Here, we show that AZD5582 and AT406, potent antagonists of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP), selectively eliminated HCT116 and RKO cells that had undergone senescence following treatment with a chemotherapeutic agent such as trifluridine, camptothecin, or doxorubicin. At physiological concentrations, TNFα sensitized non-senescent, proliferating cancer cells, but not TIS and nutlin-3a-induced senescent cancer cells, to apoptosis in the presence of IAP antagonists. Collectively, these findings suggest that IAP antagonists could serve as effective concomitant agents to TIS-inducing chemotherapy that promotes TNFα secretion within tumors, functioning not only as TNFα-independent senolytics but also as potentiators of TNFα-mediated apoptosis in adjacent non-senescent, proliferating cancer cells.

P1, N=157, Terminated, BeiGene | Trial completion date: Nov 2026 --> Jul 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2025 --> Jul 2025; The research was terminated voluntarily due to changes in the company's business strategy regarding the development of BGB-24714, rather than any safety issues.

Our study reveals for the first time that TAX restores osteogenic-adipogenic equilibrium in OP-BMSCs and promotes bone regeneration through PI3K/AKT/PPARγ activation and mitochondrial protection-mediated suppression of necroptosis. These results position TAX as a promising therapeutic candidate for osteoporosis.

Furthermore, combination treatment significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute phase proteins and decreased levels of necroptosis mediator RIPK3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumour-immune microenvironment which may explain its lack of clinical benefit.

Based on these findings, a combination therapy using the second mitochondria-derived activator of caspases (Smac) mimetic SM164 and sunitinib was developed, demonstrating a more pronounced efficacy than sunitinib monotherapy, and this sensitizing effect was dependent on the expression level of RIPK1. These results suggest that the combination of Smac mimetics with tyrosine kinase inhibitors holds potential clinical value for tumors with dysregulated SPOP/RIPK1/RIPK3 signaling.

P1, N=157, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting

NCT03270176 (https://clinicaltrials.gov/study/NCT03270176). Registered on ClinicalTrials.gov on 29 August 2017.

P3, N=19, Terminated, Groupe Oncologie Radiotherapie Tete et Cou | Trial completion date: Mar 2025 --> Sep 2024 | Completed --> Terminated; toxicity

P3, N=19, Completed, Groupe Oncologie Radiotherapie Tete et Cou | Suspended --> Completed | Trial completion date: Oct 2035 --> Mar 2025 | Trial primary completion date: Oct 2025 --> Dec 2024

Encapsulated BV6 and SM164, two bivalent second mitochondria-derived activator of caspase (Smac) mimetics, in etoposide (ETO)-lipopolymer nanoparticles (NPs) have been developed to deplete inhibitor of apoptosis proteins (IAP), impair DNA, and produce antagonistic effects on glioblastoma multiforme (GBM) in nude mice. Compared to untreated mice, the current ETO preparation carrying Smac mimetics reduced cellular IAP-1 expression to about 33 % and X-linked IAP expression to about 42 %, while enhanced about 3.8-fold caspase-3, indicating the effectiveness of the nanocarriers in accelerating apoptosis of GBM cells. Tf-WGA-CB-PVA-NPs can be promising to upgrade BV6 and SM164 activity by ETO in clinical trials for GBM management.

P3, N=19, Suspended, Groupe Oncologie Radiotherapie Tete et Cou | Trial completion date: Sep 2030 --> Oct 2035 | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=0, Withdrawn, H. Lee Moffitt Cancer Center and Research Institute | N=12 --> 0 | Recruiting --> Withdrawn