A5037020802- T-cell and Retrovirus Studies
- Immune Cell Function and Interaction
- Ovarian cancer diagnosis and treatment
- Colorectal Cancer Treatments and Studies
- Growth Hormone and Insulin-like Growth Factors
- Pancreatic and Hepatic Oncology Research
- Gastric Cancer Management and Outcomes
- Cancer-related gene regulation
- Lymphoma Diagnosis and Treatment
- IL-33, ST2, and ILC Pathways
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Histone Deacetylase Inhibitors Research
- Chronic Lymphocytic Leukemia Research
Institute of Cancer Research
2022-2023
Royal Marsden NHS Foundation Trust
2022-2023
Abstract Purpose: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus selectively taken up by α-FR–overexpressing tumors. Patients Methods: A 3+3 dose escalation design was used. During escalation, doses of 1–6 mg/m2 weekly 2–12 every 2 weeks (q2Wk) intravenously were evaluated. with high-grade serous ovarian cancer enrolled in the expansion cohorts. Results: 109 patients enrolled: 42 67 At dose/schedule 12 mg/m2/q2Wk (with without...
Abstract Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion resistance to apoptosis significant factors in tumorigenesis drug resistance. Bypassing apoptotic pathways eliciting another form regulated death, namely necroptosis, an immunogenic (ICD), may override Here, we present mechanistic rationale combining tolinapant, antagonist inhibitor proteins (IAP), with decitabine, a hypomethylating agent (HMA), T-cell lymphoma (TCL)....
<p>Figure S2. Additional viability and cytokine data from each TCL CRISPR clone experiment. (Refers to Figure 1)</p>
<p>Table S1. Details of primary antibodies used in Western blots this study (Figures 1,2,4,6 & S1).</p>
<div>Abstract<p>Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion resistance to apoptosis significant factors in tumorigenesis drug resistance. Bypassing apoptotic pathways eliciting another form regulated death, namely necroptosis, an immunogenic (ICD), may override Here, we present mechanistic rationale combining tolinapant, antagonist inhibitor proteins (IAP), with decitabine, a hypomethylating agent (HMA), T-cell...
<p>Measurement of gene expression changes in TCL cell lines after treatment with decitabine <i>in vitro</i>. <b>A,</b> Western blots human (H9 and Karpas-299) mouse (BW5147 CT26) lysates prepared for 4 days (human) or 2 (mouse). Dotted indicate a cropped blot presentation purposes. <b>B,</b> Bisulfite pyrosequencing data from four lines, showing basal (untreated) levels RIPK3 promoter methylation (top left), concentration-dependent decrease all...
<p>Synergistic interaction between decitabine and tolinapant in reducing viability of TCL cell lines <i>in vitro.</i> Viability data obtained using CTG H9 cells (<b>A</b> <b>B</b>) BW5147 (<b>C</b> <b>D</b>) after 3 days treatment with a combination (A C) raw (B D) HSA score from ComBenefit synergy analysis. <b>E,</b> Heat map showing change AUC measurements 3-day assays five different human lines, testing the (for...
<p>Table S1. Details of primary antibodies used in Western blots this study (Figures 1,2,4,6 & S1).</p>
<p>Figure S9. Analysis of tumor and plasma samples from EL4-Parental EL4-C8KO syngeneic model PD studies (Refers to Figure 6)</p>
<p>Figure S8. Additional EL4 & EL4-C8KO model in vivo efficacy data. (Refers to Figure 6)</p>
<p>Figure S8. Additional EL4 & EL4-C8KO model in vivo efficacy data. (Refers to Figure 6)</p>
<p>Figure S4. Changes in DNA methylation levels after decitabine (DAC) treatment of human TCL cell lines. (Refers to Figure 2)</p>
<p>Dosing with a combination of tolinapant plus decitabine drives increased efficacy in necroptosis-model TCL (EL4-C8KO model). Volumes EL4-PAR (<b>A</b>) and C8KO (<b>B</b>) EL4 tumors wild-type mice treated (0.3 mg/kg i.p., every day × 3 doses) dosing (25 orally, up to 46 as single agents or combination. <b>C,</b> Kaplan–Meier plot showing survival (tumors reaching 1,000 mm<sup>3</sup> endpoint) bearing EL4-C8KO (C8KO) tumors.</p>
<p>Figure S5. Combination viability assay raw data. (Refers to Figure 3)</p>
<p>Figure S6. Additional Karpas-299 cytokine data. (Refers to Figure 4)</p>
<p>Figure S10. Impact of tolinapant and decitabine on induction immunogenic cell death in TCL. (Refers to Discussion)</p>
<p>Table S2. Details of TaqMan primers used in qPCR assays this study (Figures 2,5 & S9).</p>
<p>Uncropped Western blots from Figure 2A</p>
<p>Figure S3. Additional EL4-C8KO Western blot and lytic cell death data. (Refers to Figure1)</p>
<p>Figure S2. Additional viability and cytokine data from each TCL CRISPR clone experiment. (Refers to Figure 1)</p>
<p>Table S3. Generation of CRISPR Knockout (KO) and Activation (CRISPRa) Cell Line Clones</p>
<p>Figure S9. Analysis of tumor and plasma samples from EL4-Parental EL4-C8KO syngeneic model PD studies (Refers to Figure 6)</p>
<p>Figure S7. Additional in vivo PD data. (Refers to Figure 5)</p>
<p>Effect of necrosome protein expression in TCL cell lines on tolinapant-induced death. <b>A,</b> Western blots parental BW5147, <i>RIPK3<sup>−</sup><sup>/</sup><sup>−</sup></i> BW5147 and <i>MLKL<sup>−</sup><sup>/</sup><sup>−</sup></i> lysates (untreated). <b>B,</b> Cytotox-NIR signal captured by real-time microscopy (IncuCyte), detecting membrane permeabilization...
<p>Table S3. Generation of CRISPR Knockout (KO) and Activation (CRISPRa) Cell Line Clones</p>