P=N/A, N=15, Recruiting, The First Hospital of China Medical University; The First Hospital of China Medical University

Our research reveals that low-dose ATO, by regulating LOXL3, remodels the ECM and enhances CD8+T cell infiltration, thus sensitizing the efficacy of immunotherapy, which provides a novel strategy for comprehensive treatment to PC.

With Cu-DPPZ-Py+ and Cu-Elesclomol, there is strong evidence that the triggering cuproptosis significantly drives mitochondrial DNA (mtDNA) release to activate innate immunity via cyclic GMP-AMP synthase-stimulation of interferon genes (cGAS-STING), which can improve T cell antitumor immunity in vivo. By contrast, it is observed that Cu-DPPZ-Ph treated tumor cells could release intracellular caspase-3, resulting in apoptosis-associated immunosuppression. This study supports insights into how cuproptosis bridges cGAS-STING immune pathways, contributing to the development of cuproptosis-based antitumor immunotherapy.

This review discusses several potent alkaloids, such as homoharringtonine, chaetominine, matrine, and jerantinine B, which induce apoptosis, cell cycle arrest, and autophagy and inhibit signaling pathways including PI3K/Akt/mTOR, MAPK, and NF-κB...In addition, targeting leukemia stem cells (LSCs) with alkaloids such as zalypsis offers promise due to its ability to induce apoptosis without significantly affecting normal hematopoietic stem cells...For example, jerantinine B targets AML cells, while vincristine has shown success in lymphocytic leukemia...However, adverse effects such as neutropenia and hepatotoxicity necessitate careful management. Collectively, these findings emphasize the need for further research into alkaloid-based combination therapies to enhance efficacy and minimize toxicity, providing a promising avenue for innovative leukemia treatments.

Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

P1/2, N=158, Recruiting, Genprex, Inc. | Trial completion date: Dec 2027 --> Mar 2029 | Trial primary completion date: Dec 2026 --> Mar 2028

P1/2, N=49, Recruiting, Neonc Technologies, Inc. | Trial primary completion date: Jun 2024 --> Dec 2024

P1, N=15, Not yet recruiting, Neonc Technologies, Inc. | Trial completion date: Oct 2024 --> Oct 2025 | Initiation date: May 2024 --> Dec 2024 | Trial primary completion date: Oct 2024 --> Oct 2025

Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

P=N/A, N=1000, Not yet recruiting, Karolinska Institutet

P1, N=30, Not yet recruiting, Virginia Commonwealth University

This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15 mg. Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily.

In conclusion, the anti-inflammatory effect of ATO can effectively alleviate the ALV-J pathogenic process. ALV-J serves as a model virus for antiviral tumor research, while ATO provides references for the treatment of such tumors.

P1/2, N=180, Active, not recruiting, Genprex, Inc. | Trial completion date: Nov 2028 --> Dec 2025 | Trial primary completion date: Nov 2027 --> Dec 2024

Imidazole derivatives significantly reduce proliferation of NB4 and K562 cells by inducing apoptosis, down regulating of AXL-RTK and Wnt/β-catenin target genes.

There were no chemotherapy-related deaths. ATO combined with N7-modified induction regimen had a superiority in efficacy and safety, which deserved further promotion in clinical practice.

P1/2, N=110, Recruiting, Antiva Biosciences | N=29 --> 110 | Trial completion date: May 2024 --> Jun 2025 | Trial primary completion date: Apr 2024 --> Jun 2025

P1/2, N=24, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Aug 2025 --> Sep 2024 | Trial primary completion date: Aug 2025 --> Sep 2024

The study developed an MSS CC cuproptosis model using 50 nM elesclomol and 1 μM CuCl2...Cuproptosis in MSS CC cells enhances the cytotoxicity of CD8+ T cells, which may be achieved through downregulation of the WNT signaling pathway and decreased expression of PD-L1. In the future, drugs that can induce cuproptosis may be a promising approach to improve MSS CC immunotherapy.

Elesclomol inhibits glioblastoma development via inducing cuproptosis, regulated by NFκB1/FDX1 axis.

P1/2, N=70, Not yet recruiting, University of California, San Francisco | Trial completion date: Jul 2027 --> Oct 2027 | Initiation date: Jul 2024 --> Oct 2024 | Trial primary completion date: Jan 2026 --> May 2026

Group II was taken as positive control, Group III and IV were treated with ethanol and n-hexane extract of G. latifolia, respectively, and Group V was treated with cisplatin 3.0 mg/kg/day. In conclusion, the effective therapeutic potential of G. latifolia extracts targeted oxidative stress, increasing antioxidant activities and inhibiting inflammation and liver complications at early stages. Further research on the molecular level may further explore the anticancer potential of this plant against various types of cancers.

The formation of the HIF-1α/ERβ/E2F1 feedforward loop promotes NSCLC growth and reveals a novel molecular mechanism by which HHT induces cell death in NSCLC.

In this study, we observed that combining homoharringtonine (HHT) with VEN plus azacitidine resulted in a significantly higher response and better survival than VA alone in patients with R/R-AML. Mechanistically, HHT sensitizes AML cells to VEN by downregulating the anti-apoptotic proteins MCL-1/BCL-xL, activating reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and attenuating fatty acid (FA) uptake. These findings adding HHT to VEN-based regimens may enhance outcomes in R/R-AML patients.

The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients...Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.

Taken together, there is a great potential for HOXC6 to become a prognosis biomarker and contribute to develop treatment strategies for LUAD patients. Further mechanism exploration and drug development for HOXC6 are needed.

Cell experiments were conducted to verify whether FDX1 was involved in cuproptosis of Caki-1 cells induced by Elesclomol...This study provides compelling evidence that cuproptosis is closely linked to the prognosis of KIRC. FDX1 holds promise as a viable biomarker and therapeutic target for assessing the effectiveness of tumor immunotherapy in KIRC.

P1, N=10, Active, not recruiting, Bexion Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting | N=22 --> 10 | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=195, Recruiting, Bexion Pharmaceuticals, Inc. | Phase classification: P1b/2 --> P1/2

P1, N=50, Enrolling by invitation, Bexion Pharmaceuticals, Inc. | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: May 2024 --> Sep 2024

P1, N=21, Active, not recruiting, Bexion Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

Therefore, we investigated the effects of mercuric chloride (HgCl2), cadmium chloride (CdCl2), arsenic trioxide (As2O3), and methylmercury (MeHg) on SH-SY5Y cells differentiated in the presence of insulin-like growth factor-I (IGF-I) or all-trans retinoic acid (ATRA)...Changes in the cytotoxic effects of heavy metals were observed even after 1 day of ATRA exposure in SH-SY5Y cells. Our results demonstrate that the differentiation of SH-SY5Y cells by IGF-I and ATRA induces different cellular characteristics, resulting in diverse changes in sensitivity to heavy metals, which depend not only on the differentiation agents and treatment time but also on the heavy metal species and concentration.

P=N/A, N=148, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

P1/2, N=28, Active, not recruiting, Antonio Calles Blanco | Trial completion date: Feb 2024 --> Mar 2025

P1/2, N=180, Active, not recruiting, Genprex, Inc. | Recruiting --> Active, not recruiting

Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias...In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia.

In this study, we demonstrate that TRIM44 significantly enhances autophagy in response to oxidative stress, reducing cytotoxicity in cancer cells treated with arsenic trioxide...This phosphorylation event activates NFE2L2, a key transcription factor in the oxidative stress response, highlighting the importance of TRIM44 in modulating SQSTM1-mediated autophagy. Our findings support that TRIM44 plays pivotal roles in regulating autophagic sensitivity to oxidative stress, with implications for cancer, aging, aging-associated diseases, and neurodegenerative disorders.

Our findings demonstrate that a combination of HHT/VEN is effective on ETP-ALL and represents the "backbone" of a promising and safe regimen for newly diagnosed and R/R patients with ETP-ALL.

P1/2, N=24, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Aug 2024 --> Aug 2025

Importantly, our data revealed that inhibiting p97 enhanced the effectiveness of ATO in killing AML cells. These explorations paved the way for identifying optimal synthetic lethal drugs to enhance ATO treatment on non-APL AML.

The results suggest that mild TS p53 mutants are uniquely responsive to functional rescue by ATO due to small thermostability deficits and inherent potential to regain active conformation. Combining mild hypothermia and ATO may provide an effective and safe procedure for targeting tumors with p53 TS mutations.

These results confirm the antitumoral potential of CTX. The maintenance of the antiproliferative effects in the detoxified version, with reduced enzymatic activity often liked to harm effects, supports further studies to identify active parts of the molecule responsible for the interesting effects without causing substantial toxic events, contributing to the future use of CTX-derived drugs with safety and efficacy.