Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma

Taylor, Jennie; Parikh, Mili; Phillips, Joanna J.; James, C. David; Molinaro, Annette M.; Butowski, Nicholas; Clarke, Jennifer; Oberheim-Bush, Nancy Ann; Chang, Susan M.; Berger, Mitchel S.; Prados, Michael D.

doi:10.1007/s11060-018-2977-3

Cited by 90 publications

(68 citation statements)

References 19 publications

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“…Although the latter has been shown to be ineffective for recurrent GBM, patients had been heavily pretreated, and authors say targeting CDK4/6 pathway may still deserve further exploration. [ 127 ] Poly (ADP ribose) polymerase (PARP) family of enzymes has a pleiotropic role in DNA repair and has emerged as an attractive target for sensitization of GBM cells to TMZ. [ 128 ] Clinical trials are ongoing to prove efficacy of PARP inhibitors in treating glioma/GBM patients, alone or in combination with TMZ/radiation therapy.…”

Section: Clinical Management Of Glioblastoma: New Diagnosis Opportunimentioning

confidence: 99%

Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment

2020

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Gliomas are the most common primary brain tumors in adults. They arise in the glial tissue and primarily occur in the brain. Low‐grade tumors of World Health Organization (WHO) grade II tend to progress to high‐grade gliomas of WHO grade III and, eventually, glioblastoma of WHO grade IV, which is the most common and deadly glioma, with a median survival of 12–15 months after final diagnosis. Knowledge of the molecular biology and genetics of glioblastoma has increased significantly in the past few years, giving rise to classification methods that can help in management and stratification of glioblastoma patients. However, glioblastoma remains an incurable disease. Glioblastoma cells have acquired genetic and metabolic adaptations in order to sustain tumor growth and progression, including changes in energetic metabolism, invasive capacity, migration, and angiogenesis, that make it very difficult to find suitable therapeutic targets and to develop effective drugs. The current standard of care for glioblastoma patients is surgery followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. Although progress in glioblastoma therapies in recent years has been more limited than in other tumors, numerous drugs and targets are being proposed and many clinical trials are underway to develop effective subtype‐specific treatments.

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Section: Clinical Management Of Glioblastoma: New Diagnosis Opportunimentioning

confidence: 99%

Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment

2020

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“…For GBM, palbociclib entered clinical studies, based on preclinical data showing antitumor e ffects a nd radiosensitization [33][34][35]. However, two studies were terminated prematurely because of inefficacy in second-line/relapsed patients [36] (STable 2). In upcoming preclinical studies, patient-derived GBM stem cell-enriched lines also responded with transient, but not permanent cell cycle arrest [37].…”

Section: Cdk4/6 Inhibitorsmentioning

confidence: 99%

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

Riess

Irmscher

Salewski

et al. 2020

Cancer Metastasis Rev

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Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.

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“…The palbociclib concentration used for uptake and efflux experiments was 0.1 µM. This dose was selected based on reported clinical plasma concentrations (FDA, 2014;Masuda et al, 2018;Tamura et al, 2016;Taylor et al, 2018). A concentration at the lower end of the range was chosen to assure cell viability whilst remaining above the biologically effective dose of 0.06 µM (FDA, 2014).…”

Section: In Vitro Drug Uptake and Effluxmentioning

confidence: 99%

“…Reported clinical plasma concentrations for palbociclib range from 0.062μM to 0.278μM (FDA, 2014;Masuda et al, 2018;Tamura et al, 2016;Taylor et al, 2018). Studies have not reported a direct comparison of both intratumoural and plasma palbociclib concentrations, except in the case of glioblastoma where the issue is complicated by the blood brain barrier (Taylor et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models

Jové

Spencer

Hubbard

et al. 2019

J Pharmacol Exp Ther

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Adequate drug distribution through tumours is essential for treatment to be effective. Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor approved for use in patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer (BC). It has unusual physicochemical properties, which may significantly influence its distribution in tumour tissue. We studied the penetration and distribution of palbociclib in vitro, including the use of multicellular three-dimensional models and mathematical modelling. MCF-7 and DLD-1 cell lines were grown as single cell suspensions (SCS) and spheroids; palbociclib uptake and efflux were studied using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Intracellular concentrations of palbociclib for MCF-7 SCS (C max 3.22µM) and spheroids (C max 2.91 µM) were 32 and 29 fold higher and in DLD-1, 13 and 7 fold higher, respectively than the media concentration (0.1 μM). Total palbociclib uptake was lower in DLD-1 cells than MCF-7 cells both in SCS and in spheroids. Both uptake and efflux of palbociclib were slower in spheroids than SCS. These data were used to develop a mathematical model of palbociclib transport that quantifies key parameters determining drug penetration and distribution. The model reproduced qualitatively most features of the experimental data and distinguished between SCS and spheroids, providing additional support for hypotheses derived from the experimental data. Mathematical modelling has the potential for translating in vitro data into clinically relevant estimates of tumour drug concentrations. Significance statement This study explores palbociclib uptake and efflux in single cell suspension and spheroid models of cancer. Large intracellular concentrations of palbociclib are found after drug exposure. The data from this study may aid understanding of the intratumoural pharmacokinetics of palbociclib which is useful in understanding how drug distributes within This article has not been copyedited and formatted. The final version may differ from this version.

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Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma

Abstract: In this trial, despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma. However, these were heavily pretreated patients and targeting the CDK4/6 pathway may still deserve further exploration.

Cited by 90 publications

References 19 publications

Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment

Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models

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