Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis,growth, and survival of glioblastoma and enhances chemotherapy's efficacy

Glioblastoma is characterized by extensive vascularization and is highly resistant to current therapy. Identification of drugs that target tumor directly and angiogenesis processes present an effective therapeutic strategy for glioblastoma. Mnk kinase is required for the activation of eukaryotic initiation factor 4E (eIF4E), which mediates translation of oncogenic proteins. We investigated the effects of tomivosertib, a novel MAPK-interacting kinase (MNK) inhibitor, on glioblastoma angiogenesis, growth, and survival. We found that tomivosertib inhibited growth and induced caspase-dependent apoptosis in various glioblastoma cell lines. Tomivosertib disrupted glioblastoma endothelial cell capillary network formation, growth, and survival. Mechanistically, tomivosertib acted on glioblastoma via suppressing MNK-dependent eIF4E phosphorylation and activation in tumor and endothelial cells. We further found that temozolomide activated eIF4E and this was reversed by tomivosertib. Using glioblastoma xenograft mouse model, we demonstrated that temozolomide and tomivosertib combination had higher efficacy than tomivosertib alone. Of note, tomivosertib inhibited glioblastoma angiogenesis and decreased p-eIF4E level in mice. We finally showed that p-eIF4E activation was a common molecular feature in glioblastoma patients. Our pre-clinical findings suggest that tomivosertib is a useful addition to the treatment armamentarium for glioblastoma and that targeting MNK-eIF4E pathway represents a therapeutic strategy to overcome glioblastoma chemoresistance.     

High linear-energy-transfer radiation can overcome radioresistance of glioma stem-like cells to low linear-energy-transfer radiation

Ionizing radiation is applied as the standard treatment for glioblastoma multiforme (GBM). However, radiotherapy remains merely palliative, not curative, because of the existence of glioma stem cells (GSCs), which are regarded as highly radioresistant to low linear-energy-transfer (LET) photons. Here we analyzed whether or not high-LET particles can overcome the radioresistance of GSCs. Glioma stem-like cells (GSLCs) were induced from the GBM cell line A172 in stem cell culture medium. The phenotypes of GSLCs and wild-type cells were confirmed using stem cell markers. These cells were irradiated with ⁶⁰Co gamma rays or reactor neutron beams. Under neutron-beam irradiation, high-LET proton particles can be produced through elastic scattering or nitrogen capture reaction. Radiosensitivity was assessed by a colony-forming assay, and the DNA double-strand breaks (DSBs) were assessed by a histone gamma-H2AX focus detection assay. In stem cell culture medium, GSLCs could form neurosphere-like cells and express neural stem cell markers (Sox2 and Musashi) abundantly in comparison with their parental cells. GSLCs were significantly more radioresistant to gamma rays than their parental cells, but neutron beams overcame this resistance. There were significantly fewer gamma-H2AX foci in the A172 GSLCs 24 h after irradiation with gamma rays than in their parental cultured cells, while there was no apparent difference following neutron-beam irradiation. High-LET radiation can overcome the radioresistance of GSLCs by producing unrepairable DNA DSBs. High-LET radiation therapy might have the potential to overcome GBM''s resistance to X-rays in a clinical setting.     

Phospholipase D1 inhibition sensitizes glioblastoma to temozolomide and suppresses its tumorigenicity

Resistance of glioblastoma to the chemotherapeutic compound temozolomide is associated with the presence of glioblastoma stem cells in glioblastoma and is a key obstacle for the poor prognosis of glioblastoma. Here, we show that phospholipase D1 is elevated in CD44^High glioblastoma stem cells and in glioblastoma, especially recurring glioblastoma. Phospholipase D1 elevation positively correlated with the level of CD44 and poor prognosis in glioblastoma patients. Temozolomide significantly upregulated the expression of phospholipase D1 in the low and moderate CD44 populations of glioblastoma stem cells, but not in the CD44^High population in which phospholipase D1 is highly expressed. Phospholipase D1 conferred resistance to temozolomide in CD44^High glioblastoma stem cells and increased their self-renewal capacity and maintenance. Phospholipase D1 expression significantly correlated with levels of temozolomide resistance factors, which were suppressed by microRNA-320a and -4496 induced by phospholipase D1 inhibition. Genetic and pharmacological targeting of phospholipase D1 attenuated glioblastoma stem cell-derived intracranial tumors of glioblastoma using the microRNAs, and improved survival. Treatment solely with temozolomide produced no benefits on the glioblastoma, whereas in combination, phospholipase D1 inhibition sensitized glioblastoma stem cells to temozolomide and reduced glioblastoma tumorigenesis. Together, these findings indicate that phospholipase D1 inhibition might overcome resistance to temozolomide and represents a potential treatment strategy for glioblastoma. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.     

Angiosarcomatous component in gliosarcoma: case report and consideration of diagnostic challenge and hemorrhagic propensity

An angiosarcomatous component in gliosarcoma may be associated with an increased intraoperative hemorrhagic risk and preoperative diagnostic challenge. We report a unique case of gliosarcoma with an angiosarcomatous component in a 61-year-old man. His brain MRI demonstrated a well-demarcated right occipital tumor with multiple flow voids and rim-like enhancement as well as intratumoral strip and nodular enhancements. He underwent a craniotomy for tumor resection. Intraoperatively, significant tumor hemorrhage required greater efforts to control intraoperative bleeding and to maintain hemostasis. Pathological examination of the tumor revealed alternating gliomatous and sarcomatous/angiosarcomatous components with intratumoral hemorrhage. He was postoperatively treated with chemoradiation. The tumor recurred at 9 months, for which the second resection was performed with similarly greater efforts to achieve hemostasis. The recurrent tumor was pathologically similar despite treatment-associated changes. Awareness of this angiosarcomatous component in gliosarcoma with the hemorrhagic risk is important for both the preoperative diagnosis and surgical management.     

Cytomorphology of glioblastoma metastic to a cervical lymph node diagnosed by fine needle aspiration (FNA): A case report and review of literature

Glioblastoma is an aggressive primary central nervous system tumor with a dismal prognosis. However, extracranial metastases are extremely rare. Very few cases have been reported in the literature. We present a case of a 64‐year‐old male with glioblastoma metastatic to a cervical lymph node in which the diagnosis was made on fine needle aspiration cytology (FNAC). The cytomorphologic features of glioblastoma are distinct, with pleomorphic cells in loosely cohesive clusters with prominent nucleoli, coarsely clumped chromatin and cellular processes. We suggest that FNAC, along with clinical history, is a cost effective, safe, and diagnostically accurate method of diagnosing glioblastoma metastases. Cell block is also helpful in establishing the diagnosis.     

Advances in drug development for targeted therapies for glioblastoma

Glioblastoma is the most aggressive primary brain tumor in adults. The prognosis of patients with primary glioblastoma treated with the current standard of care, tumor resection followed by radiation therapy and auxiliary temozolomide, remains poor. Integrative genomic analyses have identified essential core signaling pathways and frequent genetic aberrations, which provide potential drug targets for glioblastoma treatment. Drugs against these therapeutic targets have been developed rapidly in recent years. Although some have shown promising effects on models in preclinical studies, many have shown only modest efficacy in clinical trials. New therapeutic strategies and potent drugs are urgently needed to improve the prognosis of patients with glioblastoma. The goal of this review is to summarize the current advances in drug development for targeted glioblastoma therapies and to reveal the major challenges encountered in clinical trials or treatment. This study will provide new perspectives for future studies of targeted therapeutic drug development and provide insights into the clinical treatment of glioblastoma.     

Clinical value of CD133 and nestin in patients with glioma: a population-based study

Cancer stem cell-related (CSC) markers have been suggested to have promising potentials as novel types of prognostic and predictive markers in gliomas. However no single CSC-related marker is currently used in clinical decisions. The aim of this study was to investigate the prognostic value of CD133 and nestin separately and in combination using a novel quantitative approach in a well-characterized population-based cohort of glioma patients. The expression of CD133 and nestin was measured by systematic random sampling in stained paraffin sections from 239 glioma patients diagnosed between 2005 and 2009. We found that the expression of CD133 did not correlate with WHO grade, and there was no association with overall survival (OS). The level of nestin correlated positively with WHO grade. In patients with WHO grade II tumors, a high level of nestin was associated with short progression-free survival (PFS) in multivariate analysis. High levels of co-localization were associated with poor PFS in patients with WHO grade II tumors, but not with OS. We conclude that CD133 was not an independent prognostic factor, but a high level of nestin was associated with poor PFS in patients with WHO grade II tumors. The combination of double-immunofluorescence and automated analysis seems to be a feasible and reproducible approach for investigation of the prognostic potential of biomarkers.     

STAT3 serine 727 phosphorylation influences clinical outcome in glioblastoma

Besides STAT3 tyrosine 705 phosphorylation (pTyr705-STAT3), phosphorylation of STAT3 at serine 727 (pSer727-STAT3) is shown to contribute to tumorigenesis and be closely related with resistance to radiotherapy and chemotherapy in glioma, but there is currently no study regarding its relevance to prognosis in glioblastoma (GBM). Here, the expression of phosphorylated STAT3 was detected in tumor specimens from 88 patients with newly diagnosed GBM by immunohistochemistry, the Kaplan-Meier survival curve and COX proportional hazards regression model were applied to estimate its influences on progression-free survival (PFS) and overall survival (OS). Immunohistochemical assay showed elevated expression of pSer727-STAT3 in GBM compared with normal brain tissue. Univariate analysis indicated significant correlations of high percentage of pSer727-STAT3 positive tumor cells with shorter PFS (P = 0.006) and OS (P = 0.002). In multivariate analysis, high pSer727-STAT3 expression was demonstrated as an independent unfavorable prognostic indicator for PFS (HR 1.830, P = 0.022) and OS (HR 1.797, P = 0.040). And patients with high expression of both pTyr705-STAT3 and pSer727-STAT3 had a poorer prognosis compared with the remainder (P < 0.005). In conclusion, the high proportion of pSer727-STAT3 positive neoplastic cells in GBM is an independent unfavorable prognostic factor, and increased expression of both pTyr705-STAT3 and pSer727-STAT3 is predictive of poorer clinical outcome, thereby adding to the growing evidence that STAT3 inhibition may be a potential therapeutic strategy in glioblastoma.     

Cytological diagnosis of metastatic glioblastoma in the pleural effusion of a lung transplant patient

The extracranial metastasis of glioblastoma is a rare event. We report the case of a patient who developed metastatic glioblastoma in pleural effusion 15 months after lung transplant, with emphasis on differential diagnosis based on cytological material. In our case, tumor cells had pleomorphic nuclei, prominent nucleoli, and fine vesicular chromatin. Some were arranged in a poorly formed pseudo‐glandular architecture, mimicking a poorly differentiated adenocarcinoma. The cytological diagnosis of metastatic glioblastoma is difficult and depends critically on clinical history and suspicion, particularly in the transplant setting. Review of the literature indicates that transmission/metastasis of intracranial malignancy occurs rarely following organ transplantation, with some debate on the suitability for transplant of organs from affected donors. Although the situation is uncommon, this report of the cytological findings of extracranial glioblastoma may extend our current knowledge and provide additional differential diagnostic information for this entity. Diagn. Cytopathol. 2014;42:619–623. © 2013 Wiley Periodicals, Inc.