The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood–Brain Barrier in Glioblastoma

Pokorny, Jenny L.; Calligaris, David; Gupta, Shiv K.; Iyekegbe, Dennis O.; Mueller, Dustin; Bakken, Katrina K.; Carlson, Brett L.; Schroeder, Mark A.; Evans, Debra L.; Lou, Zhenkun; Decker, Paul A.; Eckel‐Passow, Jeanette E.; Pucci, Vincenzo; Ma, Bennett; Shumway, Stuart D.; Elmquist, William F.; Agar, Nathalie Y.R.; Sarkaria, Jann N.

doi:10.1158/1078-0432.ccr-14-2588

Cited by 84 publications

(68 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GBM cell lines) and in vivo preclinical models without BBB (i.e. GBM subcutaneous xenografts), their efficacy is dramatically reduced in GBM orthotopic xenografts and in GBM patients[122]. Several reasons might explain this reduced efficacy in patients, one of them being the limited penetration of drugs within the tumor and the BAT.The passage of cytotoxic drugs across the BBB is commonly admitted to be limited in patients and to be well-documented in the literature.…”

mentioning

confidence: 99%

Blood-brain barrier, cytotoxic chemotherapies and glioblastoma

Dréan

Goldwirt

Verreault

et al. 2016

Expert Review of Neurotherapeutics

View full text Add to dashboard Cite

Glioblastomas (GBM) are the most common and aggressive primary malignant brain tumors in adults. The blood brain barrier (BBB) is a major limitation reducing efficacy of anti-cancer drugs in the treatment of GBM patients. Areas covered: Virtually all GBM recur after the first-line treatment, at least partly, due to invasive tumor cells protected from chemotherapeutic agents by the intact BBB in the brain adjacent to tumor. The passage through the BBB, taken by antitumor drugs, is poorly and heterogeneously documented in the literature. In this review, we have focused our attention on: (i) the BBB, (ii) the passage of chemotherapeutic agents across the BBB and (iii) the strategies investigated to overcome this barrier. Expert commentary: A better preclinical knowledge of the crossing of the BBB by antitumor drugs will allow optimizing their clinical development, alone or combined with BBB bypassing strategies, towards an increased success rate of clinical trials.

show abstract

mentioning

confidence: 99%

Blood-brain barrier, cytotoxic chemotherapies and glioblastoma

Dréan

Goldwirt

Verreault

et al. 2016

Expert Review of Neurotherapeutics

View full text Add to dashboard Cite

show abstract

“…After successfully inducing an apoptotic response and disruption of cell cycle arrest in cell culture, we tested MK-1775 treatment in vivo using a flank tumor PDX model, GBM6, as MK-1775 is poorly brain penetrant (19). A short-duration, 5 day, treatment study was used to assess molecular changes, while a long-duration treatment was used to investigate any changes in tumor growth after treatment with MK-1775.…”

Section: Resultsmentioning

confidence: 99%

“…MGPP6 and MGPP7 cells were plated on poly-L-lysine coated plates. PDX cell lines (GBM6, GBM36, and GBM38) were cultured at 37°C and 5% CO2 in DMEM media supplemented with 20% FBS and 1× Penicillin-Streptomycin (Pen-Strep, Gibco) as described previously (19). …”

Section: Methodsmentioning

confidence: 99%

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

et al. 2016

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an anti-tumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in pre-clinical models of GBM.

show abstract

“…Tumor-bearing studies were conducted in female athymic nude mice (Harlan Sprague-Dawley athymic nude-Foxn1nu mice) as described in detail previously (Carlson et al, 2011;Pokorny et al, 2015). The patientderived xenografts (PDXs) were derived from individual primary human GBM at the Mayo Clinic (Rochester, MN) and maintained through serial passages in the flank (Carlson et al, 2011).…”

Section: In Vivo Studiesmentioning

confidence: 99%

Efflux Transporters at the Blood-Brain Barrier Limit Delivery and Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib (PD-0332991) in an Orthotopic Brain Tumor Model

Parrish

Pokorny

Mittapalli

et al. 2015

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

6-Acetyl-8-cyclopentyl-5-methyl-2-([5-(piperazin-1-yl)pyridin-2-yl]amino)pyrido(2,3-d)pyrimidin-7(8H)-one [palbociclib (PD-0332991)] is a cyclin-dependent kinase 4/6 inhibitor approved for the treatment of metastatic breast cancer and is currently undergoing clinical trials for many solid tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and has limited treatment options. The cyclin-dependent kinase 4/6 pathway is commonly dysregulated in GBM and is a promising target in treating this devastating disease. The blood-brain barrier (BBB) limits the delivery of drugs to invasive regions of GBM, where the efflux transporters P-glycoprotein and breast cancer resistance protein can prevent treatments from reaching the tumor. The purpose of this study was to examine the mechanisms limiting the effectiveness of palbociclib therapy in an orthotopic xenograft model. The in vitro intracellular accumulation results demonstrated that palbociclib is a substrate for both P-glycoprotein and breast cancer resistance protein. In vivo studies in transgenic mice confirmed that efflux transport is responsible for the limited brain distribution of palbociclib. There was an ∼115-fold increase in brain exposure at steady state in the transporter deficient mice when compared with wild-type mice, and the efflux inhibitor elacridar significantly increased palbociclib brain distribution. Efficacy studies demonstrated that palbociclib is an effective therapy when GBM22 tumor cells are implanted in the flank, but ineffective in an orthotopic (intracranial) model. Moreover, doses designed to mimic brain exposure were ineffective in treating flank tumors. These results demonstrate that efflux transport in the BBB is involved in limiting the brain distribution of palbociclib and this has critical implications in determining effective dosing regimens of palbociclib therapy in the treatment of brain tumors.

show abstract

The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood–Brain Barrier in Glioblastoma

Cited by 84 publications

References 36 publications

Blood-brain barrier, cytotoxic chemotherapies and glioblastoma

Blood-brain barrier, cytotoxic chemotherapies and glioblastoma

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

Efflux Transporters at the Blood-Brain Barrier Limit Delivery and Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib (PD-0332991) in an Orthotopic Brain Tumor Model

Contact Info

Product

Resources

About