The treatment of relapsed/refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed as salvage therapy. Reduced intensity conditioning protocols have been developed with the aim of reducing the leukemia burden without increasing their toxicity. We compared the reduced intensity conditioning FM140 (fludarabine, 150 mg/m2; melphalan 140 mg/m2) with FBM110 (fludarabine 150 mg/m2; BCNU, also known as carmustine, 300-400 mg/m2; and melphalan 110 mg/m2). From the European Bone Marrow Transplantation (EBMT) Acute Leukemia Working Party registry, we identified 293 adult patients (FM140, n = 118 and FBM110, n = 175) with AML with relapsed/refractory disease prior to allo-HCT. There were some differences such as age (FM140 = 59.5 years vs. FBM110 = 65.1 years, p < 0.001) and graft-versus-host disease (GvHD) prophylaxis based on in vivo T-cell depletion (TCD, FM140 = 39% vs. FBM110 = 75%, p < 0.001). No differences were observed between FM140- and FBM110-treated patients regarding overall survival (OS) (2-year OS: 39.3% vs. 45.7%, p = 0.58), progression-free survival (PFS) (2-year PFS: 36.1% vs. 37.3%, p = 0.69), non-relapse mortality (NRM) (2-year NRM: 15.3% vs. 25.7%, p = 0.10) and relapse incidence (RI) (2-year RI: 48.6% vs. 37.0%, p = 0.7). In conclusion, despite differences in age and GvHD prophylaxis, AML patients with active disease undergoing allo-HCT after FBM110 conditioning showed similar outcomes compared to FM140.
- MeSH
- Leukemia, Myeloid, Acute * therapy mortality MeSH
- Adult MeSH
- Transplantation, Homologous methods MeSH
- Carmustine therapeutic use administration & dosage MeSH
- Middle Aged MeSH
- Humans MeSH
- Melphalan * therapeutic use administration & dosage MeSH
- Transplantation Conditioning methods MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Recurrence MeSH
- Registries * MeSH
- Aged MeSH
- Hematopoietic Stem Cell Transplantation * methods MeSH
- Vidarabine * analogs & derivatives therapeutic use administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Comparative Study MeSH
Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.
- MeSH
- Azoxymethane toxicity MeSH
- Chronic Disease MeSH
- Indoles pharmacology therapeutic use MeSH
- Colitis drug therapy chemically induced metabolism pathology MeSH
- Colorectal Neoplasms * drug therapy metabolism pathology MeSH
- Disease Models, Animal * MeSH
- Molecular Mimicry MeSH
- Mice, Inbred C57BL * MeSH
- Mice MeSH
- Colitis-Associated Neoplasms pathology drug therapy metabolism MeSH
- Dextran Sulfate toxicity MeSH
- Inflammation drug therapy metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved. METHODS: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria. RESULTS: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified. CONCLUSIONS: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).
- MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Smoldering Multiple Myeloma * diagnosis mortality therapy MeSH
- Injections, Subcutaneous MeSH
- Kaplan-Meier Estimate MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma * diagnosis epidemiology prevention & control MeSH
- Antibodies, Monoclonal * administration & dosage adverse effects MeSH
- Watchful Waiting * statistics & numerical data MeSH
- Disease Progression MeSH
- Antineoplastic Agents * administration & dosage adverse effects MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
INTRODUCTION: The E3 ubiquitin ligase Cbl-b is a novel target in immune-oncology, with critical roles in regulating T-cell activation and signaling pathways. By facilitating the ubiquitination and degradation of key signaling proteins, Cbl-b modulates immune responses, maintaining immune homeostasis and preventing unwarranted T-cell proliferation. The therapeutic potential of Cbl-b as a cancer immunotherapy target is underscored by its contribution to an immunosuppressive tumor microenvironment, with efforts currently underway to develop small-molecule inhibitors. AREAS COVERED: We reviewed the small molecules, and antibody-drug conjugates targeting Cbl-b from 2018 to 2024. The patents were gathered through publicly available databases and analyzed with in-house developed cheminformatic workflow, described within the manuscript. EXPERT OPINION: Targeting Cbl-b presents a promising approach in immuno-oncology, offering a novel pathway to potentiate the immune system's ability to combat cancer beyond PDL1/PD1 inhibition. The development and clinical advancement of Cbl-b inhibitors, as evidenced by the ongoing trials, mark a significant step toward harnessing this target for therapeutic benefits. Overall, the strategic inhibition of Cbl-b holds substantial promise for improving cancer immunotherapy outcomes, heralding a new era in the fight against cancer.
- MeSH
- Adaptor Proteins, Signal Transducing MeSH
- Molecular Targeted Therapy * MeSH
- Immunoconjugates pharmacology MeSH
- Immunotherapy * methods MeSH
- Humans MeSH
- Tumor Microenvironment * immunology MeSH
- Neoplasms * immunology drug therapy MeSH
- Patents as Topic * MeSH
- Antineoplastic Agents pharmacology MeSH
- Proto-Oncogene Proteins c-cbl * immunology antagonists & inhibitors MeSH
- Signal Transduction drug effects MeSH
- T-Lymphocytes immunology drug effects MeSH
- Drug Development * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The small-molecule alkaloid halofuginone (HF) is obtained from febrifugine. Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions, which range from parasite infections and fibrosis to autoimmune diseases. In particular, HF is believed to play an excellent anticancer role by suppressing the proliferation, adhesion, metastasis, and invasion of cancers. This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF. In the studies covered in this review, the anticancer molecular mechanisms of HF mainly included transforming growth factor-β (TGF-β)/Smad-3/nuclear factor erythroid 2-related factor 2 (Nrf2), serine/threonine kinase proteins (Akt)/mechanistic target of rapamycin complex 1(mTORC1)/wingless/integrated (Wnt)/β-catenin, the exosomal microRNA-31 (miR-31)/histone deacetylase 2 (HDAC2) signaling pathway, and the interaction of the extracellular matrix (ECM) and immune cells. Notably, HF, as a novel type of adenosine triphosphate (ATP)-dependent inhibitor that is often combined with prolyl transfer RNA synthetase (ProRS) and amino acid starvation therapy (AAS) to suppress the formation of ribosome, further exerts a significant effect on the tumor microenvironment (TME). Additionally, the combination of HF with other drugs or therapies obtained universal attention. Our results showed that HF has significant potential for clinical cancer treatment.
- Publication type
- Journal Article MeSH
- Review MeSH
A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.
- MeSH
- Apoptosis * drug effects MeSH
- Cell Cycle drug effects MeSH
- Histone Deacetylases metabolism MeSH
- Histone Deacetylase Inhibitors * pharmacology chemical synthesis chemistry MeSH
- Hydroxamic Acids * pharmacology chemical synthesis chemistry MeSH
- Coumaric Acids * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology chemical synthesis chemistry MeSH
- Drug Screening Assays, Antitumor MeSH
- Molecular Docking Simulation MeSH
- THP-1 Cells MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Current antibiotics and chemotherapeutics are becoming ineffective because pathogenic bacteria and tumor cells have developed multiple drug resistance. Therefore, it is necessary to find new substances that can be used in treatment, either alone or as sensitizing molecules in combination with existing drugs. Peptaibols are bioactive, membrane-active peptides of non-ribosomal origin, mainly produced by filamentous fungi such as Trichoderma spp. This study focused on producing peptaibol-rich extracts from Trichoderma atroviride O1, cultivated on malt extract agar (MA) under circadian and constant darkness conditions for 13 days. Peptaibol production was detected by MALDI-TOF mass spectrometry after six days of cultivation. The extracts demonstrated antibacterial activity against Staphylococcus aureus strains, particularly the methicillin-resistant variant, but not against the Gram-negative Pseudomonas aeruginosa. Quorum sensing interference revealed that a peptaibol-rich extract suppressed Vibrio campbellii BAA-1119's AI-2 signaling system to a degree comparable with gentamycin. Beyond antibacterial properties, the extracts exhibited notable antiproliferative activity against human ovarian cancer cells and their adriamycin-resistant subline in both 2D and 3D models. Specifically, MA-derived extracts reduced ovarian cancer cell viability by 70% at 50 μg/mL, especially under light/dark regime of cultivation. Compared to previously published results for PDA-based extracts, MA cultivation shifted the biological effects of peptaibol-containing extracts toward anticancer potential. These findings support the idea that modifying fungal cultivation parameters, the bioactivity of secondary metabolite mixtures can be tailored for specific therapeutic applications.
- MeSH
- Agar * chemistry MeSH
- Anti-Bacterial Agents * pharmacology metabolism MeSH
- Hypocreales MeSH
- Culture Media chemistry MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Cell Line, Tumor MeSH
- Peptaibols * pharmacology metabolism biosynthesis chemistry MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology metabolism MeSH
- Pseudomonas aeruginosa drug effects MeSH
- Staphylococcus aureus drug effects MeSH
- Trichoderma * metabolism growth & development chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: The immunosuppressive roles of galectin-3 (Gal-3) in carcinogenesis make this lectin an attractive target for pharmacological inhibition in immunotherapy. Although current clinical immunotherapies appear promising in the treatment of solid tumors, their efficacy is significantly weakened by the hostile immunosuppressive tumor microenvironment (TME). Gal-3, a prominent TME modulator, efficiently subverts the elimination of cancer, either directly by inducing apoptosis of immune cells or indirectly by binding essential effector molecules, such as interferon-gamma (IFNγ). METHODS: N-(2-Hydroxypropyl)methacrylamide (HPMA)-based glycopolymers bearing poly-N-acetyllactosamine-derived tetrasaccharide ligands of Gal-3 were designed, synthesized, and characterized using high-performance liquid chromatography, dynamic light scattering, UV-Vis spectrophotometry, gel permeation chromatography, nuclear magnetic resonance, high-resolution mass spectrometry and CCK-8 assay for evaluation of glycopolymer non-toxicity. Pro-immunogenic effects of purified glycopolymers were tested by apoptotic assay using flow cytometry, competitive ELISA, and in vitro cell-free INFγ-based assay. RESULTS: All tested glycopolymers completely inhibited Gal-3-induced apoptosis of monocytes/macrophages, of which the M1 subtype is responsible for eliminating cancer cells during immunotherapy. Moreover, the glycopolymers suppressed Gal-3-induced capture of glycosylated IFNγ by competitive inhibition to Gal-3 carbohydrate recognition domain (CRD), which enables further inherent biological activities of this effector, such as differentiation of monocytes into M1 macrophages and repolarization of M2-macrophages to the M1 state. CONCLUSION: The prepared glycopolymers are promising inhibitors of Gal-3 and may serve as important supportive anti-cancer nanosystems enabling the infiltration of proinflammatory macrophages and the reprogramming of unwanted M2 macrophages into the M1 subtype.
- MeSH
- Acrylamides chemistry pharmacology MeSH
- Apoptosis drug effects MeSH
- Galectin 3 * antagonists & inhibitors MeSH
- Galectins MeSH
- Interferon-gamma * metabolism MeSH
- Blood Proteins MeSH
- Humans MeSH
- Macrophages drug effects MeSH
- Monocytes * drug effects MeSH
- Tumor Microenvironment drug effects MeSH
- Polymers * chemistry pharmacology MeSH
- Antineoplastic Agents * pharmacology chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
A series of triterpenoids of the lupane, taraxastane, friedelane and baccharane type were oxidized using selenium dioxide (SeO2) and benzeneseleninic anhydride (BSA) under various conditions. Depending on the reaction conditions, different reaction pathways were observed, including dehydrogenation, allylic oxidation, and 1,2-diketone formation. In this way, derivatives functionalized in the triterpene core (especially in rings A, D, and E), difficult to obtain by other methods, can be easily prepared. In some cases, rarely observed α-phenylseleno-ketones were isolated. An unexpected reaction involving the cleavage of the carbon-carbon double bond was observed in the presence of stoichiometric amounts of osmium tetroxide. Further transformations of selected intermediates facilitated the synthesis of new, functionally enriched derivatives. The key reaction pathways were investigated using density functional theory (DFT), focusing on bond length variations and transition states, revealing energetically favored pathways and critical transition structures, including covalent and noncovalent interactions. Solvent and isomerization equilibrium effects were proposed to explain the experimentally observed discrepancies. Cytotoxic activity of selected derivatives was investigated. Derivatives 4 and 38 showed strongest cytotoxicity in cancer cells and fibroblasts (IC50 2.6-26.4 μM); some compounds were selective for G-361 or HeLa cells. These results suggest that they may find application in pharmaceuticals.
- MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Oxidation-Reduction MeSH
- Pentacyclic Triterpenes MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Drug Screening Assays, Antitumor MeSH
- Selenium * chemistry MeSH
- Density Functional Theory MeSH
- Triterpenes * chemistry pharmacology chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
PURPOSE: Mutations or silencing of the von Hippel-Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). HIF-2α is implicated in the oncogenesis of ∼50% of patients with clear-cell renal cell carcinoma (ccRCC) but has been considered "undruggable." DFF332, an orally administered novel allosteric inhibitor of HIF-2α, showed dose-dependent antitumor efficacy in preclinical models of ccRCC. PATIENTS AND METHODS: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles, are reported. RESULTS: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, two patients (5%) achieved a partial response, and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events occurring in 25 patients (63%). Only five patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious treatment-related adverse event, hypertension, was reported in one patient. The maximum tolerated dose was not reached. CONCLUSIONS: Although clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.
- MeSH
- Adult MeSH
- Carcinoma, Renal Cell * drug therapy pathology genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Maximum Tolerated Dose MeSH
- Kidney Neoplasms * drug therapy pathology MeSH
- Antineoplastic Agents * administration & dosage adverse effects pharmacokinetics MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Basic Helix-Loop-Helix Transcription Factors * antagonists & inhibitors MeSH
- Treatment Outcome MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase I MeSH
