- |||||||||| Tagrisso (osimertinib) / AstraZeneca
ENPP1 inhibits the cGAS-STING pathway to mediate immune evasion in EGFR-TKI resistant NSCLC (Section 11) - Mar 17, 2026 - Abstract #AACR2026AACR_9239;
Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have demonstrated promising clinical efficacy in EGFR-mutant non-small cell lung cancer (NSCLC)...Finally, immune reconstitution mouse models confirmed that ENPP-1-IN-1 potentiated the efficacy of anti-PD-1 therapy in HCC827OR xenografts by increasing immune infiltration and T-cell activity. Collectively, our study highlights a critical role for ENPP1 in mediating immune evasion through suppression of the cGAMP-STING pathway in the EGFR-TKI resistant tumor, supporting ENPP1 as a promising therapeutic target to enhance immunotherapy efficacy in EGFR-TKI resistant NSCLC.
- |||||||||| Phase I dose-escalation study of ENPP1 inhibitor, vizenpistat, for the treatment of solid tumors (Section 50) - Mar 17, 2026 - Abstract #AACR2026AACR_7406;
Collectively, our study highlights a critical role for ENPP1 in mediating immune evasion through suppression of the cGAMP-STING pathway in the EGFR-TKI resistant tumor, supporting ENPP1 as a promising therapeutic target to enhance immunotherapy efficacy in EGFR-TKI resistant NSCLC. Abstract is embargoed at this time.
- |||||||||| Strensiq (asfotase alfa) / AstraZeneca
Journal: ENPP1 inhibition as a therapeutic approach for later-onset hypophosphatasia. (Pubmed Central) - Mar 7, 2026
Enzyme replacement with mineral-targeted TNAP (asfotase alfa) improves skeletal mineralization but the almost daily injections of this biologic can lead to injection site reactions and discontinuation of treatment...We tested if pharmacologically inhibiting ENPP1, the enzyme that generates PPi, could lower PPi concentrations and ameliorate soft bone disease in a mouse model of later-onset HPP. The results were efficacious and point to the potential usefulness of this strategy to treat HPP.
- |||||||||| Journal: Soft-Drug-Inspired MnSTF Nano-Adjuvant for Safe and Synergistic cGAS-STING Activation in Tumor Immunotherapy. (Pubmed Central) - Dec 16, 2025
Furthermore, MnSTF profoundly reprograms the tumor immune microenvironment and, when coadministered with radiotherapy, mRNA vaccines, or protein antigens, induces robust antigen-specific T cell responses and marked antitumor efficacy. Accordingly, by combining soft-drug design with a dual-targeted immunomodulatory mechanism, MnSTF effectively reconciles the efficacy-safety trade-off of STING agonists in preclinical settings and expands the potential for precise immunoregulation via the STING pathway.
- |||||||||| Regulation of radiation-induced innate immune signaling in patient-derived triple-negative breast cancer organoids (Poster Hall (Exhibit Halls AB); Virtual) - Oct 3, 2025 - Abstract #SITC2025SITC_1197;
PDO models can inform precision RT immunotherapy combinations.Acknowledgements Funding: Supported by BCRF 24-053 and DOD W81XWH-21-2-0034. DS is supported by a Burroughs Wellcome Physician-Scientist Award.Ethics Approval Informed consent and ethics approval was obtained via the DIGNITY Study (De-convoluting interactions between genes, the cancer environment, and the immune system to develop therapies that work for you) IRB Protocol #: 21-06023682
- |||||||||| AVA-NP-695 / Avammune
AVA-NP-695 Demonstrates Strong Anti-Cancer Activity in ICB-Refractory & Rare Cancers (Poster Hall (Exhibit Halls AB); Virtual) - Oct 3, 2025 - Abstract #SITC2025SITC_949;
AVA-NP-695 exploits ENPP1 inhibition to exert a strong anti-tumor response and obliviates metastasis. Interestingly, AVA-NP-695 doesn't restrict itself to a single combination modality and demonstrates cancer agnostic features both as monotherapy and also in combination with other existing standard of care treatment such as anti-PD-1 or Paclitaxel or PARP inhibitors.
- |||||||||| Preclinical, Review, Journal, IO biomarker: Advances in STING Pathway Modulation for Cancer and Immunotherapy: A Comprehensive Review of Preclinical and Clinical Studies (2020-2024). (Pubmed Central) - Aug 5, 2025
While challenges remain, including precise regulation of STING activation and managing immune-related adverse events, rapid progress suggests that STING-targeted therapies could become cornerstone treatments. By harnessing innate immunity and enhancing its interplay with adaptive responses, STING modulators offer a potentially more accessible, cost-effective, and broadly applicable approach to cancer immunotherapy, addressing many current treatment limitations.
- |||||||||| Strensiq (asfotase alfa) / AstraZeneca
Amelioration of osteomalacia in late-onset HPP mice via pharmacological inhibition of ENPP1 (Discovery Hall) - Jul 1, 2025 - Abstract #ASBMR2025ASBMR_750;
Enzyme replacement with mineral-targeted TNAP (asfotase alfa) improves skeletal mineralization but the required 3-6 times per week administration of this biologic can lead to injection site reactions and discontinuation of treatment...AlplPrx1/-mice manifest disorganized growth plates with a thick unmineralized chondrocytes zone, while AlplPrx1/- mice treated with REV102 exhibited a reduced unmineralized zone, similar to that seen in Wt mice. Our data indicate that ENPP1 inhibitors have the potential to be used as therapeutic drugs to improve the bone phenotype in HPP subjects.
- |||||||||| Strensiq (asfotase alfa) / AstraZeneca
Amelioration of osteomalacia in late-onset HPP mice via pharmacological inhibition of ENPP1 (Discovery Hall) - Jul 1, 2025 - Abstract #ASBMR2025ASBMR_456;
Enzyme replacement with mineral-targeted TNAP (asfotase alfa) improves skeletal mineralization but the required 3-6 times per week administration of this biologic can lead to injection site reactions and discontinuation of treatment...AlplPrx1/-mice manifest disorganized growth plates with a thick unmineralized chondrocytes zone, while AlplPrx1/- mice treated with REV102 exhibited a reduced unmineralized zone, similar to that seen in Wt mice. Our data indicate that ENPP1 inhibitors have the potential to be used as therapeutic drugs to improve the bone phenotype in HPP subjects.
- |||||||||| Oncogenic Molecular Features triggered by the Mechanoresponsive Polycystin proteins (Poster and Exhibition Hall; Poster Board No EACR25-1619) - Jun 29, 2025 - Abstract #EACR2025EACR_1409;
The research project was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the "2nd Call for H.F.R.I. Research Projects to support Faculty Members & Researchers" (Project Number: 3226).
- |||||||||| Journal, Checkpoint inhibition: ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy. (Pubmed Central) - Jun 6, 2025
Conceptually, this work establishes that a noncovalent small molecule inhibitor of ENPP1 with ultralong drug-target engagement offers a safe and precise strategy to activate STING within tumors, fulfilling an unmet need of innate immunotherapies in cancer. A small molecule blocks ENPP1, reviving immune attack on tumors and enhancing immune therapy with minimal side effects in preclinical cancer models.
- |||||||||| methotrexate / Generic mfg.
Journal: Methotrexate exerts antitumor immune activity and improves the clinical efficacy of immunotherapy in patients with solid tumors. (Pubmed Central) - Jun 4, 2025
In addition, a preliminary clinical trial demonstrated promising efficacy and safety of low-dose MTX in combination with immunotherapy and radiotherapy for patients with unresectable or metastatic solid tumors, showing improved outcomes compared with historical controls. These results highlight the previously unrecognized immunostimulatory functions of MTX and provide a rationale for combining MTX with tumor immunotherapy and radiotherapy in clinical settings.
- |||||||||| TXN10128 / Txinno Biosci
Enrollment change, Trial completion date, Trial primary completion date, Monotherapy: A Study of TXN10128 in Subjects With Solid Tumors (clinicaltrials.gov) - Apr 25, 2025
P1, N=96, Recruiting,
This review summarizes efforts made towards the discovery and development of compounds that inhibit CDN phosphodiesterases and cON ring nucleases. N=36 --> 96 | Trial completion date: Aug 2025 --> Jun 2026 | Trial primary completion date: Mar 2025 --> Dec 2025
- |||||||||| AVA-NP-695 / Avammune
Exploring the therapeutic benefit of AVA-NP-695 with combination modalities in ICB refractory and rare cancers (Section 28; Poster Board No: 18) - Mar 25, 2025 - Abstract #AACR2025AACR_2821;
The potent anti-tumor efficacy of AVA-NP-695 both as monotherapy and combination along with its safety profile provides a strong rationale for the therapeutic potential of AVA-NP-695 against solids tumors (breast cancer and Osteosarcoma). Our results uncover novel mechanistic vulnerabilities and suggest that treatment with AVA-NP-695 in combination may increase effectiveness in patients, thus preventing local and distant dissemination.
- |||||||||| SR-8541A / TGen, Stingray Therap
Enrollment change, Trial completion date, Trial primary completion date, Monotherapy, Checkpoint inhibition: StingrayTx: A Study of SR-8541A (ENPPI Inhibitor) in Advanced/Metastatic Solid Tumors (clinicaltrials.gov) - Mar 12, 2025
P1, N=25, Recruiting,
Our results uncover novel mechanistic vulnerabilities and suggest that treatment with AVA-NP-695 in combination may increase effectiveness in patients, thus preventing local and distant dissemination. N=18 --> 25 | Trial completion date: Aug 2024 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Dec 2025
- |||||||||| deoxyglucose / Generic mfg.
Journal: Dependence of NPPS creates a targetable vulnerability in RAS-mutant cancers. (Pubmed Central) - Feb 21, 2025
Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose (2-DG), or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo. In conclusion, this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway, proposing a new potential therapeutic approach for treating RAS-mutant cancers.
- |||||||||| Review, Journal: Structural and Functional Integration of Tissue-Nonspecific Alkaline Phosphatase Within the Alkaline Phosphatase Superfamily: Evolutionary Insights and Functional Implications. (Pubmed Central) - Dec 27, 2024
The review also aims to highlight the importance of oligomerization in enzyme stability and function, and the role of conserved metal ion coordination, particularly magnesium, in APs. By exploring the structural and functional diversity within the AP superfamily, and discussing to which extent its members exert redundant, complementary, or specific functions, this review illuminates the evolutionary pressures shaping these enzymes and their broad physiological roles, offering insights into TNAP's multifunctionality and its implications for health and disease.
- |||||||||| Journal: m6A-mediated gluconeogenic enzyme PCK1 upregulation protects against hepatic ischemia-reperfusion injury. (Pubmed Central) - Dec 16, 2024
By exploring the structural and functional diversity within the AP superfamily, and discussing to which extent its members exert redundant, complementary, or specific functions, this review illuminates the evolutionary pressures shaping these enzymes and their broad physiological roles, offering insights into TNAP's multifunctionality and its implications for health and disease. Our study found that activation of the methyltransferase 3/N6-methyladinosine-PCK1-gluconeogenesis axis is required to protect against hepatic I/R injury, providing potential intervention approaches for alleviating hepatic I/R injury during liver surgery.
- |||||||||| botensilimab (AGEN1181) / Agenus
Fc-enhanced anti-CTLA-4 antibody, botensilimabms, enhances the efficacy of multiple therapeutic modalities in immunotherapy-refractory tumor models (Exhibit Halls AB - George R. Brown Convention Center) - Oct 4, 2024 - Abstract #SITC2024SITC_894;
In patients with advanced solid tumors, botensilimab +/- balstilimab (anti-PD-1), demonstrates durable clinical responses across nine different immunotherapy-resistant or poorly immunogenic tumor types...Combination agents/modalities included focal radiotherapy, chemotherapy (doxorubicin, etoposide, gemcitabine and nab-paclitaxel), iNKT activation (?aGalCer), QS-21 saponin adjuvant, vaccines, ENPP1 inhibitor and immune checkpoint/co-stimulatory therapy (anti-PD-1 and anti-CD137 agonist antibodies)...In the CT26 model, combination of botensilimabms with an ENPP1 inhibitor, SR-8541A, produced superior tumor growth inhibition compared to the respective individual therapies, and was associated with enhanced T cell infiltration...Conclusions These studies highlight the versatility of botensilimab to combine with a broad range of therapeutic agents and modalities to enhance anti-tumor immunity in difficult-to-treat mouse tumor models. Clinical trials exploring botensilimab combinations are ongoing.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: Discovery of Imidazo[1,2-a]pyrazine Derivatives as Potent ENPP1 Inhibitors. (Pubmed Central) - Oct 2, 2024
In vivo pharmacokinetic and antitumor studies showed promising results, with 7 not only exhibiting efficient pharmacokinetic properties but also enhancing the antitumor efficacy of the anti-PD-1 antibody. Treatment with 7 (80 mg/kg) combined with anti-PD-1 antibody achieved a tumor growth inhibition rate of 77.7% and improved survival in a murine model.
- |||||||||| Journal: Epitranscriptomic regulation of lipid oxidation and liver fibrosis via ENPP1 mRNA m6A modification. (Pubmed Central) - Sep 9, 2024
In conclusion, PCK1 inhibition attenuates the mitochondrial fission, proliferation, and migration of VSMCs by inhibiting the STAT3/DRP1 axis, thereby suppressing vascular NIH and restenosis. We describe a novel mechanism in which WTAP catalyzes m6A methylation of ENPP1 in a YTHDF1-dependent manner to enhance lipid oxidation, promoting HSCs proliferation and migration and liver fibrosis.
- |||||||||| Journal: [1,2,4]Triazolo[1,5-a]pyrimidine derivatives: Structure-activity relationship study leading to highly selective ENPP1 inhibitors. (Pubmed Central) - Jul 28, 2024
We have previously identified small-molecule ENPP1 inhibitors having a [1,2,4]triazolo[1,5-a]pyrimidine scaffold by means of chemical screening using a fluorescence probe, TG-mAMP. In this study, we evaluated the structure-activity relationships of the hit and lead compounds in detail, and succeeded in developing compounds that strongly and selectively inhibit ENPP1 not only in vitro, but also in cellular systems.
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