unesbulin (BMIi-1) / PTC Therapeutics - LARVOL DELTA

A phase 1b study of unesbulin (PTC596) plus dacarbazine for the treatment of patients with locally recurrent, unresectable, or metastatic relapsed/refractory leiomyosarcoma. (ASCO 2022) - P1b | "Unesbulin 300 mg BIW in combination with DTIC 1,000 mg/m2 every 21 days was well tolerated and demonstrated promising efficacy in a heavily pre-treated patient population with advanced LMS; these results support further investigation. Updated clinical results will be presented as the data mature. A randomized, placebo-controlled, Phase 2/3 trial is planned."

Clinical • P1 data • Fatigue • Hematological Disorders • Leiomyosarcoma • Neutropenia • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Thrombocytopenia

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma. (PubMed, J Clin Oncol) - "Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS."

Journal • Metastases • P1 data • Hematological Disorders • Leiomyosarcoma • Neutropenia • Oncology • Sarcoma • Solid Tumor • Thrombocytopenia

A PHASE 2/3 STUDY EVALUATING THE EFFICACY AND SAFETY OF UNESBULIN IN ADVANCED LEIOMYOSARCOMA (SUNRISELMS) (CTOS 2024) - No abstract available

Clinical • Late-breaking abstract • Metastases • P2/3 data • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor

POC1A promotes the proliferation, metastasis and stemness of bladder cancer by stabilizing BMI1 via USP7. (PubMed, Oncogene) - "Furthermore, pharmacological targeting of BMI1 with Unesbulin suppressed BLCA growth in cell-line and patient-derived xenograft models, supporting the therapeutic tractability of the POC1A-BMI1 axis. Taken together, these findings reveal that POC1A facilitates the USP7-mediated deubiquitination and stabilization of BMI1, establishing the POC1A-USP7-BMI1 complex as a compelling therapeutic target in BLCA."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BMI1 • USP7

Preclinical Drug-Response Profiling Identifies BMI1 Inhibition as a Therapeutic Option for Hepatoblastoma. (PubMed, Int J Mol Sci) - "In vivo, PTC596 markedly reduced tumor burden and proliferation while inducing pro-apoptotic signaling, without detectable toxicity. Together, these findings establish BMI1 as a critical oncogenic dependency in HB, demonstrate the value of robust preclinical tumor modeling for therapeutic validation, and identify PTC596 as a promising, mechanism-based treatment strategy."

IO biomarker • Journal • Preclinical • Hepatoblastoma • Liver Cancer • Oncology • Pediatrics • Solid Tumor • Targeted Protein Degradation • BCL2 • BMI1 • CASP3 • CASP7

Dual actionability of BMI1 activation and mitotic vulnerability defines adaptive Osimertinib resistance in EGFR-mutant NSCLC. (PubMed, Cell Death Dis) - "Exploiting these vulnerabilities, Unesbulin (PTC596), a tubulin-binding agent with BMI1 inhibitory activity, triggers mitotic catastrophe, mechanistically induces apoptosis in vitro and drives regression of resistant xenografts in vivo. Our findings establish BMI1 as a key mediator of Osimertinib resistance and aggressiveness, uncovering a mutation-context-dependent mitotic vulnerability that can be therapeutically exploited, providing a rationale for targeting BMI1 and mitotic abnormalities to overcome resistance in T790M/L858R backgrounds."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BMI1 • EGFR

Enhanced Antitumor Efficacy of Combined PTC596 and PD1 Blockade in Hepatocellular Carcinoma. (PubMed, Mol Cancer Ther) - "Therefore, PTC596 is not only an effective antitumor drug for HCC but also supports the formation of a favorable tumor microenvironment that enhances the effect of PD1 blockade. This study supports that PTC596 combined with PD1 blockade could be a promising strategy for HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CD8

A new hope: Clinical advances in targeted therapies for pediatric diffuse midline glioma. (PubMed, Neurooncol Adv) - "Among these are histone deacetylase inhibitors (HDACis), receptor tyrosine kinase inhibitors, and novel agents such as ONC201 and unesbulin that target metabolic and epigenetic pathways respectively...Despite these advances, challenges such as drug delivery across the blood-brain barrier and therapeutic resistance persist, necessitating the development of combination therapies and innovative delivery methods. Ongoing research is focused on refining these strategies and exploring additional molecular and immunological targets to improve outcomes for children with DMG."

Journal • Review • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CD276

Targeting Bmi-1 suppresses cancer stemness and tumor growth in mucoepidermoid carcinoma (AACR 2026) - "Notably, PTC596 ablated cancer stem cells (ALDHhighCD44high) and produced antitumor responses in preclinical salivary gland MEC models. Collectively, these findings provide compelling preclinical evidence that Bmi-1 represents a promising and clinically relevant therapeutic target for salivary gland mucoepidermoid carcinoma, supporting further translational and clinical investigation."

Head and Neck Cancer • Oncology • Salivary Gland Cancer • Solid Tumor • Squamous Cell Carcinoma • BMI1

Determining the nuclear and cytoplasmic function of BMI-1 in diffuse intrinsic pontine glioma during M phase (AACR 2024) - "We have previously shown that PTC596, a potent BMI-1 modulator, induces chromosome scattering, M phase cell-cycle arrest, BMI-1 phosphorylation and translocation to the cytoplasm leading to the inhibition of its PRC1 canonical function and cell death...We are currently investigating potential pathways involved in BMI-1 nuclear-cytosol translocation through bioinformatic analyses, protein-protein interaction simulations, and pharmacological inhibitor assays. Collectively, these studies aim to elucidate the molecular mechanisms underlying BMI-1 functions in DIPG, thereby potentially paving the way for the development of targeted therapeutic strategies related to M phase progression."

Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • BMI1

Bmi-1 inhibition sensitizes head and neck cancer stem cells to cytotoxic chemotherapy. (PubMed, Transl Oncol) - "We and others have shown that treatment with cytotoxic chemotherapy agents (e.g. Cisplatin, Carboplatin) induce Bmi-1 expression and increase the fraction of highly tumorigenic CSC in HNSCC. In vivo, Bmi-1 inhibition with PTC596 suppressed Cisplatin-mediated increase in the fraction of ALDHhighCD44high cells (cancer stemness). Collectively, these preclinical results demonstrate that Bmi-1 is a key mediator of head and neck cancer stemness and suggest that HNSCC patients might benefit from treatment with a Bmi-1 inhibitor combined with a conventional chemotherapeutic agent."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IL6R

Leveraging Medulloblastoma Clonal Dynamics to Overcome Treatment Resistance. (PubMed, Clin Cancer Res) - "This work provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB."

Journal • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • BMI1 • PLK1

Unesbulin Overcomes Cisplatin Resistance in Pleural Mesothelioma Through Induction of Aberrant Tubulin Polymerization and Inactivation of the BMI1 Oncogene (IMIG 2025) - "Unesbulin induces a potent anti-tumor effect by disrupting microtubule assembly and inactivating BMI1, with only modest effects on non-malignant cells. Unesbulin sensitizes PM cells towards Cisplatin/Pemetrexed, thus revealing a promising therapeutic strategy to overcome PM drug resistance."

Leiomyosarcoma • Malignant Pleural Mesothelioma • Mesothelioma • Pleural Mesothelioma • Sarcoma • Solid Tumor • BMI1 • STMN1

Unesbulin overcomes Cisplatin resistance in pleural mesothelioma via induction of apotosis, aberrant tubulin polymerization and inactivation of the BMI1 oncogene (DGT 2025) - "Results Unesbulin induces a potent anti-tumor effect by disrupting microtubule assembly and inactivating BMI1, with only modest effects on non-malignant cells. Unesbulin sensitizes PM cells towards Cisplatin/Pemetrexed, thus revealing a promising therapeutic strategy to overcome PM drug resistance."

Leiomyosarcoma • Malignant Pleural Mesothelioma • Mesothelioma • Pleural Mesothelioma • Sarcoma • Solid Tumor • BMI1

SUNRISELMS: A Study of Unesbulin in Participants With Advanced Leiomyosarcoma (LMS) (clinicaltrials.gov) - P2/3 | N=360 | Terminated | Sponsor: PTC Therapeutics | Active, not recruiting ➔ Terminated; Business decision

Trial termination • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor

Phase IB Trial of the BMI-1 Inhibitor PTC596 (Unesbulin) plus Neoadjuvant Paclitaxel-Carboplatin in Advanced Ovarian Cancer (SGO 2025) - No abstract available

Clinical • Metastases • P1 data • Oncology • Ovarian Cancer • Solid Tumor

Progress and prospects of the combination of BMI1-targeted therapy and immunotherapy in cervical cancer. (PubMed, Am J Cancer Res) - "To date, there have been no reports on the combination of BMI1-targeted therapy and immunotherapy in cervical cancer. This review, therefore, elucidates the current state of research and explores the potential and perspectives of combining targeted therapy with immunotherapy for cervical cancer."

Journal • Review • Cervical Cancer • Gynecologic Cancers • Oncology • Solid Tumor • Women's Health • BMI1

Molecular and biology correlative results from the phase 1b trial of unesbulin (PTC596) with radiotherapy in children newly-diagnosed with diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): A report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT) (SNO 2024) - "Comprehensive molecular profiling of diagnostic and post-mortem tumor tissue provides valuable early biological insight, elucidating potential genomic biomarkers predictive of outcome and response to M-phase alteration and BMI-1 modulation in DIPG/HGG."

Clinical • P1 data • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Genetic Disorders • Glioma • Malignant Glioma • Oncology • Solid Tumor • ACVR1 • ATRX • BCOR • BMI1 • EGFR • H3-3A • H3C1 • MET • MSH6 • MYCN • NF1 • PDGFRA • PIK3CA • PPM1D • TP53

A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma (clinicaltrials.gov) - P1 | N=64 | Active, not recruiting | Sponsor: Nationwide Children's Hospital | Trial primary completion date: Aug 2024 ➔ Mar 2024

Trial primary completion date • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • BMI1

A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma (clinicaltrials.gov) - P1 | N=64 | Active, not recruiting | Sponsor: Nationwide Children's Hospital | Trial primary completion date: Mar 2024 ➔ Aug 2024

Trial primary completion date • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • BMI1

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma (J Clin Oncol) - P1b N=41 | NCT03761095 | Sponsor: PTC Therapeutics | "On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%."

P1 data • Leiomyosarcoma

OU-SCC-PTC-001: Unesbulin in Women With Ovarian Cancer Receiving Neoadjuvant Chemotherapy (clinicaltrials.gov) - P1 | N=27 | Completed | Sponsor: University of Oklahoma | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Mar 2024

Trial completion • Trial completion date • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

Tumor Microenvironment Landscapes Supporting EGFR-mutant NSCLC Are Modulated at the Single-cell Interaction Level by Unesbulin Treatment. (PubMed, Cancer Res Commun) - "Here we revealed how EGFR-mutant landscapes are affected at the single-cell resolution level during Unesbulin treatment. This novel drug, by targeting cancer cells and their interactions with crucial TME components, could be envisioned for future therapeutic advancements."

Biomarker • Journal • Tumor microenvironment • Hematological Malignancies • Leukemia • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BMI1 • EGFR

A Study of Unesbulin (PTC596) in Combination With Dacarbazine in Participants With Advanced Leiomyosarcoma (LMS) (clinicaltrials.gov) - P1 | N=41 | Completed | Sponsor: PTC Therapeutics | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor

PTC596-Induced BMI-1 Inhibition Fights Neuroblastoma Multidrug Resistance by Inducing Ferroptosis. (PubMed, Antioxidants (Basel)) - "Of particular interest is the observation that PTC596, alone or in combination with PRIMA-1 and etoposide, significantly reduced GSH levels, increased peroxide production, stimulated lipid peroxidation, and induced ferroptosis. Therefore, these findings suggest that PTC596, by inhibiting BMI-1 and triggering ferroptosis, could be a promising approach to fight chemoresistance."

Journal • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • BMI1 • TP53