P1/2, N=230, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Oct 2024 --> Dec 2025

P1, N=42, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Nov 2024 --> Aug 2025

P1, N=33, Not yet recruiting, National Cancer Institute (NCI)

Overexpression of USP36 disrupts the formation of the XIAP-Smac complex and promotes RIPK1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in colorectal cancer progression and is a potential therapeutic target.

P1/2, N=132, Active, not recruiting, Astex Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

In conclusion, this study reveals a novel mechanism through which NAP1L1 regulates the ubiquitination of BIRC2 through UBR4, thereby determining the progression of HCC. Based on this mechanism, suppression of NAP1L1 may inhibit tumour progression in patients with HCC with high protein expression of NAP1L1 or BIRC2.

P1, N=10, Recruiting, Emory University | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=78, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Not yet recruiting --> Recruiting

In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective...AZD5582 combined with carfilzomib therapy showed a synergistic effect...Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

Our data offer a cellular and molecular insight into a case of clinical pseudoprogression observed during tolinapant treatment. Understanding pseudoprogression is important for clinical investigators and patients to ensure treatment with tolinapant, or other IAP antagonists, are not discontinued prematurely.

In summary, BIRC2 knockdown alleviated necroptosis, oxidative stress, and inflammation in LPS-mediated C28/I2 cells, which might correlate to the regulatory role of TRADD, indicating a novel target for the treatment of RA.

IAP antagonists have shown great promise for head and neck cancer, especially in combination with radiation therapy. Here, we review recent preclinical and clinical studies on the use of these novel targeted agents for head and neck cancer.

Xevinapant appears to be a potent new drug for HNSCC therapy, especially in combination with IR. IAP levels could be an indicator for impaired DNA damage repair and increased susceptibility to cellular stress.

P1b, N=78, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris

Therefore, future work will explore these pathways under hypoxic conditions. Additionally changes in cell proliferation and protein expression of IAPs will be measured following exposure of cervical cancer cell lines to different hypoxic conditions in combination with irradiation, cisplatin and tolinapant.

While there are limited studies using decitabine as a hypomethylating agent (HMA) in PTCL, a recent guadecitabine prospective study showed 40% ORR (Wong et al., Leukemia, 2022)...Subjects with CD30-positive disease must have received or be ineligible for brentuximab vedotin... The Study opened in June 2022 with primary completion estimated to be December 2025. Pharmacokinetic, Oral, Peripheral T-cell lymphoma

IAPs were found to be overexpressed in cancerous tissues and to contribute to therapeutic resistance. The present review focuses on the IAP members cIAP1, cIAP2, XIAP, Survivin and Livin and their importance as potential therapeutic targets in bladder cancer.

In addition, BIRC2 was highly-expressed in NPC tissues, and positively correlated with the TNM stage and negatively correlated with the expression of BRD7. Therefore, these results suggest that BRD7 suppresses tumor growth and metastasis thus functioning as a tumor suppressor at least partially by negatively regulating the enhancer activity and expression of BIRC2, and targeting the BRD7/BIRC2 regulation axis might be a potential strategy for the diagnosis and treatment of NPC.

In this review, we summarize the inflammatory responses in acute and chronic gout, specifically focusing on innate immune cell mechanisms and genetic and epigenetic characteristics of participating molecules. Unprecedently, a novel UA binding protein - the neuronal apoptosis inhibitor protein (NAIP) - is suggested as responsible for the asymptomatic hyperuricemia paradox.Abbreviation: β2-integrins: leukocyte-specific adhesion molecules; ABCG2: ATP-binding cassete family/breast cancer-resistant protein; ACR: American college of rheumatology; AIM2: absent in melanoma 2, type of pattern recognition receptor; ALPK1: alpha-protein kinase 1; ANGPTL2: angiopoietin-like protein 2; ASC: apoptosis-associated speck-like protein; BIR: baculovirus inhibitor of apoptosis protein repeat; BIRC1: baculovirus IAP repeat-containing protein 1; BIRC2: baculoviral IAP repeat-containing protein 2; C5a: complement anaphylatoxin; cAMP: cyclic adenosine monophosphate; CARD: caspase activation and recruitment domains; CARD8: caspase recruitment domain-containing protein 8; CASP1: caspase 1; CCL3: chemokine (C-C motif) ligand 3; CD14: cluster of differentiation 14; CD44: cluster of differentiation 44; Cg05102552: DNA-methylation site, usually cytosine followed by guanine nucleotides; contains arbitrary identification code; CIDEC: cell death-inducing DNA fragmentation factor-like effector family; CKD: chronic kidney disease; CNV: copy number variation; CPT1A: carnitine palmitoyl transferase - type 1a; CXCL1: chemokine (CXC motif) ligand 1; DAMPs: damage associated molecular patterns; DC: dendritic cells; DNMT(1): maintenance DNA methyltransferase; eQTL: expression quantitative trait loci; ERK1: extracellular signal-regulated kinase 1; ERK2: extracellular signal-regulated kinase 2; EULAR: European league against rheumatism; GMCSF: granulocyte-macrophage colony-stimulating factor; GWAS: global wide association studies; H3K27me3: tri-methylation at the 27th lysine residue of the histone h3 protein; H3K4me1: mono-methylation at the 4th lysine residue of the histone h3 protein; H3K4me3: tri-methylation at the 4th lysine residue of the histone h3 protein; HOTAIR: human gene located between hoxc11 and hoxc12 on chromosome 12; IκBα: cytoplasmatic protein/Nf-κb transcription inhibitor; IAP: inhibitory apoptosis protein; IFNγ: interferon gamma; IL-1β: interleukin 1 beta; IL-12: interleukin 12; IL-17: interleukin 17; IL18: interleukin 18; IL1R1: interleukin-1 receptor; IL-1Ra: interleukin-1 receptor antagonist; IL-22: interleukin 22; IL-23: interleukin 23; IL23R: interleukin 23 receptor; IL-33: interleukin 33; IL-6: interleukin 6; IMP: inosine monophosphate; INSIG1: insulin-induced gene 1; JNK1: c-jun n-terminal kinase 1; lncRNA: long non-coding ribonucleic acid; LRR: leucine-rich repeats; miR: mature non-coding microRNAs measuring from 20 to 24 nucleotides, animal origin; miR-1: miR followed by arbitrary identification code; miR-145: miR followed by arbitrary identification code; miR-146a: miR followed by arbitrary identification code, "a" stands for mir family; "a" family presents similar mir sequence to "b" family, but different precursors; miR-20b: miR followed by arbitrary identification code; "b" stands for mir family; "b" family presents similar mir sequence to "a" family, but different precursors; miR-221: miR - followed by arbitrary identification code; miR-221-5p: miR followed by arbitrary identification code; "5p" indicates different mature miRNAs generated from the 5' arm of the pre-miRNA hairpin; miR-223: miR followed by arbitrary identification code; miR-223-3p: mir followed by arbitrary identification code; "3p" indicates different mature miRNAs generated from the 3' arm of the pre-miRNA hairpin; miR-22-3p: miR followed by arbitrary identification code, "3p" indicates different mature miRNAs generated from the 3' arm of the pre-miRNA hairpin; MLKL: mixed lineage kinase domain-like pseudo kinase; MM2P: inductor of m2-macrophage polarization; MSU: monosodium urate; mTOR: mammalian target of rapamycin; MyD88: myeloid differentiation primary response 88; n-3-PUFAs: n-3-polyunsaturated fatty-acids; NACHT: acronym for NAIP (neuronal apoptosis inhibitor protein), C2TA (MHC class 2 transcription activator), HET-E (incompatibility locus protein from podospora anserina) and TP1 (telomerase-associated protein); NAIP: neuronal apoptosis inhibitory protein (human); Naip1: neuronal apoptosis inhibitory protein type 1 (murine); Naip5: neuronal apoptosis inhibitory protein type 5 (murine); Naip6: neuronal apoptosis inhibitory protein type 6 (murine); NBD: nucleotide-binding domain; Nek7: smallest NIMA-related kinase; NET: neutrophil extracellular traps; Nf-κB: nuclear factor kappa-light-chain-enhancer of activated b cells; NFIL3: nuclear-factor, interleukin 3 regulated protein; NIIMA: network of immunity in infection, malignancy, and autoimmunity; NLR: nod-like receptor; NLRA: nod-like receptor NLRA containing acidic domain; NLRB: nod-like receptor NLRA containing BIR domain; NLRC: nod-like receptor NLRA containing CARD domain; NLRC4: nod-like receptor family CARD domain containing 4; NLRP: nod-like receptor NLRA containing PYD domain; NLRP1: nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 1; NLRP12: nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 12; NLRP3: nod-like receptor family pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain; NRBP1: nuclear receptor-binding protein; Nrf2: nuclear factor erythroid 2-related factor 2; OR: odds ratio; P2X: group of membrane ion channels activated by the binding of extracellular; P2X7: p2x purinoceptor 7 gene; p38: member of the mitogen-activated protein kinase family; PAMPs: pathogen associated molecular patters; PBMC: peripheral blood mononuclear cells; PGGT1B: geranylgeranyl transferase type-1 subunit beta; PHGDH: phosphoglycerate dehydrogenase; PI3-K: phospho-inositol; PPARγ: peroxisome proliferator-activated receptor gamma; PPARGC1B: peroxisome proliferative activated receptor, gamma, coactivator 1 beta; PR3: proteinase 3 antigen; Pro-CASP1: inactive precursor of caspase 1; Pro-IL1β: inactive precursor of interleukin 1 beta; PRR: pattern recognition receptors; PYD: pyrin domain; RAPTOR: regulatory associated protein of mTOR complex 1; RAS: renin-angiotensin system; REDD1: regulated in DNA damage and development 1; ROS: reactive oxygen species; rs000*G: single nuclear polymorphism, "*G" is related to snp where replaced nucleotide is guanine, usually preceded by an id number; SLC2A9: solute carrier family 2, member 9; SLC7A11: solute carrier family 7, member 11; SMA: smooth muscular atrophy; Smac: second mitochondrial-derived activator of caspases; SNP: single nuclear polymorphism; Sp3: specificity protein 3; ST2: serum stimulation-2; STK11: serine/threonine kinase 11; sUA: soluble uric acid; Syk: spleen tyrosine kinase; TAK1: transforming growth factor beta activated kinase; Th1: type 1 helper T cells; Th17: type 17 helper T cells; Th2: type 2 helper T cells; Th22: type 22 helper T cells; TLR: tool-like receptor; TLR2: toll-like receptor 2; TLR4: toll-like receptor 4; TNFα: tumor necrosis factor alpha; TNFR1: tumor necrosis factor receptor 1; TNFR2: tumor necrosis factor receptor 2; UA: uric acid; UBAP1: ubiquitin associated protein; ULT: urate-lowering therapy; URAT1: urate transporter 1; VDAC1: voltage-dependent anion-selective channel 1.

Specifically, xevinapant demonstrated superior efficacy in combination with CRT vs placebo + CRT in a randomized, double-blind, phase 2 trial in patients with unresected LA SCCHN. Here, we describe the current treatment landscape in LA SCCHN and provide the rationale for targeting IAPs and the clinical data reported for xevinapant.

In addition, re-expression of RIPK3 in CT26 cells increased lytic cell death on treatment with tolinapant indicating its essential role in the necroptosis pathway.Objectives: 1) Characterize the single-agent activity of tolinapant in a range of TCL lines; 2) Determine the synergy of tolinapant in combination with drugs active against PTCL (romidepsin, pralatrexate) and HMAs (azacytidine-AZA; decitabine-DAC), and 3) Define the role of necroptosis in the mechanism of synergy. Thus, activation of the necroptosis pathway, is a possible mechanism for the high degree of synergy displayed when HMAs are used in combination with tolinapant in the TCL lines in vitro. These data provided the rationale for a phase 1-2 study of the combination of tolinapant and oral decitabine/cedazuridine treatment in relapsed/refractory PTCL (NCT05403450).

Subjects with CD30-positive disease must have received, be ineligible for, or intolerant to brentuximab vedotin. In Phase 2, there will be efficacy analysis for every 34 subjects, without a pause in enrollment. Study initiated in May 2022.

Inhibition or downregulation of STAT3 specifically compromised the growth of cIAP1-restored MEFs but not that of MEFs expressing a cIAP1-mutant and treating mice with the STAT3 inhibitor niclosamide completely abrogated cIAP1/TRAF2-mediated tumor growth. Altogether, we demonstrate that cIAP1/TRAF2 binding is essential to promote tumor growth via the activation of the JAK/STAT3 signaling pathway.

This was due, at least in part, to reduce MAPKs, Akt, NF-κB, AP-1 and STAT-3 activation. Taken together, our results suggested that DCF potentiated the anticancer effect of cisplatin in SRCGC via the regeneration of intracellular ROS, which in turn promoted cell death as an autophagy mechanism and potentially modulated the cell survival signal transduction pathway.

The mice were randomly divided into control, hydrogenation (inhalation of 60% hydrogen gas), and cisplatin groups (intraperitoneal injection of cisplatin [4 mg/kg])...Hydrogen gas further decreased the levels of XIAP and BIRC3 expression than in nude mice (P < 0.01). Hydrogen gas promoted apoptosis of A549 cells by reducing the expression of XIAP and BIRC3 protein.

Anti-diabetic drug, metformin, has attracted attentions as an anti-cancer agent due to the suppression of mTORC1 as a master switch of cell growth in various cancers. Importantly, inclusion of the proteasome inhibitor, Bortezomib, caused the upregulation of the tested anti-apoptotic proteins in both cell lines. These observations suggest that mTORC1 inhibition has a bifold effect; first upregulation of IRES-dependent survival proteins to prevent untimely cell death followed by an opposite effect, which is the enhanced proteosomal degradation of these protein in order to maintain a balanced response.

Overall, these data provide the rationale for additional mechanistic and preclinical in-vivo studies targeting AC and Bcl-2 in AML.

IAP antagonists such as SM-164, AT-406, and BV6, do not kill MDA-MB-231 cells alone, but allow LPS to induce cancer cell apoptosis rapidly. In summary, LPS sensitizes the therapeutic response of both triple-negative and ER breast cancer to IAP antagonist therapy by inducing rapid apoptosis of the cancer cells through TLR4- and MyD88-mediated production of TNFα. We conclude that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy.

The BIRC2-BIRC3 gene signature was found to be associated with the prognosis of HNSCC. Thus, BIRC2 and BIRC3 could be potential targets for improving HNSCC prognosis.

In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.

Immunofluorescence and western-blot results revealed that AZD5582- and SM-164-encapsulated liposomes facilitated mutual curative intensity, effectively triggered apoptosis of U87 MG and HBCSCs, reduced the expression of cellular IAP 1 (cIAP1) and X-linked IAP (XIAP), and enhanced the expression of caspase-3. Hence, RGV-Lf-liposomes carrying AZD5582 and SM-164 can be promising formulations to activate apoptosis of U87 MG and HBCSCs, and this functionalized drug delivery system targeting cIAP and XIAP is a potential strategy to cure glioblastoma in clinical cancer management.

In the present study, sensitivity of this same panel of MRT cell lines to small-molecule mediated inhibition of the IAPs via the survivin inhibitor YM155 and the XIAP/cIAP1/cIAP2 inhibitor BV6 was demonstrated. Importantly, we have demonstrated, for the first time, expression of XIAP, its target caspase-3 and its endogenous inhibitor SMAC in rhabdoid tumour patient tissue. In conclusion, this study provides pre-clinical evidence that IAP inhibition may be a new therapeutic option in MRT.

These results support the continued development of tolinapant for the treatment of R/R PTCL and CTCL. A drug combination study using tolinapant in R/R PTCL is being developed.

Methods On-target effects of decitabine and tolinapant were measured by analysing levels of DNMT1 and cIAP1, respectively, by Western blotting in mouse and human cell lines. In addition, modulation of cytokine response and cancer/testis antigen expression could enhance anti-tumour response. These findings provide a strong rationale to explore this combination clinically.

Aims We explored the sensitivity of a range of TCL lines to tolinapant, established the synergy coefficient and interrogated the role of necroptosis in the mechanism of synergy between tolinapant and drugs active against PTCL, the HMAs; azacytidine and decitabine Methods A panel of 10 human TCL lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10 ng/ml of TNFa. Thus, activation of the necroptosis pathway, is a possible mechanism for the high degree of synergism displayed when HMAs are used in combination with tolinapant in the TCL lines in vitro . These data provide the rationale to initiate clinical trials with the combination of tolinapant and decitabine.

Our study, for the first time, shows that PSMD10 is required for the activation of the pro-survival arm via NFκB transcriptional activation to prevent cancer cells from succumbing to TNF-induced cell death. In addition by transcriptional regulation of two major antiapoptotic players RB1 and β-catenin, PSMD10 proves to be a coveted oncoprotein with a key role in tumorigenesis.

Our study highlights that ASTX660 can overcome the limitation of apoptosis induction via triggering necroptosis in BC cells. Therefore, our findings may provide some important clues for the design of a novel treatment strategy for BC.

Overall, NSP-B reduces cell viability by mitochondrial and caspase-dependent apoptosis. The inhibition of AKT and SKP2 axis could be a promising therapeutic target for leukemia treatment.

These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.