dc.contributor.author | Fok, JHL | |
dc.contributor.author | Hedayat, S | |
dc.contributor.author | Zhang, L | |
dc.contributor.author | Aronson, LI | |
dc.contributor.author | Mirabella, F | |
dc.contributor.author | Pawlyn, C | |
dc.contributor.author | Bright, MD | |
dc.contributor.author | Wardell, CP | |
dc.contributor.author | Keats, JJ | |
dc.contributor.author | De Billy, E | |
dc.contributor.author | Rye, CS | |
dc.contributor.author | Chessum, NEA | |
dc.contributor.author | Jones, K | |
dc.contributor.author | Morgan, GJ | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Davies, FE | |
dc.date.accessioned | 2018-05-22T08:16:18Z | |
dc.date.issued | 2018-05-15 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (10), pp. 2395 - 2407 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/1679 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-17-1594 | |
dc.description.abstract | Purpose: Myeloma is a plasma cell malignancy characterized by the overproduction of immunoglobulin, and is therefore susceptible to therapies targeting protein homeostasis. We hypothesized that heat shock factor 1 (HSF1) was an attractive therapeutic target for myeloma due to its direct regulation of transcriptional programs implicated in both protein homeostasis and the oncogenic phenotype. Here, we interrogate HSF1 as a therapeutic target in myeloma using bioinformatic, genetic, and pharmacologic means.Experimental Design: To assess the clinical relevance of HSF1, we analyzed publicly available patient myeloma gene expression datasets. Validation of this novel target was conducted in in vitro experiments using shRNA or inhibitors of the HSF1 pathway in human myeloma cell lines and primary cells as well as in in vivo human myeloma xenograft models.Results: Expression of HSF1 and its target genes were associated with poorer myeloma patient survival. ShRNA-mediated knockdown or pharmacologic inhibition of the HSF1 pathway with a novel chemical probe, CCT251236, or with KRIBB11, led to caspase-mediated cell death that was associated with an increase in EIF2α phosphorylation, CHOP expression and a decrease in overall protein synthesis. Importantly, both CCT251236 and KRIBB11 induced cytotoxicity in human myeloma cell lines and patient-derived primary myeloma cells with a therapeutic window over normal cells. Pharmacologic inhibition induced tumor growth inhibition and was well-tolerated in a human myeloma xenograft murine model with evidence of pharmacodynamic biomarker modulation.Conclusions: Taken together, our studies demonstrate the dependence of myeloma cells on HSF1 for survival and support the clinical evaluation of pharmacologic inhibitors of the HSF1 pathway in myeloma. Clin Cancer Res; 24(10); 2395-407. ©2018 AACRSee related commentary by Parekh, p. 2237. | |
dc.format | Print-Electronic | |
dc.format.extent | 2395 - 2407 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Multiple Myeloma | |
dc.subject | Disease Models, Animal | |
dc.subject | Caspases | |
dc.subject | Antineoplastic Agents | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Gene Expression Profiling | |
dc.subject | Computational Biology | |
dc.subject | Signal Transduction | |
dc.subject | Apoptosis | |
dc.subject | Cell Survival | |
dc.subject | Gene Knockdown Techniques | |
dc.subject | Kaplan-Meier Estimate | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | Biomarkers, Tumor | |
dc.subject | Heat Shock Transcription Factors | |
dc.title | HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-12-29 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-17-1594 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 10 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Myeloma Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Myeloma Target Treatment | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Myeloma Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Myeloma Target Treatment | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 24 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicinal Chemistry 3 | |
icr.researchteam | Myeloma Biology and Therapeutics | |
icr.researchteam | Myeloma Target Treatment | |
icr.researchteam | Functional Genomics | |
dc.contributor.icrauthor | Fok, Jacqueline | |
dc.contributor.icrauthor | Hedayat-Husseyin, Somaieh | |
dc.contributor.icrauthor | Pawlyn, Charlotte | |
dc.contributor.icrauthor | Chessum, Nicola | |
dc.contributor.icrauthor | Jones, Keith | |
dc.contributor.icrauthor | Workman, Paul | |