Amanda Swain

Successful cancer immunotherapy requires not only tumor cell killing but also the activation of innate and adaptive immune responses. The inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2 and XIAP act as key suppressors of RIPK1-driven immunogenic cell death, thereby enabling tumor immune evasion and limiting the effectiveness of immune checkpoint blockade (ICB). ASTX660 (tolinapant) is a non-peptidomimetic antagonist with a balanced activity against all clinically relevant IAPs, designed to lower the TNF cytotoxicity threshold and sensitize tumors to T cell-mediated killing. Here, we present results from the phase I ASTEROID trial (NCT05082259), evaluating ASTX660 in combination with pembrolizumab in patients with advanced solid tumors. Primary endpoints were recommended phase 2 dose (RP2D) and safety, while secondary endpoints were anti-tumor activity and pharmacokinetics. The combination was well tolerated and demonstrated early evidence of efficacy. RP2D was ASTX660 150 mg (7-days-on/14-days-off) with pembrolizumab. Overall response rate was 33%, including responses in ER⁺ breast cancers typically resistant to ICB. Integrated translational analyses reveal that response is associated with a TNF/IFN-enriched inflammatory tumor microenvironment, increased tumor antigenicity and enhanced TCR clonal diversity, whereas resistance correlates with a CCR4/6/7/8-driven TAM/Treg-dominant niche. Together, these results provide clinical proof-of-concept that dual IAP and PD-1 blockade sensitize tumors, while identifying candidate biomarkers to guide patient stratification in future studies.

Development and characterization of BAG-1 knockout mice.

List of the 44 3D structures of HSC70 (HSPA8) in complex with the BAG domain of BAG-1 used in comparative structural analyses.

Thio-2 downregulates C-MYC expression through a BAG-1 independent mechanism.

BAG-1 knockout female mice are fertile and viable with reduced gestation.

Synthego BAG-1 sgRNA for BAG-1 CRISPR knockout clones.

Mouse organ hematoxylin and eosin, and BAG-1 immunohistochemistry, in BAG-1 knockout mice.

Thio-2 reduces genome-wide androgen receptor binding in LNCaP prostate cancer cells.

Protocols and antibodies for immunohistochemical analyses.

Thio-2, may bind the N-terminus of the androgen receptor through a similar binding mode to EPI-001.