Evidence map›Paper›PMID 30467317›Full record

ArticleScientific reports2018

High-throughput screens identify HSP90 inhibitors as potent therapeutics that target inter-related growth and survival pathways in advanced prostate cancer.

Keith H Jansson, John B Tucker, Lauren E Stahl, John K Simmons, Caitlyn Fuller, Michael L Beshiri, Supreet Agarwal, Lei Fang, Paul G Hynes, Aian Neil Alilin and 16 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed
2.6field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 33 citations in OpenAlex.

  1. Review
  2. Review
  3. Review
  4. Review
  5. Review
  6. Review
  7. Computational drug discovery for castration-resistant prostate cancers through in vitro drug response modeling.Proceedings of the National Academy of Sciences of the United States of America · 2023
    Article
  8. Review
  9. Heliyon · 2023
    Review
  10. Review
  11. Article
  12. Article
  13. Review
  14. Heat Shock Proteins in Benign Prostatic Hyperplasia and Prostate Cancer.International journal of molecular sciences · 2022
    Review
  15. Review
  16. Article
  17. High-Throughput Imaging Assay for Drug Screening of 3D Prostate Cancer Organoids.SLAS discovery : advancing life sciences R & D · 2021
    Article
  18. Article
  19. Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

26 authors at 4 institutions in 1 country.

Keith H JanssonLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
John B TuckerLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Lauren E StahlLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
John K SimmonsLaboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, Bethesda, MD, USA.
Caitlyn FullerLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Michael L BeshiriLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Supreet AgarwalLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Lei FangLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Paul G HynesLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Aian Neil AlilinLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Ross LakeLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Yasmine C AbbeyLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Jacob CawleyLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Caitlin M TiceLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
JuanJuan YinLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA.
Crystal McKnightDivision of Pre-clinical Innovation, NCATS, Rockville, MD, USA.
Carleen Klummp-ThomasDivision of Pre-clinical Innovation, NCATS, Rockville, MD, USA.
Xiaohu ZhangDivision of Pre-clinical Innovation, NCATS, Rockville, MD, USA.
Rajarshi GuhaDivision of Pre-clinical Innovation, NCATS, Rockville, MD, USA.
Shelley HooverLaboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, Bethesda, MD, USA.
R Mark SimpsonLaboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, Bethesda, MD, USA.
Holly M NguyenDepartment of Urology, University of Washington, Seattle, WA, USA.
Eva CoreyDepartment of Urology, University of Washington, Seattle, WA, USA.
Craig J ThomasDivision of Pre-clinical Innovation, NCATS, Rockville, MD, USA.
David A ProiaC4 Therapeutics, Cambridge, MA, USA.
Kathleen KellyLaboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA. kellyka@mail.nih.gov.
National Cancer Institute · USNational Center for Advancing Translational Sciences · USUniversity of Washington · USC4 Therapeutics (United States) · US

Funding

Molecular Pathology Research for Cancer Diagnostics and BiomarkersZICBC010953 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI SIMPSON, ROBERT · 2009 to 2025
$22.9M
6 · The paper itself

Abstract

The development of new treatments for castrate resistant prostate cancer (CRPC) must address such challenges as intrinsic tumor heterogeneity and phenotypic plasticity. Combined PTEN/TP53 alterations represent a major genotype of CRPC (25-30%) and are associated with poor outcomes. Using tumor-derived, castration-resistant Pten/Tp53 null luminal prostate cells for comprehensive, high-throughput, mechanism-based screening, we identified several vulnerabilities among >1900 compounds, including inhibitors of: PI3K/AKT/mTOR, the proteasome, the cell cycle, heat shock proteins, DNA repair, NFκB, MAPK, and epigenetic modifiers. HSP90 inhibitors were one of the most active compound classes in the screen and have clinical potential for use in drug combinations to enhance efficacy and delay the development of resistance. To inform future design of rational drug combinations, we tested ganetespib, a potent second-generation HSP90 inhibitor, as a single agent in multiple CRPC genotypes and phenotypes. Ganetespib decreased growth of endogenous Pten/Tp53 null tumors, confirming therapeutic activity in situ. Fifteen human CRPC LuCaP PDX-derived organoid models were assayed for responses to 110 drugs, and HSP90 inhibitors (ganetespib and onalespib) were among the select group of drugs (<10%) that demonstrated broad activity (>75% of models) at high potency (IC50 <1 µM). Ganetespib inhibits multiple targets, including AR and PI3K pathways, which regulate mutually compensatory growth and survival signals in some forms of CRPC. Combined with castration, ganetespib displayed deeper PDX tumor regressions and delayed castration resistance relative to either monotherapy. In all, comprehensive data from near-patient models presents novel contexts for HSP90 inhibition in multiple CRPC genotypes and phenotypes, expands upon HSP90 inhibitors as simultaneous inhibitors of oncogenic signaling and resistance mechanisms, and suggests utility for combined HSP90/AR inhibition in CRPC.

Indexed as

Androgen Receptor AntagonistsAnimalsAntineoplastic AgentsApoptosisBenzamidesCell CycleCell Line, TumorCell ProliferationGenotypeHigh-Throughput Screening AssaysHSP90 Heat-Shock ProteinsHumansIsoindolesMaleMicePhenotype(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanoneAndrogen Receptor AntagonistsAntineoplastic AgentsBenzamidesHSP90 Heat-Shock ProteinsIsoindolesPhosphatidylinositol 3-KinasesPTEN PhosphohydrolaseSTA 9090TOR Serine-Threonine KinasesTriazolesTumor Suppressor Protein p53

Identifiers

PMID30467317
PMCPMC6250716
OpenAlexW2900680219

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.