Evidence map›Paper›PMID 32067197›Full record

ArticleJournal of neuro-oncology2020

Rationale for the advancement of PI3K pathway inhibitors for personalized chordoma therapy.

N L Michmerhuizen, J H Owen, M E Heft Neal, J E Mann, E Leonard, J Wang, J Zhai, H Jiang, J B McHugh, J C Brenner and 1 more

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

Article in Journal of neuro-oncology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
1.6field-weighted citation impact, top 17% 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

11 citing papers in PubMed, 13 citations in OpenAlex.

  1. Review
  2. Article
  3. Review
  4. Review
  5. Article
  6. Article
  7. Article
  8. Advancement of PI3 Kinase Inhibitor Combination Therapies for PI3K-Aberrant Chordoma.Journal of neurological surgery. Part B, Skull base · 2022
    Article
  9. Review
  10. Article
  11. Article
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

11 authors at 1 institution in 1 country.

N L MichmerhuizenDepartment of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.ORCID http://orcid.org/0000-0002-9960-5119
J H OwenDepartment of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.
M E Heft NealDepartment of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.
J E MannDepartment of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.
E LeonardDepartment of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.
J WangDepartment of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.
J ZhaiDepartment of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
H JiangDepartment of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
J B McHughDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
J C BrennerDepartment of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA. chadbren@umich.edu.ORCID http://orcid.org/0000-0003-3238-1111
M E P PrinceDepartment of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.ORCID http://orcid.org/0000-0002-1120-9008
University of Michigan · US

Funding

XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Alexey I Nesvizhskii · 1988 to 2026
$178.2M
Robust Immuno-prevention Strategies for High-Risk Oral Epithelial DysplasiaU01DE029255 · NIDCR · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI BRENNER, JOHN CHADWICK, LEI, YU LEO · 2019 to 2021
$4.2M
Dissecting Co-Dependent Pathways in Oral CancersU01DE025184 · NIDCR · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BRENNER, JOHN CHADWICK, CAREY, THOMAS E. · 2015 to 2018
$3.7M
Advanced Research Training in OtolaryngologyT32DC005356 · NIDCD · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CORFAS, GABRIEL · 2002 to 2021
$3.5M
AAO-HNS 513933National Science Foundation DGE-1256260NCI NIH HHS P30 CA046592NIDCD NIH HHS T32 DC005356NIDCR NIH HHS U01 DE025184NIDCR NIH HHS U01 DE029255NIH/NCI P30CA046592
6 · The paper itself

Abstract

purposeChordomas are rare and serious tumors with few effective treatments outside of aggressive surgery and radiation. Targeted therapies may present a more effective option for a subset of patients with lesions possessing certain genetic biomarkers.

methodsA small molecule inhibitor library was tested in patient-derived UM-Chor1 cells to identify targeted therapies with potential efficacy. Targeted exome sequencing of UM-Chor1 and UM-Chor2 cells was performed to investigate genetic aberrations in relevant pathways. Chordoma cell lines were treated with inhibitors of the phosphotidylinositol 3-kinase (PI3K), epidermal growth factor receptor (EGFR), and cyclin dependent kinase (CDK) pathways, and responses were determined using resazurin cell viability assays, Annexin V apoptosis assays, and western blotting. Pan-PI3K inhibitor BKM120 was also tested in five chordoma xenograft models.

resultsUnbiased small molecule profiling nominated PI3K-AKT-mTOR pathway inhibitors as a promising therapy in chordoma, and genetic analyses of UM-Chor1 and UM-Chor2 cell lines revealed aberrations in PTEN, EGFR, and CDKN2A. Treatment of UM-Chor1 and UM-Chor2 with targeted PI3K, EGFR, and CDK inhibitors inhibited growth and proliferation and induced apoptosis more robustly than imatinib, a currently used chordoma therapy. Furthermore, BKM120 significantly inhibited tumor growth in a subset of the xenograft models tested.

conclusionTargeted therapies, especially those inhibiting PI3K, display promising effects in multiple chordoma cell line and xenograft models. Nevertheless, the limited effects of PI3K, EGFR, and CDK targeting agents in other models reveal the presence of resistance mechanisms, which motivates future research to both identify biomarkers of response and develop combination therapies.

Indexed as

AminopyridinesAnimalsAntineoplastic AgentsCell Line, TumorChordomaHumansMiceMorpholinesPhosphatidylinositol 3-KinasePhosphoinositide-3 Kinase InhibitorsPrecision MedicineProto-Oncogene Proteins c-aktSignal TransductionTOR Serine-Threonine KinasesAminopyridinesAntineoplastic AgentsMorpholinesMTOR protein, humanNVP-BKM120Phosphatidylinositol 3-KinasePhosphoinositide-3 Kinase InhibitorsProto-Oncogene Proteins c-aktTOR Serine-Threonine KinasesAKTChordomaPersonalized medicinePI3KPTEN

Identifiers

PMID32067197
PMCPMC7474463
OpenAlexW3005907466

What OpenQuestion holds

Textmetadata
LicenceTDM
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.