AVA-NP-695与DDRi联用展现出强烈协同作用,在罕见儿童癌症中产生强效抗肿瘤活性

Background: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) overexpression is linked to poor prognosis in various cancers, including astrocyte tumors, triple-negative breast cancer (TNBC), Ewing sarcoma (EWS), and osteosarcoma (OS). Transcriptomics and proteomic analyses highlight the highest ENPP1 expression in EWS, OS, and breast cancer. Importantly, ENPP1 is increasingly implicated in driving lung and bone metastasis, a major clinical challenge for cancers like TNBC, Ewing sarcoma, and osteosarcoma. Overall, ENPP1 is a clinically relevant and druggable target for several hard-to-treat ICB-refractory cancers. Therefore, the therapeutic of ENPP1 inhibition was explored as monotherapy as well as in combination with DDR inhibitors like Ceralasertib and Olaparib. Methods: The potency of AVA-NP-695, a small-molecule ENPP1 inhibitor, was validated through enzymatic assays using different substrates. Pharmacokinetic profiles were evaluated in mice, rats, and beagle dogs. ENPP1 expression and cGAMP export were evaluated after dsDNA stimulation, and ENPP1 activity was measured using a biochemical assay in OS cell lines, including OSPDX-cell lines. Mono and combination therapy effects of AVA-NP-695 and Olaparib/Ceralasertib were evaluated in OS and EWS models. Results: AVA-NP-695 demonstrated potent and selective ENPP1 inhibition with no adverse effects in repeat-dose and dose-escalation toxicity studies. In OS models, AVA-NP-695 induced tumor regression in both paratibial (orthotopic) and metastatic (lung) contexts. Interestingly, targeted pharmacological screen revealed synthetic lethality between AVA-NP-695 and both Olaparib/Ceralasertib in osteosarcoma cell lines. In two patient-derived xenograft (PDX) OS models (OS384 and OS526), as well as in a EWS (A673) CDX model, AVA-NP-695 administered as a monotherapy showed similar efficacy as olaparib alone, and the combination of the two agents combination resulted in significant tumour regression. In GS383 intrapulmonary model, it achieved strong tumor shrinkage in lung nodules on post-treatment scans and prolonged progression-free survival. Similar effects were observed in combination with Ceralasertib in case of Osteosarcoma syngeneic model. Conclusions: These findings underscore the therapeutic potential of AVA-NP-695 across hard-to-treat ICB-refractory pediatric cancers such as OS and EWS. AVA-NP-695 exploits ENPP1 inhibition to exert a strong anti-tumor response and obliviates metastasis. Additionally, AVA-NP-695 also demonstrates strong synergy with DDR inhibitors like Olaparib and Ceralasertib in both these cancers. Overall, these findings demonstrate that AVA-NP-695 has strong potential as a therapeutic modality in OS and EWS as a monotherapy and combination with DDR inhibitors.