Evidence map›Paper›PMID 31173106›Full record

ArticleNeuro-oncology2019

Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases.

Franziska Maria Ippen, Julia Katharina Grosch, Megha Subramanian, Benjamin Macfarlane Kuter, Bianca M Liederer, Emile G Plise, Joana Liliana Mora, Naema Nayyar, Stephen Paul Schmidt, Anita Giobbie-Hurder and 5 more

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

Article in Neuro-oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
64citing papers in PubMed, 1 pooled it
10.8field-weighted citation impact, top 1% 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

64 citing papers in PubMed, 1 synthesis or guideline pooled it, 97 citations in OpenAlex.

  1. Guideline
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  6. PI3 K/AKT/mTOR pathway and its role in breast cancer stem cells.Naunyn-Schmiedeberg's archives of pharmacology · 2025
    Review
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  18. Human vascular organoids with a mosaicbioRxiv : the preprint server for biology · 2024
    Article
  19. Article
  20. Review

4 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

15 authors at 3 institutions in 2 countries.

Franziska Maria IppenCancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Julia Katharina GroschCancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Megha SubramanianGenentech, Inc, Drug Metabolism and Pharmacokinetics, South San Francisco, California, USA.
Benjamin Macfarlane KuterCancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Bianca M LiedererGenentech, Inc, Drug Metabolism and Pharmacokinetics, South San Francisco, California, USA.
Emile G PliseGenentech, Inc, Drug Metabolism and Pharmacokinetics, South San Francisco, California, USA.
Joana Liliana MoraCancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Naema NayyarCancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Stephen Paul SchmidtCenter for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Anita Giobbie-HurderDivision of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Maria Martinez-LageDepartment of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Scott L CarterJoint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Daniel P CahillDepartment of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Hiroaki WakimotoDepartment of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Priscilla Kaliopi BrastianosCancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Harvard University · USBrigham and Women's Hospital · USDana-Farber Cancer Institute · US

Funding

Identification of genomic drivers of brain metastases in lung adenocarcinomaR01CA227156 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI BRASTIANOS, PRISCILLA KALIOPI, CARTER, SCOTT · 2018 to 2022
$3.5M
EPA EP-D-18-001NCI NIH HHS R01 CA227156
6 · The paper itself

Abstract

backgroundActivating mutations in the pathway of phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) occur in 43-70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood-brain barrier. GDC-0068 is a pan-Akt inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model.

methodsIn in vitro studies, antitumor activity of GDC-0068 was assessed in breast cancer cells of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis, and western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry.

resultsGDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared with sham, whereas no effect was detected in a PIK3CA-wildtype model.

conclusionsThis study suggests that the Akt inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases.

Indexed as

AnimalsApoptosisBiomarkers, TumorBrain NeoplasmsBreast NeoplasmsCell CycleCell ProliferationClass I Phosphatidylinositol 3-KinasesFemaleGene Expression Regulation, NeoplasticHumansMiceMice, NudeMutationPhosphatidylinositol 3-KinasesPiperazinesBiomarkers, TumorClass I Phosphatidylinositol 3-KinasesipatasertibMTOR protein, humanPhosphatidylinositol 3-KinasesPIK3CA protein, humanPiperazinesProtein Kinase InhibitorsPyrimidinesTOR Serine-Threonine KinasesAkt inhibitionbrain metastasesbreast cancerGDC-0068PI3K/Akt/mTOR pathway

Identifiers

PMID31173106
PMCPMC6827829
OpenAlexW2962705255

What OpenQuestion holds

Textmetadata
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.