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

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

Results of Phase 1/2 trial of RSO-021 and dose justification for a pivotal trial in patients (pts) with pleural mesothelioma (PM) (ESMO 2026) - No abstract available

Clinical • P1/2 data • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor

Artificial Intelligence-Guided Phenotypic Drug Repurposing Against Streptococcus pneumoniae. (PubMed, Adv Sci (Weinh)) - "The most potent drugs, thiostrepton and ceftiofur, had IC50 values of 0.0001 µg/mL (60.1 pM) and 0.0004 µg/mL (764 pM), respectively. Thiostrepton remained highly potent even against multidrug-resistant strains, suggesting it could be effectively deployed to treat common non-invasive S. pneumoniae infection as part of antibiotic stewardship efforts."

Journal • Infectious Disease • Pneumococcal Infections • Pneumonia

Deletion of Peroxiredoxin 3 (PRX3) impairs mitochondrial bioenergetics and tumor growth in mesothelioma: Results from the first in human phase 1/2 clinical trial of the PRX3 inhibitor RSO-021 (EORTC-NCI-AACR 2026) - "Abstract will be available as of 4 November (with consent of the author)"

Clinical • First-in-human • P1/2 data • Mesothelioma • Oncology • Solid Tumor

Iron starvation induced by vacidobactin A impairs the growth of pyoverdine-deficient Pseudomonas aeruginosa. (PubMed, Microbiol Spectr) - "Furthermore, the synergy between vacidobactin A and thiostrepton illustrates how siderophore systems integrate with other cellular vulnerabilities. These findings illuminate fundamental principles of bacterial resource competition and highlight how environmental microorganisms exploit iron metabolism as a competitive strategy, advancing our understanding of microbial community dynamics and bacterial physiology."

Journal

CD155 regulates tumor growth and susceptibility to T cell mediated killing in diffuse midline glioma. (PubMed, Neuro Oncol) - "These studies demonstrate that CD155 regulates immune evasion and tumor growth in DMG, and suggest that targeting CD155 could be a valuable two-pronged therapeutic strategy for this disease."

Journal • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CD8 • FOXM1 • PVR

Comprehensive derivatization of thiostrepton via heterologous expression. (PubMed, J Antibiot (Tokyo)) - "Thiostrepton can induce expression of the tipA promoter of Streptomyces lividans 1326. It is highly intriguing that the antimicrobial activity of thiostrepton and its derivatives is correlated with induction of the tipA promoter."

Journal • Infectious Disease

MITOPE: Study of RSO-021 in Patients With Malignant Pleural Effusion Due to Advanced/Metastatic Solid Tumors Including Mesothelioma (clinicaltrials.gov) - P1/2 | N=50 | Completed | Sponsor: RS Oncology LLC | Recruiting ➔ Completed | N=186 ➔ 50 | Trial completion date: Apr 2025 ➔ May 2026 | Trial primary completion date: Apr 2025 ➔ Nov 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pleural Mesothelioma • Respiratory Diseases • Solid Tumor

Preclinical characterization and phase 1 clinical testing of targeting mitochondrial peroxiredoxin 3 in cancer. (PubMed, Nat Commun) - P1/2 | "Primary endpoints of safety, tolerability and dose finding were met, and secondary endpoints of pharmacokinetics, objective response rate, disease control rate, and progression free survival are explored. Genomic screening identified Solute Carrier Family 7 member 11 (SLC7A11) as a mediator of TS resistance, suggesting combined targeting may further enhance the pro-oxidant activity of RSO-021."

Journal • P1 data • Preclinical • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Respiratory Diseases • Solid Tumor • SLC7A11

CD155 regulates tumor growth and immune evasion in diffuse midline glioma (ISPNO 2026) - "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

Structural Insights into the Cyclic Peptide Antibiotic Thiostrepton via NMR Spectroscopy. (PubMed, J Phys Chem A) - "Therefore, although functional activity is not examined directly, the integrated solution- and solid-state NMR results deliver site-specific structural information and local nuclear spin dynamics at individual carbon sites of this cyclic polypeptide antibiotic. These characteristics are associated with the functional state of thiostrepton and offer a foundation for the rational design of next-generation polypeptide antibiotics."

Journal • RPL11

All Screens Lead to Polo-like kinase 1: A Central Node in Cancer Therapeutics and Resistance. (PubMed, Pharmacol Res) - "Emerging evidence supports synergistic potential of new-generation PLK1 inhibitors, such as Onvansertib, with chemo- and immune-therapies. This mini-review and perspective present current insights on PLK1 overexpression and its mechanistic impact on cancer aggressiveness and therapy resistance. We highlight the need for refined patient stratification and innovative combination regimens to exploit PLK1 inhibition in cancer treatment."

Journal • Review • Oncology • PLK1

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

FOXM1 and NFκB Form a Positive Feedback Loop to Promote Cell Growth and Drug Resistance in Mantle Cell Lymphoma. (PubMed, Cells) - "In MCL cell lines, inhibition of FOXM1 using thiostrepton or shRNA effectively triggered apoptosis and significantly reduced cell growth...Confocal microscopy revealed that FOXM1 and p65 colocalize with each other. In conclusion, FOXM1 and NFκB work collaboratively in promoting the growth and drug resistance of MCL, and FOXM1 may be a potentially useful therapeutic target."

Journal • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1 • FOXM1 • NFKBIA • RELA

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

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

The co-targeting of PLK1 and FoxM1 contributes to synergistic antitumor effects in PTC (AACR 2024) - "The combined inhibition of PLK1 with volasertib and FoxM1 with thiostrepton synergistically attenuated PTC cell growth in vitro and in vivo. Our findings suggest that co-targeting of PLK1 and FoxM1 could be a viable therapeutic strategy for treating patients with an aggressive subtype of PTC."

Oncology • FOXM1 • PLK1

Mechanistic Insights into the FOXM1/BUB1 axis-Mediated Oncogenic Signaling in Hepatocellular Carcinoma. (PubMed, Int J Biol Sci) - "Furthermore, combined pharmacological inhibition of FOXM1 (FDI-6, RCM-1, thiostrepton) and BUB1 (BAY-1816032) synergistically inhibited the proliferation of HCC cells and xenograft tumors. These findings establish FOXM1-mediated BUB1 upregulation as a key driver of HCC malignancy. Targeting the FOXM1/BUB1 axis represents a promising therapeutic strategy for the treatment of advanced and metastatic HCC, offering new opportunities for HCC therapy."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • BUB1 • FOXM1

First-in-class peroxiredoxin 3 (PRX3) inhibitor RSO-021 triggers mesenchymal-to-epithelial transition in mesothelioma (AACR 2024) - P1/2 | "In summary PRX3 is a clinically actionable drug target, inhibition of which correlates with EMT modulation. This activity suggests a mechanism to alter mesothelioma progression and prevent the emergence of the most aggressive mesothelioma phenotype."

Biphasic Mesothelioma • Mesothelioma • Oncology • Sarcoma • Solid Tumor • COL5A2 • ITK • MSLN • TGFB1

SLC7A11 modulates sensitivity to the first-in-class mitochondrial peroxiredoxin 3 inhibitor thiostrepton (RSO-021) via a ferroptosis independent pathway (AACR 2024) - P1/2 | "Erastin, an SLC7A11 inhibitor exhibited the greatest synergy when combined with TS, potentiated PRX3 covalent crosslinking and cellular ROS levels. In summary, SLC7A11 up-regulation confers tolerance to TS through a mechanism involving a cysteine-dependent modulation of the redox state independent of canonical ferroptosis, that can be overcome by the addition of an SLC7A11 inhibitor. The correlation between SLC7A11 with response to TS in a 33-patient primary mesothelioma explant co-clinical trial, and patients enrolled into the MITOPE phase 1/2 trial will be presented."

First-in-human • Mesothelioma • Oncology • Solid Tumor • SLC7A11

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."

First-in-human • 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

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