Cyncado Therapeutics Presents First Evidence of A2B Receptor Inhibition's Direct Anti-Tumor Effects in Mesothelioma
核心洞察
Cyncado Therapeutics (搜索) presented first evidence that selective A2B receptor (搜索) inhibition directly suppresses mesothelioma (搜索) tumor growth and reduces PD-L1 (搜索) expression through decreased CREB (搜索) phosphorylation.
The company's lead candidate TT-4 demonstrated superior monotherapy activity compared to anti-PD-1 therapy in immunocompetent mesothelioma (搜索) models, with combination treatment showing enhanced anti-tumor effects.
TT-4 is advancing toward first-patient dosing in Q1 2026, supported by mechanistic data showing both tumor-intrinsic effects and immune-mediated growth inhibition.
Cyncado Therapeutics (搜索), a wholly owned subsidiary of AlphaTON Capital Corp (搜索), has presented groundbreaking preclinical data demonstrating that selective adenosine A2B receptor (搜索) inhibition exerts direct anti-tumor effects in mesothelioma (搜索) while simultaneously modulating immune responses. The research, conducted in collaboration with the Italian Group for Mesothelioma (G.I.Me), provides the first evidence of this dual mechanism of action for the company's lead candidate TT-4.
Novel Mechanism of Action Revealed
The new data, presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, shows that selective A2B receptor (搜索) inhibition produces direct anti-tumor effects in both epithelial and non-epithelial mesothelioma (搜索) cells. The mechanism involves decreases in phosphorylated CREB (搜索) (pCREB) with an associated reduction in PD-L1 (搜索) expression, alongside modulation of YAP (搜索) signaling consistent with proteomic shifts.
In human mesothelioma (搜索) spheroid systems, hypoxia-linked adenosine signaling increased tumor growth and PD-L1 (搜索) expression. Selective A2B receptor (搜索) inhibition reduced cell growth and lowered PD-L1 protein through reduced CREB (搜索) phosphorylation. In murine models, TT-4 blocked NECA-induced pCREB activation and growth stimulation in AB1 and AB22 mesothelioma cells.
Superior Efficacy in Preclinical Models
The in vivo studies revealed particularly compelling efficacy signals. TT-4 demonstrated meaningful monotherapy activity in an immunocompetent mesothelioma (搜索) model, with performance exceeding that of anti-PD-1 therapy. Combination treatment with TT-4 plus anti-PD-1 further increased tumor growth inhibition, with immunohistochemistry showing higher T-cell infiltration and increased immune infiltration with tertiary lymphoid structures.
"In vitro, we see a direct anti-tumor effect in both epithelial and non-epithelial mesothelioma (搜索) cells, with PD-L1 (搜索) falling in step with reduced pCREB. In vivo, TT-4 is active as a single agent and adds benefit with anti-PD-1, clear signals that are guiding our clinical strategy," said Rob Kramer, PhD, Chief Scientific Officer at Cyncado Therapeutics (搜索).
Clinical Translation Strategy
The mechanistic insights help explain TT-4's previously observed efficacy profile and support its translation into first-in-human evaluation. The company is advancing TT-4 toward first-patient dosing in Q1 2026, with an initial focus on mesothelioma (搜索) patients.
"Mesothelioma (搜索) is a hypoxic, adenosine-rich disease, and these data add a clear tumor-intrinsic mechanism to the case for targeting the A2B receptor (搜索)," Kramer noted. "We are advancing TT-4 toward first-patient dosing in Q1 2026 to translate these signals clinically."
Broader Development Pipeline
Cyncado Therapeutics (搜索) is developing potentially best-in-class small molecule adenosine receptor antagonists targeting A2A and A2B receptors to overcome immune suppression in oncology. Beyond TT-4, the company has TT-10, an A2A receptor (搜索) antagonist currently in Phase 1 dose escalation for advanced solid tumors. The company is also developing dual-antagonist strategies designed to achieve comprehensive blockade of adenosine-mediated immune evasion.
"AlphaTON focuses on programs where biology and translational markers converge," said Brittany Kaiser, Chief Executive Officer of AlphaTON Capital. "This first-evidence package strengthens our conviction in TT-4 for mesothelioma (搜索) and informs how we prioritize resources to reach proof of concept in patients."
The research represents a significant advancement in understanding adenosine pathway targeting in mesothelioma (搜索), a challenging malignancy with limited treatment options. The dual mechanism of action—combining direct anti-tumor effects with immune system activation—positions TT-4 as a potentially differentiated therapeutic approach for this hypoxic, adenosine-rich tumor type.