Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

Reardon, David A.; Dresemann, G.; Taillibert, Sophie; Campone, Mario; Bent, Martin J. van den; Clément, Paul M.; Blomquist, Erik; Gordower, Laurence; Schultz, Henrik; Raizer, Jeffrey J.; Hau, Peter; Easaw, Jacob C.; Gil, Miguel; Tonn, Jörg C.; Gijtenbeek, Anja; Schlegel, Uwe; Bergström, Per; Green, S.; Weir, Alexander; Nikolova, Zariana

doi:10.1038/sj.bjc.6605411

Cited by 119 publications

(73 citation statements)

References 37 publications

(48 reference statements)

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“…PFS of 16% at 6 months was observed in one phase II trial of patients with recurrent disease (50). Further multicenter phase II studies confirmed that imatinib as a monotherapy or in combination therapy failed to improve PFS or OS in patients with GBM (51,52). Multikinase inhibitors influencing tumor angiogenesis, namely sunitinib, sorafenib, and vandetanib, also have inhibitory effect on PDGFR.…”

Section: Inhibitors Of Growth Factors and Their Receptors Inhibitorsmentioning

confidence: 88%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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Abstract. Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single antiangiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.Glioblastoma multiforme (GBM) belongs to the largest group of primary central nervous system (CNS) tumors, so-called gliomas, which are formed from supporting glial cells in the brain parenchyma (1, 2). GBM represents the most common and most malignant tumor in this class, with an incidence of 3-4/100,000/year (3, 4). GBM is an extremely invasive and difficult to treat tumor, characterized by intense and aberrant vascularization and high resistance to radiotherapy (RT) and chemotherapy (CHT). The current standard of care for patients with newly-diagnosed GBM comprises of neurosurgery and subsequent concomitant chemoradiotherapy by fractionated external-beam RT and systemic temozolomide followed by systemic temozolomide in the adjuvant setting (5). There are only very limited possibilities for the treatment of subsequent recurrences, generally with minimal clinical efficacy (6). Despite intensive multimodal treatment strategies, the median survival of patients with GBM is still 12.1-14.6 months and only 3-5% of patients survive longer than 3 years (7).Enormous progress has been made in the genetics and epigenetics of GBM during the past decade. The Cancer 21Τhis article is freely accessible online.Correspondence to: Jiri Polivka, Department of Neurology, Faculty Hospital Plzen, alej Svobody 80, 304 60, Plzen, Czech Republic. E-mail: polivka@fnplzen.cz Key Words: Glioblastoma multiforme, GBM, targeted therapy, immunotherapy, immune checkpoint inhibitors, PD1 inhibition, CTLA4 inhibition, clinical trials, personalized medicine, review. ANTICANCER RESEARCH 37: 21-34 (2017) [8][9][10][11][12]. The most important genetic...

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Section: Inhibitors Of Growth Factors and Their Receptors Inhibitorsmentioning

confidence: 88%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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“…Alterations in this subgroup include amplification of wild-type PDGFRA, activating mutations, or intragenic rearrangements of this kinase that are age-specific, resulting in constitutively increased tyrosine kinase signaling and activation of downstream mitogen-activated protein kinase (MAPK) and PI3K pathways (210,211). Inhibiting PDGFRA with imatinib, a small molecule that also targets BCR-ABL and c-KIT, showed only very limited effects in cohorts of adults with progressive or recurrent high-grade malignant gliomas in past studies (212)(213)(214). Preliminary results using the second-generation tyrosine kinase inhibitors, tandutinib or dasatinib, which have a higher ability to cross the blood-brain barrier, also have not had a substantial effect against gliomas in adult patients (168), suggesting that careful stratification and improved methods of drug delivery may be important strategies for further consideration.…”

Section: H3 or Idh Wild-type Subgroupmentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

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“…In the subsequent Phase II trial involving both imatinib and hydroxyurea, no patient achieved either complete or partial response, and 14 patients achieved disease stability. 66 Horak et al 26 recently published a retrospective study looking at the role of imatinib treatment on progressionfree survival in patients with meningioma. Of the 18 patients in their study, 9 received imatinib based on PDGFR positivity; of those 9, 7 had stable disease and 2 showed disease progression at the time of their first 3-month follow-up imaging.…”

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confidence: 99%

“…Imatinib mesylate, a chemotherapeutic agent already in use for the treatment of leukemias and gastrointestinal stromal tumors, is a potent inhibitor of the PDGFR and has been proposed as a possible therapeutic agent. Two Phase II trials have been conducted looking at the use of imatinib alone 80 and in conjunction with hydroxyurea, 66 enrolling 23 and 21 patients, respectively. Both trials had single arms.…”

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confidence: 99%

Recent developments in chemotherapy for meningiomas: a review

Moazzam

Wagle

Zada

2013

FOC

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Object Currently, few medical options exist for refractory and atypical/anaplastic meningiomas. New developments in chemotherapeutic options for meningiomas have been explored over the past decade. The authors review these recent developments, with an emphasis on emerging avenues for therapy, clinical efficacy, and adverse effects. Methods A review of the literature was performed to identify any studies exploring recent medical and chemotherapeutic agents that have been or are currently being tested for meningiomas. Results from included preclinical and human clinical trials were reviewed and summarized. Results Current guidelines recommend only 3 drugs that can be used to treat patients with refractory and highgrade meningiomas: hydroxyurea, interferon-α 2B, and Sandostatin long-acting release. Recent developments in the medical treatment of meningiomas have been made across a variety of pharmacological classes, including cytotoxic agents, hormonal agents, immunomodulators, and targeted agents toward a variety of growth factors and their signaling cascades. Promising avenues of therapy that are being evaluated for efficacy and safety include antagonists of platelet-derived growth factor receptor, epidermal growth factor receptor, vascular endothelial growth factor receptor, and mammalian target of rapamycin. Because malignant transformation in meningiomas is likely to be mediated by numerous processes interacting via a complex matrix of signals, combination therapies affecting multiple molecular targets are currently being explored and hold significant promise as adjuvant therapy options. Conclusions Improved understanding of the molecular mechanisms driving meningioma tumorigenesis and malignant transformation has resulted in the targeted development of more specific agents for chemotherapeutic intervention in patients with nonresectable, aggressive, and malignant meningiomas.

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Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

Cited by 119 publications

References 37 publications

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Molecular mechanisms and therapeutic targets in pediatric brain tumors

Recent developments in chemotherapy for meningiomas: a review

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