Vorinostat

A preclinical study from the University of Pittsburgh and Magee-Womens Research Institute & Foundation identifies a two-drug strategy for killing quiescent, treatment-resistant cancer cells that can seed relapse after chemotherapy, according to a paper published August 13 in Cancer Gene Therapy. Most cytotoxic regimens preferentially target actively dividing cells, allowing slow-cycling or non-dividing cancer cells to survive treatment and potentially drive recurrence. The problem is particularly relevant in ovarian cancer, where high initial response rates to platinum-based chemotherapy are frequently followed by relapse. The study, led by corresponding author Ronald J. Buckanovich, proposes exploiting a vulnerability created by cancer-cell quiescence rather than waiting for residual cells to resume proliferation. The researchers found that downregulation of the nucleosome remodeling and deacetylase (NuRD) complex — specifically its components MBD3 and CHD4 — promotes entry into a quiescent, drug-tolerant state. Genetic knockdown of either component induced G0 arrest across ovarian cancer models. Histone deacetylase inhibitors (HDACi) phenocopied this effect pharmacologically, altering chromatin accessibility at RHO/RAC GTPase-associated loci, suppressing the MRTFA/SRF pro-proliferative transcriptional axis, and driving cells into reversible G0 arrest. Rather than directly killing these cells, HDAC inhibition helps establish a quiescent state that creates a second vulnerability: increased dependence on proteasome and autophagy activity to maintain protein homeostasis. Combining HDACi with the proteasome inhibitor carfilzomib or the autophagy inhibitors hydroxychloroquine or chloroquine exploited that dependency and produced synergistic cell death. The HDACi-carfilzomib combination produced synergy indices of 25–73 under the highest single agent (HSA) model in vitro. In an ovarian cancer patient-derived xenograft (PDX) mouse model, the HDACi vorinostat (SAHA) plus carfilzomib produced greater tumor growth inhibition than either monotherapy or vehicle control across groups of 8–10 tumors. HDACi-induced quiescence was also demonstrated in triple-negative breast cancer patient-derived organoids and breast and lung cancer cell lines, suggesting the underlying biology may extend beyond ovarian cancer. Activity was additionally evaluated in an ex vivo co-culture model incorporating primary murine hepatocytes to approximate aspects of the liver microenvironment. HDAC inhibitors including vorinostat and belinostat have previously been evaluated as single agents in ovarian cancer with limited efficacy, consistent with the study's finding that HDAC inhibition can induce arrest without killing the cells. There is also clinical precedent for combining HDAC and proteasome inhibition: panobinostat plus bortezomib was previously FDA-approved for multiple myeloma, although panobinostat was subsequently withdrawn from the US market for commercial reasons. The rationale here is distinct, using HDAC inhibition to establish quiescence before exploiting the resulting proteostasis dependency. The approach also differs from cancer dormancy strategies aimed at maintaining residual cells in a dormant state or preventing their reactivation. Here, quiescence itself becomes a targetable vulnerability. The most immediately translatable strategy pairs the HDACi valproic acid (VPA) with chloroquine. Both are repurposed drugs with extensive human clinical experience, potentially shortening the translational path compared with new molecular entities. The authors said they are planning a window-of-opportunity clinical study of the combination in ovarian cancer. The approach remains preclinical, with relatively small in vivo groups, and established safety profiles for the individual drugs do not establish the safety or optimal dosing of the combination in ovarian cancer. No industry partner or regulatory designation has been disclosed. If translated successfully, the strategy would turn a conventional obstacle in cancer treatment into a therapeutic vulnerability: rather than waiting for dormant residual cells to resume proliferation, it seeks to exploit the biological dependencies created by quiescence itself. Access the AllSci platform to explore the science behind the news. Spot something wrong? Report an issue with this article

Advanced analytical methods integrating clinical trial and real-world data address key evidence gaps in rare, difficult-to-treat blood cancers Across both studies, mogamulizumab was associated with improved survival outcomes compared to standard of care PRINCETON, N.J., June 30, 2026 (GLOBE NEWSWIRE) -- Researchers at the World Congress of Cutaneous Lymphoma 2026 presented two indirect treatment comparison (ITC) analyses examining the impact of mogamulizumab on long-term outcomes, including overall survival (OS), in patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS), two subtypes of cutaneous T-cell lymphoma (CTCL). These findings, which drew on clinical trial and real-world data, expand the growing body of evidence supporting mogamulizumab use and address critical information gaps where comparative survival data have been limited. The research was funded by Kyowa Kirin Co. Ltd (TSE: 4151). “Indirect treatment comparisons help to bridge critical evidence gaps in MF and SS, giving clinicians a clearer picture of long-term outcomes in real-world practice,” said Professor H. Miles Prince, Principal Investigator, Peter MacCallum Cancer Centre in Melbourne, Australia. “This deeper understanding enables us to make informed treatment decisions and ultimately provide more personalized, effective care for our patients.” MF and SS are rare, progressive forms of CTCL associated with substantial morbidity in advanced stages and often require multiple lines of treatment. In the phase 3 MAVORIC trial, mogamulizumab improved progression-free survival versus vorinostat in adult patients with relapsed or refractory MF or SS, but a high rate of treatment crossover limited direct assessment of overall survival. To address this limitation, two independent studies used MAVORIC and real-world data to estimate comparative OS using ITC methods while accounting for patient differences across treatment groups and data sources. These findings aim to help address evidence gaps that limit access in some countries and support informed treatment decision-making. “In rare diseases like CTCL, clinical trials are often not designed to evaluate long-term treatment outcomes like overall survival,” said Dr. Angela Williams, PhD, Global Head Health Economics and Outcomes Research at Kyowa Kirin. “By applying advanced analytical approaches, we can integrate clinical trial and real-world data to better assess the long-term impact of a treatment like mogamulizumab on overall survival and other outcomes. This approach reflects our continued commitment to advancing research that informs treatment decisions in rare, hard-to-treat hematologic malignancies like CTCL, helping to improve the lives of patients and their care partners.” ITC Methodology and Results In two separate ITC studies, researchers analyzed survival outcomes in cohorts of patients with relapsed or refractory MF or SS by comparing patient-level data from the mogamulizumab arm of the MAVORIC trial (n=186) with real-world registry data from Australia and Denmark. Vorinostat, the active comparator in MAVORIC, is part of the standard of care in Australia but unavailable in Denmark. Key limitations of these analyses include the retrospective nature of the studies and potential differences in advances and standards of care over time. Australia (Campbell BA, et al): Real-world data from the Australian Peter MacCallum Cancer Centre Cutaneous Lymphoma database included 67 patients treated with vorinostat between January 2005 and November 2024. After adjusting for baseline differences: Median OS was not reached for patients receiving mogamulizumab, compared with 31.0 months for patients receiving vorinostat.Mogamulizumab was associated with a significantly lower risk of death compared with vorinostat (hazard ratio [95% confidence interval]: 0.48 [0.30, 0.76]; p=0.002).Median time to next treatment (TTNT) was numerically longer with mogamulizumab versus vorinostat (9.13 months vs. 5.82 months; hazard ratio [95% confidence interval]: 0.76 [0.52, 1.11]; p=0.20), though this difference was not statistically significant. Denmark (Morgante N, et al): Real-world data from Danish national registries included 209 patients receiving standard of care treatment between January 1996 and April 2024. After statistical weighting: Patients receiving mogamulizumab did not reach median OS, compared with 17.0 months for patients receiving standard of care.Mogamulizumab was associated with a significantly lower risk of death versus standard of care (hazard ratio [95% confidence interval]: 0.38 [0.25, 0.59]; p<0.001). U.S. POTELIGEO (mogamulizumab-kpkc) Indication POTELIGEO injection for intravenous infusion is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. Important Safety Information WARNINGS AND PRECAUTIONS Dermatologic toxicity: Monitor patients for rash throughout the course of treatment. For patients who experienced dermatologic toxicity in Trial 1, the median time to onset was 15 weeks, with 25% of cases occurring after 31 weeks. Interrupt POTELIGEO for moderate or severe rash (Grades 2 or 3). Permanently discontinue POTELIGEO for life-threatening (Grade 4) rash or for any Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Infusion reactions: Most infusion reactions occur during or shortly after the first infusion. Infusion reactions can also occur with subsequent infusions. Monitor patients closely for signs and symptoms of infusion reactions and interrupt the infusion for any grade reaction and treat promptly. Permanently discontinue POTELIGEO for any life-threatening (Grade 4) infusion reaction. Infections: Monitor patients for signs and symptoms of infection and treat promptly. Autoimmune complications: Interrupt or permanently discontinue POTELIGEO as appropriate for suspected immune-mediated adverse reactions. Consider the benefit/risk of POTELIGEO in patients with a history of autoimmune disease. Complications of allogeneic HSCT after POTELIGEO: Increased risks of transplant complications have been reported in patients who received allogeneic HSCT after POTELIGEO. Follow patients closely for early evidence of transplant-related complications. ADVERSE REACTIONS The most common adverse reactions (reported in ≥10% of patients) with POTELIGEO in the clinical trial were rash, including drug eruption (35%), infusion reaction (33%), fatigue (31%), diarrhea (28%), drug eruption (24%), upper respiratory tract infection (22%), musculoskeletal pain (22%), skin infection (19%), pyrexia (17%), edema (16%), nausea (16%), headache (14%), thrombocytopenia (14%), constipation (13%), anemia (12%), mucositis (12%), cough (11%), and hypertension (10%). You are encouraged to report suspected adverse reactions to Kyowa Kirin, Inc. at 1-844-768-3544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see additional Important Safety Information in full Prescribing Information as well as Patient Information. About Kyowa Kirin Kyowa Kirin aims to discover and deliver novel medicines and treatments with life-changing value. As a Japan-based Global Specialty Pharmaceutical Company, we have invested in drug discovery and biotechnology innovation for more than 70 years and are currently working to engineer the next generation of antibodies and cell and gene therapies with the potential to help patients with high unmet medical needs, such as bone & mineral, intractable hematological diseases/hemato-oncology, and rare diseases. A shared commitment to our values, to sustainable growth, and to making people smile unites us across the globe. You can learn more about the business of Kyowa Kirin at www.kyowakirin.com. COR-US-POT-0016 June 2026 CONTACT: Susan Thiele Head of Therapeutic Communications, North America susan.thiele.38@kyowakirin.com