guadecitabine (SGI-110) / Otsuka - LARVOL DELTA

An Assembly of the Global Phosphoproteomic Network of an Underexplored Kinase CDK17: Possible Implications in Cell Cycle Regulation. (PubMed, DNA Cell Biol) - "Notably, sequence conservation of CDK17 (S146, S137, and S180) with CDK16 (S119, S110, and S153) and CDK18 (S98, S89, and S132), respectively, was observed, where CDK16 (S119) is a part of the binding motif for multiple upstream kinases, 14-3-3 protein, and CCNYL1...Statistical analysis revealed phosphoregulation of CDK17 through other kinases, regulation of CDK17 substrates, protein-protein interactions, and conserved co-differential regulation in multiple datasets. Specifically, this analysis derived through global data integration with a replicable analytical framework lays a groundwork for experimental validation of CDK17 phosphorylation in its functional regulation."

Journal • CDK7

PagMYB74 orchestrates flavonoid-mediated plant-microbe feedback for drought resilience in poplar. (PubMed, New Phytol) - "We further found that Pseudomonas putida S110 colonization establishes positive feedback through enhanced phenylpropanoid metabolism and activation of nutrient transport pathways in PagMYB74-overexpressing plants, reinforcing the symbiotic interaction. Our findings establish a complete mechanistic continuum from a single host gene to metabolite-driven recruitment and symbiotic reprogramming, facilitating the improvement of environmental adaptation by regulating their interaction with beneficial soil microorganisms."

Journal

ETCTN: Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma (clinicaltrials.gov) - P2 | N=19 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jan 2027

Trial completion date • Oncology • Sarcoma • Solid Tumor

Effects of the Hypomethylating Agent Guadecitabine on Peripheral Blood Mononuclear Cell Methylomes and Immune Cell Populations in Small-Cell Lung Cancer Patients. (PubMed, bioRxiv) - P2 | "Guadecitabine, a hypomethylating agent (HMA), has shown promising clinical activity when combined with carboplatin in preclinical models. Methylome changes in peripheral blood mononuclear cell (PBMCs) from small cell lung cancer (SCLC) patients treated with an epigenetic therapy revealed global hypomethylation and altered cancer signaling processes associated with tumor progression, immune response, therapy resistance and significant change in the proportion of immune cells. Integrating blood-based methylation biomarkers into clinical trials of epigenetic therapy and methylomic analysis of PBMCs provides direct monitoring of treatment effects in cancer patients, which may improve patient selection and enable real-time response assessment in patients receiving hypomethylating agents."

Journal • Gene Therapies • Immunology • Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Small Cell Lung Cancer • Solid Tumor • NGFR

The phase II NIBIT-ML1 study of nivolumab plus ipilimumab and ASTX727 or nivolumab plus ipilimumab in PD-1 resistant metastatic melanoma: Tumor methylation landscape and correlation with clinical outcomes. (ASCO 2025) - P2 | "Funded by No funding sources reported Clinical Trial Registration Number: NCT04250246 Background: In the NIBIT Foundation-sponsored phase Ib NIBIT-M4 study, we firstly showed that the hypomethylating agent (HMA) guadecitabine (guade), a prodrug of decitabine (D), followed by ipilimumab (I) was safe with promising clinical and immunologic activity in cutaneous metastatic melanoma (MM) patients (pts) (Di Giacomo, Clin Cancer Res 2019; Noviello, Nat Commun 2023). Treatment with ASTX727 plus I+N is feasible and has meaningful clinical and immunologic activity in PD-1 refractory MM pts."

Clinical • Clinical data • Late-breaking abstract • Metastases • P2 data • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-1

NCI-2016-01233: Guadecitabine and Atezolizumab in Treating Patients With Advanced Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia That Is Refractory or Relapsed (clinicaltrials.gov) - P1/2 | N=33 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Dec 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Checkpoint inhibition • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Final results of phase Ib/II study of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma (ccRCC) and biomarker analysis. (ASCO-GU 2023) - P1/2 | "The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396."

Biomarker • Clinical • Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD4 • CD8 • CXCL10 • CXCL9 • FOXP3 • IFNG • IL17A

Durvalumab and guadecitabine in advanced clear cell renal cell carcinoma: results from the phase Ib/II study BTCRC-GU16-043. (PubMed, Nat Commun) - P1/2 | "Asymptomatic neutropenia was the most common adverse event. Even though the trial did not meet the primary objective in cohort 1, the tolerability and PFS signal in CPI naive patients are worth further investigation."

Journal • Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Neutropenia • Oncology • Solid Tumor

A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-associated Renal Cell Carcinoma. (PubMed, Clin Cancer Res) - "Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. While 4/9 patients had prolonged stable disease there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, though signs of biologic activity were noted."

Journal • P2 data • CNS Tumor • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Genito-urinary Cancer • Hematological Disorders • Neuroendocrine Tumor • Neutropenia • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • PDGFRA

Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: randomized phase 3 ASTRAL-2 trial. (PubMed, Blood Adv) - P3 | "Patients with relapsed/refractory acute myeloid leukemia (AML) were randomized to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy; low-intensity treatment with HMAs, or low-dose cytarabine; or best supportive care (BSC). There was an OS benefit for guadecitabine in several prespecified subgroups. This study was registered as ClinicalTrials.gov as NCT02920008."

Journal • P3 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology

A Hanks-type bacterial kinase, PknS, directly phosphorylates the alternative sigma factor EcfK to promote resistance to protist predation. (PubMed, FEBS J) - "PknS directly phosphorylates EcfK at five Ser/Thr residues located in two distinct regions of the sigma factor: the conserved σ2 domain (residue T51) and a nonconserved linker connecting domains σ2 and σ4 (residues T104, T106, S108, and S110)...Structural studies indicated that, in addition to T51, phosphorylation at T106 activates EcfK by promoting its interaction with a positively charged pocket within the RNA polymerase β' subunit. Collectively, our findings describe a previously unknown signal transduction pathway involving a Hanks-type kinase and a sigma factor, providing new insights into the mechanisms of sigma factor activation via phosphorylation in bacteria."

Journal

Lactate Enhances Non-Homologous End Joining Repair and Chemoresistance Through Facilitating XRCC4-LIG4 Complex Assembly in Ovarian Cancer. (PubMed, Biomedicines) - "Finally, the physiological relevance of lactate-mediated NHEJ was validated in a preclinical ovarian cancer mouse model treated with cisplatin...Mechanistically, lactate directly binds to XRCC4 at key residues, including Y66, E55, and S110, thereby strengthening the XRCC4-LIG4 association... Our findings reveal lactate as a novel metabolic regulator of the NHEJ pathway by directly allosterically modulating the XRCC4-LIG4 complex. This work establishes a direct molecular link between the Warburg effect and DNA repair-driven chemoresistance, offering new insights into potential therapeutic strategies for ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • XRCC4

Guadecitabine and Durvalumab in Treating Patients With Advanced Liver, Pancreatic, Bile Duct, or Gallbladder Cancer (clinicaltrials.gov) - P1 | N=55 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Dec 2025 ➔ Jul 2026

Trial completion date • Biliary Cancer • Cholangiocarcinoma • Gallbladder Cancer • Hepatocellular Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Location and deprivation in silicosis cases: data from the SWORD scheme 1996–2024 (BTS WM 2025) - "Download figure Open in new tab Download powerpoint Abstract S110 Figure 1 Conclusion Despite being preventable silicosis continues to occur in the UK. Most cases were from low/middle IMD deciles and from regions with higher levels of deprivation suggesting silicosis disproportionately affects people with higher deprivation in the UK. More research should focus on the complex factors increasing the risk of disease, and on improved disease prevention, for these groups."

Clinical • Pulmonary Disease • Respiratory Diseases

Analysis of ASXL1 Mutated T Cells in Patients with Myeloid Malignancies (ASH 2023) - "in 2022, patients with MDS and CMML previously exposed to HMA were treated with a combination of atezolizumab, an immune checkpoint inhibitor (ICI), and guadecitabine, an HMA. We obtained peripheral blood samples from eight patients with ASXL1 mutated myeloid neoplasms detected by commercial NGS testing; aspirate was also obtained from a diagnostic BM biopsy in one patient. Table 1 shows patient demographics, characteristics and mutational analyses in both T and myeloid cells. Most patients were treatment-naïve, but one had been treated with HMA until 6 months prior to sample collection, and one patient had received cyclosporine for over 20 years for an undiagnosed autoimmune condition."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • ASXL1 • CD34 • CD8

Long-Term Follow-up and T Cell Characteristics of Patients with ASXL1-Mutated Relapsed or Refractory MDS or CMML Treated with Guadecitabine and Atezolizumab (ASH 2023) - "Herein we report long-term follow-up of this cohort of patients, along with T cell programmed death-1 (PD-1) expression analyzed based on mutational status. Significant upregulation of PD-1 was noted in T lymphocytes from both wild-type and co-mutated patients. The effect of mutant ASXL1 on T cell responsiveness to ICI deserves further investigation; patients with ASXL1-mutated HMA-refractory myeloid malignancies may benefit from ICI."

Clinical • IO biomarker • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • CD8 • PD-1 • TP53

Update of a Phase II Trial of Guadecitabine in Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia Under the International Working Group 2023 Criteria (ASH 2023) - "From 2014 to 2018, 82 patients with MDS and 18 patients with CMML were enrolled and treated. Median age was 69 (IQR 62.5 – 75), 62% were male, 38.4% had complex karyotype, 86.6% were categorized as IPSS-M high or very-high risk. Additionally, 33.7% were TP53mut, 21.4% were TP53multi-hit."

P2 data • Chronic Myelomonocytic Leukemia • Constipation • Fatigue • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • ASXL1 • DNMT3A • NRAS • SRSF2 • TET2 • TP53

Anti-CD40 and Epigenetic Modifier Inhibitors to Augment Treatment of High-Risk Neuroblastoma (SITC 2025) - "We identified inhibitors of DNMTs (guadecitabine, 'Guad') and HDACs (entinostat, 'Ent') that, when combined with aGD2 and aCD40, cause tumor regression.Methods HR-NBL cells were treated with EMis and assessed for MHCI expression changes via qPCR and flow cytometry. Therapies geared towards restoring MHCI expression, combined with effective immunotherapy regimens that allow for persistent immune responses, might augment immune responses and improve efficacy of combination immunotherapy for HR-NBL.Ethics Approval Our research is conducted under strict oversight by the IACUC and in compliance with all applicable federal and institutional policies.Acknowledgements This research was supported by Midwest Athletes Against Childhood Cancer; and by public health service grants from the National Cancer Institute: Alex's Lemonade Stand Foundation, the Hartwell Foundation, Midwest Athletes Against Childhood Cancer, R35 CA197078, U54 CA232568 as well as the Data..."

IO biomarker • Neuroblastoma • Oncology • Solid Tumor

ETCTN: Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma (clinicaltrials.gov) - P2 | N=19 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Oncology • Sarcoma • Solid Tumor

Epigenetic Modulation and Bone Metastasis: Evolving Therapeutic Strategies. (PubMed, Pharmaceuticals (Basel)) - "DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling...Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases."

IO biomarker • Journal • Review • Gene Therapies • Lung Cancer • Oncology • Solid Tumor • KLF5 • MIR34A • NORAD • RASSF1 • SMARCA4

S-110: Chrononutrition to optimize health (WSS 2025) - No abstract available

Pembrolizumab (Immunotherapy Drug) in Combination With Guadecitabine and Mocetinostat (Epigenetic Drugs) for Patients With Advanced Lung Cancer. (clinicaltrials.gov) - P1 | N=28 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2025 ➔ Jul 2026 | Trial primary completion date: Jul 2025 ➔ Jul 2026

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

NCI-2016-01233: Guadecitabine and Atezolizumab in Treating Patients With Advanced Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia That Is Refractory or Relapsed (clinicaltrials.gov) - P1/2 | N=33 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Nov 2025 ➔ Dec 2026 | Trial primary completion date: Nov 2024 ➔ Dec 2025

Checkpoint inhibition • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Guadecitabine improved relapse-free survival in high-risk acute myeloid leukemia and myelodysplastic syndrome patients after transplant: phase II results from a single center. (PubMed, Haematologica) - "No unexpected adverse events (AEs) occurred, and no graft failures were observed. Guadecitabine demonstrated efficacy and a favorable safety profile across all cohorts, supporting the investigations of hypomethylating agents."

Journal • P2 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis. (PubMed, J Biol Chem) - "Molecular dynamics simulations showed that p.E143Q mutation destabilized these interactions between residues E143 and S110/Y114, or between S141 and W290 in the ND1...The m.3733G>C mutation-induced deficiencies reshaped the cellular homeostasis via impairing autophagy process and promoting intrinsic apoptosis. Our findings provide new insights into pathophysiology of LHON arising from the m.3733G>C mutation-induced mitochondrial dysfunctions and reprograming organellular and cellular homeostasis."

Journal • Inherited Retinal Dystrophy • Leber Hereditary Optic Neuropathy • Metabolic Disorders • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain • Retinal Disorders • Targeted Protein Degradation