ORCID Profile
0000-0003-0547-2480
Current Organisation
University Health Network
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Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544420
Abstract: Detailed protocol of the HYDRA-1 (NCT03081702) Trial. TITLE: A phase I/II trial investigating the tolerability, toxicity and efficacy of hydroxychloroquine and itraconazole in patients with advanced platinum-resistant epithelial ovarian cancer (EOC) (HYDRA-1 study).
Publisher: American Association for Cancer Research (AACR)
Date: 04-05-2022
DOI: 10.1158/2767-9764.CRC-22-0037
Abstract: Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. In vitro, itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation. The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544405.V1
Abstract: Supplementary Tables 1 and 2 show respectively the fold change of lysosomal function and size in treated sensitive/resistant cells obtained by mixed effect modelling. Supplementary Table 3 shows patients enrolled per dose-level (DL) and dose limiting toxicities (DLTs). Supplementary Tables 4 and 5 show the summary of all and treatment related adverse effects.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/2767-9764.22544411
Abstract: CRISPR screen TOV1946. Results of the Itra sensitizing CRISPR screen on the TOV1946 cell line using drugZ algorithm.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544417
Abstract: Supplementary Figure 1: Itra dose response in ovarian cancer cell lines. - Supplementary Figure 2: Analysis on ovarian cancer cell lines used in the Itra-sensitizing CRISPR screen (OVCAR5 and TOV1946). - Supplementary Figure 3: c18orf8 and VPS54 Knockout effects on the TOV1946 cell line. - Supplementary Figure 4: Itra+CQ dose responses. - Supplementary Figure 5: 5/10 uM CQ response and apoptosis assay results. - Supplementary Figure 6: Itra+CQ dose response in c18orf8 and VPS54 knockout cells and calculation of synergy scores. - Supplementary Figure 7: Intratumoural Itra/CQ detection and Ki-67 analysis in patient s les.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544405
Abstract: Supplementary Tables 1 and 2 show respectively the fold change of lysosomal function and size in treated sensitive/resistant cells obtained by mixed effect modelling. Supplementary Table 3 shows patients enrolled per dose-level (DL) and dose limiting toxicities (DLTs). Supplementary Tables 4 and 5 show the summary of all and treatment related adverse effects.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544411.V1
Abstract: CRISPR screen TOV1946. Results of the Itra sensitizing CRISPR screen on the TOV1946 cell line using drugZ algorithm.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544408
Abstract: - List of cell lines - Lentiviral constructs, lentivirus generation and infection - Apoptosis Assay - FILIPIN staining - Lysosomal assay and immunofluorescence
Publisher: American Association for Cancer Research (AACR)
Date: 30-09-2015
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544414
Abstract: CRISPR screen OVCAR5. Results of the Itra sensitizing CRISPR screen on the OVCAR5 cell line using drugZ algorithm.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544417.V1
Abstract: Supplementary Figure 1: Itra dose response in ovarian cancer cell lines. - Supplementary Figure 2: Analysis on ovarian cancer cell lines used in the Itra-sensitizing CRISPR screen (OVCAR5 and TOV1946). - Supplementary Figure 3: c18orf8 and VPS54 Knockout effects on the TOV1946 cell line. - Supplementary Figure 4: Itra+CQ dose responses. - Supplementary Figure 5: 5/10 uM CQ response and apoptosis assay results. - Supplementary Figure 6: Itra+CQ dose response in c18orf8 and VPS54 knockout cells and calculation of synergy scores. - Supplementary Figure 7: Intratumoural Itra/CQ detection and Ki-67 analysis in patient s les.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544414.V1
Abstract: CRISPR screen OVCAR5. Results of the Itra sensitizing CRISPR screen on the OVCAR5 cell line using drugZ algorithm.
Publisher: American Association for Cancer Research (AACR)
Date: 04-02-2021
DOI: 10.1158/1078-0432.CCR-20-3260
Abstract: Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance. We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical s les showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.C.6550634
Abstract: Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. i In vitro /i , itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation. Significance: The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544408.V1
Abstract: - List of cell lines - Lentiviral constructs, lentivirus generation and infection - Apoptosis Assay - FILIPIN staining - Lysosomal assay and immunofluorescence
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.C.6550634.V1
Abstract: Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. i In vitro /i , itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation. Significance: The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22544420.V1
Abstract: Detailed protocol of the HYDRA-1 (NCT03081702) Trial. TITLE: A phase I/II trial investigating the tolerability, toxicity and efficacy of hydroxychloroquine and itraconazole in patients with advanced platinum-resistant epithelial ovarian cancer (EOC) (HYDRA-1 study).
Publisher: Springer Science and Business Media LLC
Date: 27-05-2014
DOI: 10.1038/PCAN.2014.20
Abstract: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test. Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity. Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.
No related grants have been discovered for Marianne Koritzinsky.