the SMAC-mimetic birinapant (TL32711) plus irinotecan in irinotecan-relapsed/refractory metastatic colorectal cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3621. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3621.

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3621 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs and has potent preclinical anti-tumor synergy combined with TNFa-inducing chemotherapies [i.e irinotecan (I)]. B and I combination is well-tolerated and has encouraging activity in a phase 1 study. This study tested B+I with an ascending dose strategy (ADS) of B to mitigate Bell’s palsy (BP) risk, an unusual and reversible side effect of SMAC mimetics. Methods: I at 350mg/m2 IV q3weeks was administered with B weekly (2 of 3 weeks). The dose of B was titrated incrementally during Cycle 1: C1D1 at 5.6mg/m2 and C1D8 at 11mg/m2 for ADS. For Cycle 2 (C2) and ongoing treatment, the B dose was 22mg/m2 or 35mg/m2, which were the MTD and DLT (BP) dose levels when combined with I from the Ph 1 study. Safety and clinical activity for KRAS mutant (KRAS-MT) and wild-type (KRAS-WT) were assessed in 3 cohorts: (1) at 22mg/m2 for CRC KRAS MT; (2) 22mg/m2 for CRC KRAS WT; (3) 35mg/m2 for CRC KRAS MT. Results: 51 patients (pts) with CRC had a median number of 4 prior regimens with 47 refractory/relapsed to irinotecan (92%). Tolerability was comparable to I alone. There were 2 PRs (4%), 27 SD (>2 cycles; 53%, median 4.7 mo), 17 PD (33%), and 5 non- evaluable pts (9%) for an overall clinical benefit (CR+PR+SD) rate of 57%. Median progression-free survival (PFS) was 2.1 months, and 6 mo PFS was 20%. KRAS MT CRC with prior I had a median PFS of 2.9 mo and 6 mo PFS of 25% (n=20). KRAS WT CRC with prior I had a median PFS of 1.4 mo and 6 mo PFS of 17% (n=18). The ADS seemed to reduce BP risk. No BP events occurred among 40 pts (22mg/m2 with ADS), compared to 1 of 7 pts (22mg/m2 without ADS). In the 35mg/m2 cohort, 1 BP event occurred among 12 pts (with ADS), compared to 3 of 6 (35mg/m2 without ADS). Conclusions: B + I demonstrated clinical benefit in pts refractory/relapsed to irinotecan, with greatest benefit in KRAS MT CRC. The ADS may provide a mitigation strategy for BP risk. Prior studies with I retreatment have showed no benefit in KRAS MT CRC. Comparable CRC pts with best supportive care have 6 mo PFS of 2%. Clinical activity supports the hypothesis for therapeutic synergy of B + I, with I as a TNFa-inducing agent. Further study of this combination is warranted. Clinical trial information: NCT01188499.
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