Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
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ABSTRACT:
PROVIDER: PRJNA722034 | ENA |
REPOSITORIES: ENA
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Project description:Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.
2021-04-15 | GSE172112 | GEO
Project description:Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.
| S-EPMC8187399 | biostudies-literature
Project description:High mortality rate of muscle-invasive bladder cancer (MIBC) and complexity of disease demand new multi-targeting treatment strategies. Targeting proliferating cell nuclear antigen (PCNA) with a peptide containing the AlkB homologue 2 PCNA interacting motif (APIM), is shown to impair multiple vital cellular stress responses and induce hypersensitivity against several chemotherapeutics in different pre-clinical models. This study examine the anti-cancer efficacy of the novel APIM-peptide drug when combined with cisplatin-based therapies (cisplatin, cisplatin/gemcitabine (GC) and methotrexate/vinblastine/adriamycin/cisplatin (MVAC)) in a panel of bladder cancer (BC) cells and with intravenous cisplatin-therapy in a rat MIBC-model. Furthermore, we explore the molecular mechanisms underlying the observed effects on a genomic, proteomic and metabolomic level using microarray, multiplexed inhibitor bead (MIB)-assay, and targeted mass spectrometric metabolite profiling. The APIM-peptide significantly increased the efficacy of all cisplatin-based therapies in all BC cell lines tested, including a cisplatin resistant cell line and reduced the tumor load in cisplatin treated MIBC-bearing rats. Genome and proteome analysis of APIM-peptide/cisplatin treated BC cells revealed reduced expression of multiple proteins frequently overexpressed in MIBC. Of notice, the EGFR/ERBB2, PI3K/Akt and MAPK signaling pathways and anti-apoptosis were downregulated. We suggest that the anti-cancer effect of the APIM-peptide is through the downregulation of several known oncogenic signaling pathways including anti-apoptosis. Together our results indicate that the APIM-peptide represents a potential improved treatment approach for patients with MIBC.
2018-09-10 | PXD008724 | Pride
Project description:Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. This study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1-oleate, formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intra-vesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17mM) on days 3-11. A dose-dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor bearing mice or in healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose-dependent therapeutic effect of alpha1-oleate in a murine bladder cancer model.
2020-04-09 | GSE148308 | GEO
Project description:Pluripotent stem cells (PSCs) derived chimeric antigen receptor macrophages (iCAR-Ms) hold great potential for immunotherapy, particularly against T-cell malignancies which are challenging in CAR-T therapy. Here, we generate human iCAR-Ms targeting CD5 for treating T-cell malignancies. iCAR-Ms display tumoricidal activities against various T- malignant cells expressing CD5 such as Jurkat, SUP-T1 and primary tumor cells. However, The iCAR-M tumoricidal activities are largely dependent on CD5 density on tumor cells. The escaped tumor cells show reversible CD5 loss without changes on its mRNA level. Meanwhile, the retrieved iCAR-Ms show little reduced tumoricidal activities against new tumor cells expressing CD5. Based on time lapse imaging and transcriptional analysis, we show that iCAR-Ms mainly medicate trogocytosis while less phagocytosis when approach tumor cells. Our data reveal trogocytosis as an important limitation factor in iCAR-M tumoricidal activities and tumor escape, providing a rational to develop enhanced CAR-M for immunotherapies.
2025-09-01 | GSE305641 | GEO
Project description:Recent studies revealed that treatment resistant cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be targeted by cytotoxic T lymphocytes (CTLs). CTLs recognize antigenic peptide derived from tumor-associated antigens (TAAs), thus identification of tumor-associated antigens (TAAs) expressed in CSCs/CICs is essential. Human leucocyte antigen (HLA) ligandome analysis using mass spectrometry enables analysis of naturally expressed antigenic peptides; however, HLA ligandome analysis requires large scale of sample and it is challenging for CSCs/CICs. In this study, we established novel bladder CSC/CIC model from a bladder cancer cell line UM-UC-3 cells using ALDEFLUOR assay. CSCs/CICs were isolated as aldehyde dehydrogenase (ALDH) high cells and several ALDHhigh clone cells were established. ALDHhigh clone cells were enriched with CSCs/CICs by sphere formation and tumorigenicity in immune deficient mouse. HLA ligandome analysis and gene expression (CAGE) using ALDHhigh clone cells revealed distinctive antigenic peptide repertoire in bladder CSCs/CICs, and we identified GRIK2 derived antigenic peptide is specifically expressed in CSCs/CICs. GRIK2 peptide-specific CTL clone recognized GRIK2-overexpressed UM-UC-3 cells and ALDHhigh clone cells indicating that GRIK2 peptide can be a novel target for bladder CSCs/CICs-targeting immunotherapy.
2021-10-01 | GSE166947 | GEO
Project description:The tumoricidal effects of CD8+T cells are well acknowledged, but how MHC Ib-restricted CD8+T (Ib-CD8+T) cells contribute to anti-tumor immunity remains obscure. Here, we show that infusion of MHC Ia+ cells to Kb-/-Db-/- mice induced the expansion of Ib-CD8+T cells in tumors and potently inhibited tumor progression. Such priming of Ib-CD8+T cells by MHC-Ia is not MHC haplotype restricted and MHC Ia tetramers alone can prime Ib-CD8+T cells for activation. The MHC Ia priming promoted Tbet expression in Ib-CD8+T cells and in absence of Tbet, such priming effect diminished. Importantly, these tumoricidal Ib-CD8+T cells are positive for CX3CR1, and exhibit rapid proliferation, high expression of cytotoxic factors, and prolonged persistence at tumor sites. Adoptive transfer of CX3CR1+Ib-CD8+T cells to wild type mice resulted in potent anti-tumor effects. Our findings unravel an uncharacterized function of MHC Ia molecules in immunoregulation and raise the possibility of using Ib-CD8+T cells in tumor immunotherapy.
2023-10-03 | GSE164271 | GEO
Project description:Heme-TAMs are resistant to tumoricidal transformation by INFγ
| PRJNA993273 | ENA
Project description:Background: Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. Objective: To evaluate immune and stromal signatures in MIBC treated with TMT.
2019-03-23 | GSE128701 | GEO
Project description:Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils
| PRJNA565424 | ENA