Phase II trial of ponatinib in patients with bevacizumab‐refractory glioblastoma

Lee, Eudocia Q.; Muzikansky, Alona; Duda, Dan G.; Gaffey, Sarah; Dietrich, Jörg; Nayak, Lakshmi; Chukwueke, Ugonma; Beroukhim, Rameen; Doherty, Lisa; Laub, Caroline Kane; LaFrankie, Debra C.; Fontana, Brittney; Stefanik, Jennifer; Ruland, Sandra; Caruso, Victoria; Bruno, Jennifer; Ligon, Keith L.; Reardon, David A.; Wen, Patrick Y.

doi:10.1002/cam4.2505

Cited by 24 publications

(14 citation statements)

References 23 publications

(24 reference statements)

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“…Bevacizumab could develop drug resistance within months. The efficacy of multi-kinase inhibitor Ponatinib in GBM patients is very limited in Bevacizumab-refractory GBM (NCT02478164) [ 132 ]. Also, patients who progress on VEGF R-TKi with Bevacizumab only benefit modestly [ 133 ].…”

Section: Glioblastomamentioning

confidence: 99%

Glioma targeted therapy: insight into future of molecular approaches

et al. 2022

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Gliomas are the common type of brain tumors originating from glial cells. Epidemiologically, gliomas occur among all ages, more often seen in adults, which males are more susceptible than females. According to the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), standard of care and prognosis of gliomas can be dramatically different. Generally, circumscribed gliomas are usually benign and recommended to early complete resection, with chemotherapy if necessary. Diffuse gliomas and other high-grade gliomas according to their molecule subtype are slightly intractable, with necessity of chemotherapy. However, for glioblastoma, feasible resection followed by radiotherapy plus temozolomide chemotherapy define the current standard of care. Here, we discuss novel feasible or potential targets for treatment of gliomas, especially IDH-wild type glioblastoma. Classic targets such as the p53 and retinoblastoma (RB) pathway and epidermal growth factor receptor (EGFR) gene alteration have met failure due to complex regulatory network. There is ever-increasing interest in immunotherapy (immune checkpoint molecule, tumor associated macrophage, dendritic cell vaccine, CAR-T), tumor microenvironment, and combination of several efficacious methods. With many targeted therapy options emerging, biomarkers guiding the prescription of a particular targeted therapy are also attractive. More pre-clinical and clinical trials are urgently needed to explore and evaluate the feasibility of targeted therapy with the corresponding biomarkers for effective personalized treatment options.

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Section: Glioblastomamentioning

confidence: 99%

Glioma targeted therapy: insight into future of molecular approaches

et al. 2022

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“…VEGFR2 inhibitors induce FGF2 expression and accelerate the growth murine pancreatic neuroendocrine tumors (Casanovas et al, 2005). Clinical studies on glioblastoma furthers confirmed this observation (Batchelor et al, 2007;Lee et al, 2019).…”

Section: Fibroblast-growth Factorsmentioning

confidence: 77%

Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs

Montemagno

Pagès

2020

Front. Cell Dev. Biol.

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Angiogenesis, the formation of new blood vessels from preexisting one, represents a critical process for oxygen and nutrient supply to proliferating cells, therefore promoting tumor growth and metastasis. The Vascular Endothelial Growth Factor (VEGF) pathway is one of the key mediators of angiogenesis in cancer. Therefore, several therapies including monoclonal antibodies or tyrosine kinase inhibitors target this axis. Although preclinical studies demonstrated strong antitumor activity, clinical studies were disappointing. Antiangiogenic drugs, used to treat metastatic patients suffering of different types of cancers, prolonged survival to different extents but are not curative. In this review, we focused on different mechanisms involved in resistance to antiangiogenic therapies from early stage resistance involving mainly tumor cells to late stages related to the adaptation of the microenvironment.

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“…Due to ponatinib's unique multitargeted characteristics, further studies have demonstrated its ability in other human malignancies, such as GBM [ 47 ]. Eudocia Q Lee et al reported that they performed a phase II trial of ponatinib in patients with bevacizumab-refractory GBM and variants [ 48 ]. In addition, tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA tyrosine-protein kinase inhibitors could reduce the VEGFA expression.…”

Section: Discussionmentioning

confidence: 99%

Systematic Profiling of mRNA Splicing Reveals the Prognostic Predictor and Potential Therapeutic Target for Glioblastoma Multiforme

Zhang

Cheng

et al. 2021

Journal of Oncology

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Despite many changes in alternative splicing events (ASEs) are frequently involved in various cancers, prognosis-related ASEs and drug treatment targets in glioblastoma multiforme (GBM) have not been well explored. ASEs participate in many biological behaviors in the initiation and progression of tumors, the aberrant ASE has been considered another hallmark of cancer, and the systematic study of alternative splicing may provide potential biomarkers for malignancies. In this study, we carried out a systematic analysis to characterize the ASE signatures in GBM cohort. Through comparing GBM tissues and nontumor tissues, a total of 48,191 differently expressed ASEs from 10,727 genes were obtained, and these aberrant ASEs play an important role in the oncogenic process. Then, we identified 514 ASEs independently associated with patient survival in GBM by univariate and multivariate Cox regression, including exon skip in CD3D, alternate acceptor site in POLD2, and exon skip in DCN. Those prognostic models built on ASEs of each splice type can accurately predict the outcome of GBM patients, and values for the area under curve were 0.97 in the predictive model based on alternate acceptor site. In addition, the splicing-regulatory network revealed an interesting correlation between survival-associated splicing factors and prognostic ASE corresponding genes. Moreover, these three hub splicing factors in splicing regulation network are the potential targets of some drugs. In conclusion, a systematic analysis of ASE signatures in GBM could serve as an indicator for identifying novel prognostic biomarkers and guiding clinical treatment.

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Phase II trial of ponatinib in patients with bevacizumab‐refractory glioblastoma

Cited by 24 publications

References 23 publications

Glioma targeted therapy: insight into future of molecular approaches

Glioma targeted therapy: insight into future of molecular approaches

Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs

Systematic Profiling of mRNA Splicing Reveals the Prognostic Predictor and Potential Therapeutic Target for Glioblastoma Multiforme

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