bortezomib

Herein, a multiorganelle homeostasis disruptor (denoted BLL) is constructed by encapsulating liposomes and bortezomib (BTZ) within a layered double hydroxide (LDH) nanocage to continuously activate inflammasomes for inducing efficient pyroptosis...Our results suggest that the BLL nanocage induces homeostatic imbalance in various organelles and efficient pyroptosis. We hope this work can provide new insights into the design of an efficient pyroptosis inducer by disrupting the homeostatic balance of multiple organelles and promote the development of novel antineoplastic platforms.

There is a limited strategy for the second-line option of intrahepatic cholangiocarcinoma (ICC). This investigator-initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent-to-treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.

CYP2A6, EPHX1, MTHFR, ALDH1A1, HTR7, MME and BIPN are linked in Chinese MM patients. BIPN is more likely to occur in patients with lower MTHFR mRNA expression, which might result in higher serum Hcy levels.

P1, N=50, Active, not recruiting, Takeda | Phase classification: P1b --> P1 | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P2, N=145, Not yet recruiting, St. Jude Children's Research Hospital

P3, N=706, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Feb 2024 --> Jun 2024

P1/2, N=0, Withdrawn, Indiana University | N=72 --> 0 | Not yet recruiting --> Withdrawn

P2, N=33, Completed, Peking Union Medical College Hospital | Recruiting --> Completed | Trial completion date: Aug 2023 --> Mar 2024 | Trial primary completion date: Aug 2022 --> Mar 2024

P3, N=795, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jun 2027 --> Apr 2026

P3, N=220, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

BTZ also increased mitochondrial superoxide levels in KG-1a cells, and BTZ-induced apoptosis was partially prevented by pretreatment with the antioxidant N-acetylcysteine, indicating that BTZ induces oxidative stress-mediated apoptosis in KG-1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45-positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG-1a cells with tolerable toxicity. Taken together, these data indicate that the anti-LSC potential of BTZ appears to be an important strategy for AML treatment.

When we knocked down NCOA4 or blocked autophagy using chloroquine, BTZ-induced ferritin degradation and the increase in intracellular free Fe2+ were significantly reduced in MM cells, confirming the role of BTZ in enhancing ferritinophagy. The induction of ferroptosis inhibitor liproxstatin-1 successfully counteracted the synergistic effect of BTZ and RSL-3 in MM cells. Altogether, our findings reveal that BTZ elevates intracellular free Fe2+ by enhancing NCOA4-mediated ferritinophagy and synergizes with RSL-3 by increasing ferroptosisin MM cells.

P2, N=50, Active, not recruiting, Ida Bruun Kristensen | Recruiting --> Active, not recruiting

We show that TRIM33 knockdown sensitizes MM cells to the PARP inhibitor Olaparib, and this is synergistic with the standard of care therapy bortezomib, even in co-culture with bone marrow stromal cells (BMSCs). These findings suggest that TRIM33 loss contributes to the pathogenesis of high-risk MM and that this may be therapeutically exploited through the use of PARP inhibitors.

P2; Trial completion date: Feb 2026 --> Aug 2026 | Trial primary completion date: Feb 2024 --> Aug 2024

P2, N=67, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Mar 2024 --> Jun 2024 | Trial primary completion date: Mar 2024 --> Jun 2024

P3, N=220, Recruiting, Prothena Biosciences Ltd. | N=150 --> 220

P2, N=52, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Jun 2022 --> Jun 2025 | Trial primary completion date: Jun 2022 --> Dec 2024

P3, N=177, Active, not recruiting, University of Arkansas | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Aug 2024 --> Aug 2025

Furthermore, it was determined that the increased circ_0000337 level in bortezomib-resistant cells was due to an increased N6-methyladenosine (m6A) level, resulting in enhanced RNA stability. In conclusion, the m6A level of circ_0000337 and its regulation may be a new and potential therapeutic target for overcoming bortezomib resistance in MM.

P2, N=103, Not yet recruiting, Nantes University Hospital

Notably, Bortezomib enhances anti-tumor immunity to an extent comparable to anti-PD-1 therapies with no obvious toxicity. Our findings reveal the potential of inhibiting TRAF6 to stimulate internal anti-tumor immunological effect for TRAF6-PD-L1 overexpressing cancers.

Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.

P3, N=338, Not yet recruiting, SWOG Cancer Research Network | Initiation date: Oct 2023 --> May 2024

P3, N=525, Active, not recruiting, National Cancer Institute (NCI)

P2, N=135, Active, not recruiting, National Cancer Institute (NCI)

P2, N=39, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center

Our findings demonstrated that a combination therapy commencing with the administration of OVs followed by bortezomib infusions yields an effective tumor-killing outcome. These results could provide valuable guidance for the development of clinical administration protocols in cancer treatment.

The study findings underscore a significant association between genetic polymorphisms and treatment response outcomes, suggesting their utility in prognostic determinations and clinical outcomes prediction in multiple myeloma patients.

Bortezomib affects the activities of GST and GPx. GST activity was associated with GSTT1 and GSTM1 variants but only at some bortezomib doses.

Our study uncovered a novel mechanism through which cisplatin disrupts the BTZ-induced proteasome bounce-back effect by suppressing the ZEB1/Nfe2l1 axis in cholangiocarcinoma. This finding provides a theoretical basis for developing proteasome inhibitor-based strategies for the clinical treatment of cholangiocarcinoma and other tumours.

Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, like bortezomib, with an autophagy inducer, like rapamycin, may improve patient outcomes in MM, where low GABARAP in the form of del(17p) is common and leads to worse outcomes.

Additionally, the response of MM cells to bortezomib was substantially reduced in collagen, indicating the importance of 3D culture in the investigation of myeloma cell behavior, as drug-resistance is one of the most pertinent issues in cancer therapy. Impact statement: The application of 3D models in the investigation of multiple myeloma will provide better insight into their behaviour and drug resistance, allowing us to develop better treatment strategies. Here, we optimized a collagen-based approach which has shown to be reproducible, cost-effective and already providing an altered feedback in therapy response.

P2, N=18, Recruiting, Larysa Sanchez | N=38 --> 18 | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

P2, N=36, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jan 2025 --> Sep 2024

P3, N=395, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Mar 2026 --> Oct 2028

P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=60 --> 40

P1/2, N=300, Active, not recruiting, Karyopharm Therapeutics Inc | Phase classification: P1b/2 --> P1/2 | N=518 --> 300 | Trial completion date: Jan 2025 --> Apr 2027 | Trial primary completion date: Jan 2025 --> Apr 2027

P=N/A, N=18, Active, not recruiting, Wake Forest University Health Sciences | Recruiting --> Active, not recruiting

P1/2, N=33, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Jun 2023

P1, N=18, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024

We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-β1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future.