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

The first-in-class covalent peroxiredoxin 3 (PRX3) inhibitor RSO-021 modulates immune phenotypes in mesothelioma (AACR 2026) - P1/2 | "The combo of TS plus anti-PD1/anti-CTLA4 antibody showed complete tumor reduction in 6 of 6 mice. Together, these data highlight the immunomodulatory activity in cells, mouse models, and human tissue with RSO-021 and support further clinical development of RSO-021 in combination with immune-oncology therapies."

IO biomarker • Mesothelioma • Oncology • Solid Tumor • CXCL8 • IFNG • IL6 • RETN • TGFB1 • TNFA

FOXM1 as a drug target in NF1-associated malignant peripheral nerve sheath tumors (AACR 2026) - "Synergistic killing of MPNST cells was obtained by combining thiostrepton with a MEK inhibitor (mirdametinib), CDK4/6 inhibitor (palbociclib), or EGFR inhibitor (gefitinib), while NB drugs synergized best with gefitinib. Our data demonstrate FOXM1 is an important driver of MPNST pathogenesis. FOXM1 expression and transcriptional activity are greatly increased in MPNSTs compared to benign precursors from the same patients. In agreement, genetic and therapeutic inactivation of FOXM1 promoted MPNST cell arrest and death."

Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • FOXM1 • NF1

Inhibition of the mitochondrial antioxidant response blocks ex vivo lung colonization in pediatric osteosarcoma (AACR 2026) - "We evaluated thiostrepton (TS), a Streptomyces-derived thiopeptide antibiotic with demonstrated PRDX3-inhibitory activity in preclinical and clinical cancer studies, to determine its effect on metastatic OS tumor cells...Furthermore, we found that combining TS with the chemotherapeutic agents doxorubicin or etoposide, which are commonly used to treat pediatric pulmonary OS metastasis, produced a synergistic increase in cell death compared to either drug alone. Lastly, we studied TS as a single agent therapy using the pulmonary metastasis assay, an ex vivo lung explant system, and found that treatment significantly decreased OS lung tumor burden. Our findings provide promising preclinical data supporting the use of TS as a possible anti-metastatic therapeutic for pediatric OS."

Preclinical • Lung Cancer • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • PRDX3 • TXN

Profiling the effects of Peroxiredoxin 3 (PRX3) pharmacological inhibition and genetic deletion with the AVITI24™ multi-omic spatial biology platform (AACR 2026) - P1/2 | "Thiostrepton (TS), the active pharmaceutical ingredient of RSO-021, is a clinical stage peroxiredoxin 3 (PRX3) covalent inhibitor currently in phase 2 testing for the treatment of pleural mesothelioma (NCT05278975)...MAPK13 and MAP3K5). Together the AVITI24™ multi-omic spatial biology platform provides a robust workflow that supported profiling genetic and pharmacological targeting of PRX3 in mesothelioma tumor cells, further supporting PRX3 as a novel and actionable therapeutic target in cancer."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • CDK1 • FASLG • KIF11 • MAP3K5 • MAPK1 • MAPK10 • MAPK11 • MAPK13

Deletion of peroxiredoxin 3 (PRX3) impairs mitochondrial bioenergetics and tumor growth in mesothelioma, supporting the first in human clinical testing of the PRX3 inhibitor RSO-021 (AACR 2026) - P1/2 | "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. Phase 2 testing of RSO-021 is ongoing."

Clinical • First-in-human • P1 data • Mesothelioma • Oncology • Solid Tumor • MYC • SLC7A11

ETV4 Khib Promotes Intrahepatic Cholangiocarcinoma Progression by Suppressing Ferroptosis Through TXNIP Downregulation. (PubMed, Cancer Lett) - "Notably, the small-molecule compound thiostrepton significantly inhibits ETV4 K97-Khib, thereby promoting ferroptosis and suppressing ICC cell migration, invasion, and lung metastasis. Together, our study reveals a novel ETV4 Khib-driven mechanism underlying ferroptosis suppression and malignant progression in ICC, and highlights ETV4 Khib as a potential therapeutic target in cholangiocarcinoma."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • Targeted Protein Degradation • ETV4 • HDAC1 • TXNIP

ALDH1L2 induces resistance to chemotherapy in small cell lung cancer by inhibiting ferroptosis. (PubMed, Redox Biol) - "Mechanistically, ALDH1L2 interacts with the TRX2-PRDX3 antioxidant network to reduce the levels of hyperoxidized PRDX3 and oxidized PRDX3 dimers in the plasma membrane under cisplatin-induced stress and decrease cellular susceptibility to ferroptosis, thus promoting SCLC chemoresistance. In addition, we found that thiostrepton, a PRDX3 inhibitor, can synergize with chemotherapy to suppress tumor growth in SCLC, suggesting that thiostrepton might be a promising new tool for overcoming SCLC chemoresistance."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Phase 2 study to evaluate the novel mitochondrial PRX3 inhibitor, RSO-021, as an intrapleural monotherapy and in combination with IV paclitaxel in patients with malignant pleural effusion due to mesothelioma or another advanced solid tumor. (ASCO 2024) - P1/2 | "The first patient was treated in 4Q2023 and the trial is actively recruiting to all 4 arms at 9 UK sites. Additional sites are planned."

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

Targeting FOXM1 regulates metabolic signatures through ROS-dependent JNK/Bmi1/Skp2 axis in human cutaneous T-cell lymphoma. (PubMed, Cell Death Dis) - "Moreover, thiostrepton treatment sensitized the CTCL cells to proteasome inhibitor bortezomib, promoting apoptosis and autophagy. Collectively, these findings demonstrate that FOXM1 targeting disrupts the metabolic status and stemness features of CTCL cells via JNK activation, thereby offering novel insights into potential therapeutic strategies for overcoming therapeutic challenges in CTCL."

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Metabolic Disorders • Oncology • T Cell Non-Hodgkin Lymphoma • BMI1 • CDKN1A • FOXM1 • KLF4 • SKP2

Characterization of Bacillus velezensis EV17 and K-3618 and Their Polyketide Antibiotic Oxydifficidin, an Inhibitor of Prokaryotic Translation with Low Cytotoxicity. (PubMed, Int J Mol Sci) - "Although spontaneous mutations conferring resistance to oxydifficidin in ribosomal protein bL12 located relatively close to the thiostrepton binding site on uL11, our data show that oxydifficidin binding does not interfere with thiostrepton, thereby refining previous findings about its putative ribosomal target. We are the first to show that this compound does not affect eukaryotic translation and has two orders of magnitude lower effect on eukaryotic cells compared to bacteria. These facts are important to further investigate its potential as a bioprotectant against phytopathogens or even as a therapeutic agent."

Journal

Distinct fibroblast assemblies establish scarless regeneration. (PubMed, Cell Rep) - "We identified two therapeutic categories: compounds disrupting reticulation/clustering that inhibit scarring and compounds (fluvastatin, thiostrepton, fenbendazole) disrupting sprouting that blocked pro-inflammatory fibroblast/myofibroblast commitment, promoted angiogenesis, reduced inflammatory infiltration, and enabled scar-free regenerative healing with hair follicle papillae regrowth in mice. These findings establish fibroblast supracellular organization as fundamental to tissue recovery, providing novel therapeutic targets for wound healing and fibrotic disorders."

Journal • Fibrosis • Immunology

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