Evidence map›Paper›PMID 38758815›Full record

ArticleOncotarget2024

GZ17-6.02 kills PDX isolates of uveal melanoma.

Laurence Booth, Jane L Roberts, Ivan Spasojevic, Kaitlyn C Baker, Andrew Poklepovic, Cameron West, John M Kirkwood, Paul Dent

Registry-linked trialAbstract read
In one paragraph

Article in Oncotarget, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03775525 (A Phase I/Ib, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic and Pharmacokinetic Study of GZ17-6.02 Monotherapy and in Combination With Capecitabine, Given Orally on a Daily Schedule in Patients With Advanced Solid Tumors or Lymphoma), which is not on this map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
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.

NCT03775525 phase1unknown statusnot on this map

A Phase I/Ib, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic and Pharmacokinetic Study of GZ17-6.02 Monotherapy and in Combination With Capecitabine, Given Orally on a Daily Schedule in Patients With Advanced Solid Tumors or Lymphoma

TypeinterventionalSponsorGenzada Pharmaceuticals USA, Inc.Ran2019 to 2023Enrolled127ConditionsAdvanced Cancer, Gastric Cancer, Breast Cancer, Pancreatic CancerArmsGZ17-6.02, Capecitabine
3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Article
  3. 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

8 authors.

Laurence BoothDepartment of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Jane L RobertsDepartment of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Ivan SpasojevicDepartment of Medicine, and PK/PD Core Laboratory, Duke University School of Medicine, Durham, NC 27710, USA.
Kaitlyn C BakerDepartment of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Andrew PoklepovicDepartment of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
Cameron WestGenzada Pharmaceuticals, Hutchinson, KS 67502, USA.
John M KirkwoodMelanoma and Skin Cancer Program, Hillman Cancer Research Pavilion Laboratory, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Paul DentDepartment of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.

Funding

Women's Cancer Research ProgramP30CA014236 · NCI · DUKE UNIVERSITY · PI Laura Fish · 1985 to 2026
$174.8M
NCI NIH HHS P30 CA014236
6 · The paper itself

Abstract

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.

Indexed as

MelanomaUveal NeoplasmsXenograft Model Antitumor AssaysAnimalsAntineoplastic AgentsAutophagyCell Line, TumorDoxorubicinHumansMiceSignal TransductionTOR Serine-Threonine KinasesTumor Suppressor ProteinsUbiquitin ThiolesteraseUveal MelanomaAntineoplastic AgentsDoxorubicinTOR Serine-Threonine KinasesTumor Suppressor ProteinsUbiquitin ThiolesteraseafatinibautophagydoxorubicinER stressGZ17-6.02neratinib

Identifiers

PMID38758815
PMCPMC11101052

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Registered trials

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.