Dataset Information

Tumor drug concentration and phosphoproteomic profiles after two weeks of treatment with sunitinib in patients with newly-diagnosed glioblastoma

ABSTRACT: Despite currently available treatment, the prognosis of patients with glioblastoma (GBM) is poor and recurrence is inevitable. Several new systemic treatment strategies have been evaluated in the past two decades, but most of those revealed disappointing results. Especially, newly developed tyrosine kinase inhbitors (TKIs) have been studied extensively. These agents inhibit intracellular signaling, i.e. tyrosine kinases, that exert a variety of biological activities, including cell proliferation and migration, and play an important role in GBM. Clinical trials evaluating TKIs have been evaluated for recurrent GBM resulted in minimal improvement in progression-free survival and no overall survival benefit, despite clinical significant benefit in other malignancies such as renal cell cancer. Whether these disappointing results are due to a restricted drug delivery of TKIs through the blood-brain barrier, or due to differential biological characteristics of GBM compared to other malignancies is unknown. MS-based phosphoproteomics was used as an approach for molecular tumor profiling to obtain insight into aberrantly activated signaling pathways and potential drug targets. The objective was to test the feasibility of determining the (phospho)proteomic profiles and kinase activity profiles in tumor tissue by mass spectrometry (MS) after treatment for 10 to 14 days. These profiles were compared to tumor tissue of a control group of patients with newly-diagnosed GBM, who were treated with a resection only.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Astrocyte

DISEASE(S): Glioblastoma

SUBMITTER: Sander Piersma

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD019038 | Pride | 2023-03-10

REPOSITORIES: Pride

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Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma.

van Linde Myra E ME Labots Mariette M Brahm Cyrillo G CG Hovinga Koos E KE De Witt Hamer Philip C PC Honeywell Richard J RJ de Goeij-de Haas Richard R Henneman Alex A AA Knol Jaco C JC Peters Godefridus J GJ Dekker Henk H Piersma Sander R SR Pham Thang V TV Vandertop William P WP Jiménez Connie R CR Verheul Henk M W HMW

Clinical cancer research : an official journal of the American Association for Cancer Research 20220401 8

<h4>Purpose</h4>Tyrosine kinase inhibitors (TKI) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood-brain barrier penetration or more to biological characteristics of GBM.<h4>Patients and methods</h4>Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its in vitro inhibitory concentration (IC50) in GBM cell lines. In addition, phos ...[more]

PMID: 35165100

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Project description:The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.

Project description:Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down regulated in GBMs such as SPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM. The reduced representation bisulfite sequencing (RRBS) approach (Meissner et al., 2008) was used to generate genome-wide single-base resolution CpG methylation profiles of three primary GBMs (1063T, 1133T, and 1142T) and three GSC lines (1063S, 1133S, 1142S) derived from these primary GBM tumors. The NSC line and the normal brain (NB) tissue sample were used as controls for comparison purposes. In addition, we analyzed three GBM xenograft tumor tissue samples (Mayo22, Mayo39, Mayo59) developed by Dr. Jann N. Sarkaria of Mayo Clinic.

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			Action	DRS
	Lysatepeptidetable.xlsx	Xlsx
	Lysateproteintable.xlsx	Xlsx
	MaxQuant_Lysate.zip	Other
	MaxQuant_pTyrIP.zip	Other
	Phosphopeptidetable.xlsx	Xlsx