thiostrepton (RSO-021) / RS Oncology - LARVOL DELTA

CD155 regulates tumor growth and immune evasion in diffuse midline glioma (SNO 2025) - "FOXM1 silencing also led to reduced proliferation of DMG cells in vitro and in vivo, and treatment of DMG-bearing mice with Thiostrepton, a FOXM1-targeting antibiotic, delayed tumor growth and prolonged survival. These studies demonstrate that CD155 functions as a modulator of tumor cell sensitivity to T cells and also regulates tumor cell survival in a T cell-independent manner. Our studies suggest that targeting CD155 or its downstream mediators could be a valuable double-pronged therapeutic strategy for this devastating disease."

IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • CD8 • CD96 • FOXM1 • PVR • TIGIT

CD155 regulates tumor growth and immune evasion in diffuse midline glioma (WFNOS 2025) - "FOXM1 silencing also led to reduced proliferation of DMG cells in vitro and in vivo, and treatment of DMG-bearing mice with Thiostrepton, a FOXM1-targeting antibiotic, delayed tumor growth and prolonged survival. These studies demonstrate that CD155 functions as a modulator of tumor cell sensitivity to T cells and also regulates tumor cell survival in a T cell-independent manner. Our studies suggest that targeting CD155 or its downstream mediators could be a valuable double-pronged therapeutic strategy for this devastating disease."

IO biomarker • Brain Cancer • Diffuse Midline Glioma • Oncology • Solid Tumor • CD8 • CD96 • FOXM1 • PVR • TIGIT

Mechanism-based peroxiredoxin 3 inhibitors exploit a covalent warhead for cancer therapy. (PubMed, Sci Adv) - "Thiostrepton (TS) inhibits the peroxidase activity of the mitochondrial antioxidant protein peroxiredoxin 3 by forming a covalent crosslink between the two active site cysteine residues...These findings represent a promising start toward a pro-oxidant approach for cancer therapy. Moreover, the data support that the DHA moiety should be added to the covalent warhead arsenal."

Journal • Mesothelioma • Oncology • Solid Tumor

Integrated bioinformatics and molecular docking analysis reveal potential hub genes and targeted therapeutics in sepsis-associated acute lung injury. (PubMed, Front Immunol) - "Five candidate small molecules were predicted; molecular docking revealed Celastrol had the strongest binding to all six proteins, particularly GDF15 (-9.988 kcal/mol), while Thiostrepton showed strong binding to PGM3, GFOD2, and GDF15. Six diagnostic hub genes and two priority candidate drugs, Celastrol and Thiostrepton, were identified for SA-ALI, providing potential biomarkers and therapeutic targets."

Journal • Acute Lung Injury • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock • E2F2 • GDF15

Mitochondrial antioxidant peroxiredoxin 3 is a tractable therapeutic target in mesothelioma (AACR-NCI-EORTC 2025) - P1/2 | "Targeting PRX3, especially in combination with SLC7A11 inhibition, represents a promising approach for treating aggressive and treatment-resistant forms of cancer. Collectively, these findings identify PRX3 as a key regulator of redox metabolism, mitochondrial function, and mesothelioma tumorigenesis, and establish RSO-021 as a novel first-in-class PRX3 inhibitor with significant therapeutic potential in oncology."

Mesothelioma • Oncology • Solid Tumor • SLC7A11 • TGFB1

ISS01 - MITOPE Clinical Trial Updates - Targeting Redox Metabolism Via Intrapleural Therapy (IMIG 2025) - P1/2 | "The company's lead program, RSO-021, has demonstrated strong safety and early efficacy in the ongoing MITOPE Phase I/II trial (NCT05278975) in patients with malignant pleural mesothelioma and other metastatic diseases to the lung associated with pleural effusion. Scientific and trial updates will be presented during the breakfast symposium Monday, October 27th. rsoncology.com"

Clinical • Malignant Pleural Mesothelioma • Mesothelioma • Metabolic Disorders • Pleural Mesothelioma • Respiratory Diseases • Solid Tumor

Mitochondrial Peroxiredoxin 3 is a Tractable Target in Mesothelioma (IMIG 2025) - "These findings establish PRX3 as a tractable therapeutic target in mesothelioma, with a first-in-class inhibitor, RSO-021, demonstrating clinical activity in heavily pretreated patients. Combined targeting of SLC7A11 may serve as a rational strategy to further enhance the pro-oxidant effect of RSO-021."

Mesothelioma • Respiratory Diseases • Solid Tumor • SLC7A11

Thiostrepton Suppresses the Progression of Rhabdomyosarcoma by Inhibiting the PI3K-AKT Signaling Pathway. (PubMed, Pediatr Discov) - "This was confirmed by PI3K activator 740 Y-P rescue experiments, which partially reversed the effects of TST (p < 0.05). These findings establish TST as a multi-mechanism PI3K-AKT inhibitor for refractory RMS while validating Connectivity Map (Cmap)-driven drug repurposing for pediatric oncology."

Journal • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Drug-Repurposing Screen Identifies Thiostrepton as a Novel Regulator of the Tumor Suppressor DAB2IP. (PubMed, Biomolecules) - "Functional experiments revealed that the cancer-inhibitory effect of thiostrepton is reduced in the absence of DAB2IP, suggesting that upregulation of this protein contributes to its action. These findings encourage further development of thiostrepton for the treatment of solid cancers and unveil a novel molecular target underlying its anti-tumoral activity."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • DAB2IP

The Streptomyces Metabolite Thiostrepton Inhibits Regulatory T Cell Differentiation and Function to Boost Antitumor Immune Responses. (PubMed, Eur J Immunol) - "These effects are conserved in human T cells, as thiostrepton also inhibits the differentiation of human Tregs. Our findings highlight thiostrepton as a promising Treg-targeting immunomodulatory compound with the potential to enhance antitumor immune responses."

IO biomarker • Journal • Oncology • FOXP3

Thiostrepton induces apoptotic cell death at the level of BCL-2/CED-9 in C. elegans. (PubMed, Sci Rep) - "Furthermore, we have unlinked the high ROS (reactive oxygen species) induction reported in earlier in vitro studies from apoptosis induction upon thiostrepton treatment in C. elegans. Overall, our genetic data indicate that apoptosis induction mediated by thiostrepton occurs at the level of the core apoptotic machinery."

Journal • Oncology • BCL2

Catalyst-Controlled Site-Selective and Epimer-Selective Hydrogenations of Thiostrepton. (PubMed, J Am Chem Soc) - "The structures and stereochemistry of the products are identified using multidimensional nuclear magnetic resonance methods, X-ray crystallography, and comparison to model substrates with confirmed absolute stereochemistry. The new thiostrepton derivatives are benchmarked for their antibiotic activity against representative antibiotic-resistant bacterial strains, revealing significant effects of Dha hydrogenation, and a number of new insights, most notably about the significance of Dha3 for antibiotic activity."

Journal

Peroxiredoxin 3 is a key regulator of mesothelioma progression and a target for therapeutic intervention (AACR 2025) - P1/2 | "PRX3 is a novel molecular target of the first-in-human covalent inhibitor RSO-021...Results showed that the most sensitive explants had a reduction in EMT gene expression, a key signature associated with tumor cell migration and metastasis. Our results show that PRX3 supports mesothelioma tumor progression and survival through regulating redox metabolism and signaling while maintaining gene expression signatures supporting tumor aggressiveness, highlighting PRX3 as an important therapeutic target in oncology."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • ITK

The first-in-class PRX3 inhibitor RSO-021 modulates the protein composition of malignant pleural effusions by increasing immunomodulating phenotypes and decreasing epithelial to mesenchymal protein expression (AACR 2025) - P1/2 | "Studies are underway correlating patient responses to MPE composition to identify biomarkers of sensitivity and resistance to RSO-021. Together, these data show the positive effects of RSO-021 on anti-tumor protein signatures related to tumor immunophenotypes and EMT and support the continued investigation of RSO-021 in MPE associated solid tumors."

Immunomodulating • Pleural effusion • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • POSTN • RETN • TGFBI

The first-in-class PRX3 inhibitor RSO-021 modulates the composition of malignant pleural effusions by eliciting immunomodulation and decreasing epithelial to mesenchymal protein expression (BTOG 2025) - P1/2 | "Using Metascape Gene Annotation software we determined enrichment pathways for differential levels of peptides within the MPE fluid collected pre and post treatment. Pathways increased by RSO-021 include neutrophil degranulation, cell killing, hydrogen peroxide metabolic processes, aerobic glycolysis, and apoptosis. Increased levels of the cytokine resistin were identified in treated patient MPE fluid by proteomics and ELISA assays."

Immunomodulating • Pleural effusion • Immunology • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Respiratory Diseases • Solid Tumor • EFEMP1 • POSTN • RETN • TGFBI

Combining KPNA2 and FOXM1 Expression as Prognostic Markers and Therapeutic Targets in Hormone Receptor-Positive, HER2-Negative Breast Cancer. (PubMed, Cancers (Basel)) - "These findings suggest that FOXM1 inhibition could be particularly effective in patients with high KPNA2 expression, offering a novel therapeutic strategy for this specific molecular subtype. Several FOXM1 inhibitors, including thiostrepton and FDI-6, warrant investigation as potential targeted treatments for KPNA2-high HR+HER2- breast cancer patients."

Biomarker • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCNB1 • CCNB2 • FOXM1 • HER-2 • KPNA2

Thiostrepton suppresses intrahepatic cholangiocarcinoma progression via FOXM1-mediated tumor-associated macrophages reprogramming. (PubMed, Transl Oncol) - "Overall, our results indicate that FOXM1 can serve as a novel target for ICC immunotherapy. By targeting FOXM1, TST exerts "dual anti-tumor" effects and has the potential to become a promising immunotherapy agent for ICC patients."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • FOXM1

Fast event-based electron counting for small-molecule structure determination by MicroED. (PubMed, Acta Crystallogr C Struct Chem) - "Fast EBEC data collected with a fluence of 2.25 or 3.33 e-/Å2 also facilitated a 1.5 Å structure of thiostrepton (1665 Da)...However, CL adjustment only marginally improved the refinement of their corresponding structures, signaling the already high counting accuracy of detectors with counting rates in the kilohertz range. Overall, by delivering low-dose structure-worthy data, fast EBEC collection strategies open new possibilities for high-throughput MicroED."

Journal

Optimizing genome editing efficiency in Streptomyces fradiae via a CRISPR/Cas9n-mediated editing system. (PubMed, Appl Environ Microbiol) - "Therefore, the nickase mutation D10A, high-fidelity mutations including N497A, R661A, Q695A, and Q926A, and thiostrepton-induced promotor PtipA were incorporated into the Cas9 expression cassette, which reduced its toxicity...Additionally, the established tool was applied to facilitate the rapid deletion of nagB, replacement of Pfrr with PermE*, and integration of exogenous vgbS, with respective efficiencies of 77.8%, 100%, and 67.8%, and all of the above modification strategies benefited neomycin synthesis in S. fradiae. Taken together, this research established an efficient CRISPR/Cas9n-mediated genome editing toolkit in S. fradiae, paving the way for developing high-performance neomycin-producing strains and facilitating the genetic modification of Streptomyces.IMPORTANCEThis study describes the development and application of a genome editing system mediated by CRISPR/Cas9n in Streptomyces fradiae for the first time, which overcomes the challenges associated with..."

Journal

Thiostrepton suppresses colorectal cancer progression through reactive oxygen species related endoplasmic reticulum stress. (PubMed, Toxicol Appl Pharmacol) - "Thiostrepton-related changes in cell survival and cell migration, as well as mechanistical processes, were almost completely reversed by treatment with the antioxidant N-acetylcysteine (NAC), suggesting that the mechanism is dependent on reactive oxygen species (ROS). These results demonstrated that thiostrepton induced apoptosis and inhibited migration through ROS-induced ER stress and proteotoxic stress in colorectal cancer."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ATF4 • HSPA5

Thiostrepton: multifaceted biological activities and its applications in treatment of inflammatory diseases. (PubMed, Inflammopharmacology) - "In this review, we describe the various pharmacological activities of TST, particularly its anti-inflammatory activity demonstrated in a variety of inflammatory diseases and the underlying mechanisms. These effects highlight the potential of TST as an anti-inflammatory agent for the treatment of inflammation diseases and for enhancing cellular therapies."

Journal • Review • Dental Disorders • Dermatology • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Periodontitis • Psoriasis • Septic Shock

Light inducible gene expression system for Streptomyces. (PubMed, Sci Rep) - "The constructed multiple-copy number plasmid, pLit19, carried five genetic elements: pIJ101rep, the thiostrepton resistance gene, litR, litS, and σLitS-recognized light-inducible crtE promoter...We successfully established an optogenetically controlled hyperproduction system for S. griseus NBRC 13350 and Streptomyces sp. NBRC 13304."

Journal

Complete sequences of pIJ101-based Streptomyces-Escherichia coli shuttle vectors. (PubMed, Access Microbiol) - "pEM4 was found to be 8.3 kbp long, containing a β-lactamase gene, thiostrepton resistance marker, the lacZɑ fragment, a ColE1 origin of replication and the Streptomyces pIJ101 origin of replication...Interestingly, the sequences for both pEM4 and pUWL201 exceed their previously reported size by 1.1 and 0.4 kbp, respectively. This report updates the literature with the corrected sequences for these shuttle vectors, ensuring their compatibility with modern synthetic biology cloning methodologies."

Journal

Peroxiredoxin 3 (PRX3) – a new target for the treatment of aggressive cancers. (EORTC-NCI-AACR 2024) - P1/2 | "RSO-021 reduces EMT gene expression, a key signature associated with tumor cell migration and metastasis. Loss of PRX3 in mesothelioma tumor cells results in reduced proliferation and migratory capacity further warranting continued clinical evaluation of the first-in-class PRX3 inhibitor RSO-021."

Mesothelioma • Oncology • Solid Tumor • ITK • PRDX2 • PRDX4 • PRRX2

MITOPE: Phase 2 evaluation of RSO-021, a novel mitochondrial PRX3 inhibitor, as a monotherapy and in combination with paclitaxel in patients with malignant pleural effusion due to mesothelioma or other advanced solid tumors (EORTC-NCI-AACR 2024) - P1/2 | "RSO-021 demonstrated early signs of safety and efficacy as a monotherapy in the phase 1 portion of the MITOPE trial. This warrants continued investigation in the dose expansion phase 2 portion of the trial presented here."

Clinical • Combination therapy • Metastases • Monotherapy • P2 data • Pleural effusion • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor