Bortezomib

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

In a historic breakthrough for targeted protein degradation, Bristol Myers Squibb has secured the first FDA approval for a CELMoD therapy, with clearance of Zenbexus (iberdomide) as part of a combination regimen for previously treated multiple myeloma. In a regulatory milestone, Zenbexus also marks the first FDA nod for a new drug in multiple myeloma driven directly by minimal residual disease (MRD) as a surrogate endpoint rather than traditional longer-term metrics such as progression-free survival (PFS). The groundbreaking decision not only validates protein degradation—and BMS’ CELMoD specifically—as a viable modality, but also establishes a regulatory benchmark that serves as an example for future clinical trial designs. “As the first approved CELMoD, Zenbexus marks the arrival of a new treatment class and is an important milestone in our efforts to expand what is possible for patients with multiple myeloma. And we believe this is only the beginning,” BMS’ chief medical officer and head of development, Cristian Massacesi, M.D., said in an Aug. 13 statement. Zenbexus is specifically approved in combination with Johnson & Johnson’s Darzalex and dexamethasone to treat adults with multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent. In the phase 3 Excaliber-RRMM trial, the novel combo topped the traditional cocktail of Darzalex, Takeda’s Velcade (bortezomib) and dexamethasone on one of the trial’s dual primary endpoints, with an MRD-negative complete response rate of 41% compared with 21% for the traditional regimen at any time during a median follow-up of 16 months. The data had not been disclosed before Thursday’s approval. The trial remains ongoing to assess PFS as its other primary endpoint, which is expected this year. As Zenbexus is cleared with an accelerated approval, BMS is on the hook to provide confirmatory evidence, such as PFS. MRD-negativity is a stringent measure of response in multiple myeloma. In Excaliber-RRMM, MRD-negativity is defined as the ability to detect one myeloma cell among 100,000 normal cells in patients who achieved a complete response or better. Before Zenbexus’ approval, the FDA issued a draft guidance in January on the potential use of MRD and complete response to support accelerated approval in myeloma, following unanimous endorsement of the endpoint from an external advisory committee in 2024. A few days after publishing the draft guidance, the FDA approved J&J’s Darzalex within a quadruplet combination to treat first-line, transplant-ineligible myeloma patients based on results from the phase 3 Cepheus trial, which used MRD-negativity as its primary endpoint. At that time, Darzalex had been marketed for over a decade, and the Cepheus trial had already read out its PFS data. Now, Zenbexus is the first new drug to win an accelerated approval based directly on MRD. Its Excaliber-RRMM trial design also follows the spirit of the FDA’s Project FrontRunner , which encourages drug companies to use a single phase 3 trial in earlier cancer treatment settings to support both an accelerated approval based on an earlier endpoint and its full nod. Zenbexus’ arrival brings an additional growth catalyst for BMS as its older blood cancer blockbuster Revlimid continues to see revenue decline after losing U.S. market exclusivity in 2022. In an Aug. 14 note, analysts at William Blair projected that Zenbexus’ U.S. sales could surpass $1 billion in early 2031. Despite the landmark approval, the drug’s market potential in its first indication may be limited. With only 4% of patients in Excaliber-RRMM having received a prior anti-CD38 antibody, there’s “limited data” for the combination in CD38-pretreated patients, as the FDA spells out in the drug’s label. As anti-CD38 antibodies such as Darzalex become the standard first-line treatment, the pool of patients without prior CD38 exposure is dwindling. Zenbexus’ label also includes a boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism. BMS is running another phase 3, called Excaliber-Maintenance, testing Zenbexus as first-line maintenance therapy following stem cell transplant in patients with newly diagnosed multiple myeloma. In addition, the New Jersey pharma’s second CELMoD agent, mezigdomide, is also under FDA review in second-line-plus multiple myeloma, with a target decision date of May 13, 2027. Both meds will be compete with autologous CAR-T therapies such as Legend Biotech's and J&J’s Carvykti, as well as BMS’ own Abecma, as well as bispecific antibodies, including J&J’s Tecvayli . “[E]ach incremental contribution from the CELMoD franchise helps strengthen the transition from a company dependent on legacy products to one supported by a more diversified set of growth assets as LOE exposure grows,” Citi analysts said of BMS in an Aug. 13 note.