Novel anti-angiogenic therapies for malignant gliomas

Norden, Andrew D.; Drappatz, Jan; Wen, Patrick Y.

doi:10.1016/s1474-4422(08)70260-6

Cited by 213 publications

(152 citation statements)

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“…The processes of pathological angiogenesis and possible Polivka Jr. et al: Targeted Therapy and Immunotherapy in Patients with GBM (Review) 23 mechanisms for their therapeutic inhibition have been extensively studied in GBM (19,71,72). The major role in tumor angiogenesis is played by vascular growth factors, especially vascular endothelial growth factor (VEGF) and its variant VEGF-A, primarily through its interactions with the VEGFR1 and VEGFR2 receptors found on endothelial as well as cancer cells.…”

Section: Inhibition Of Angiogenesis In Gbmmentioning

confidence: 99%

“…Excessive microvascular proliferation and VEGF overexpression were identified in tumor tissues from patients with GBM. Higher intra-tumoral as well as plasma VEGF concentrations were associated with rapid disease progression and presence of early recurrence of GBM (72)(73)(74)(75)(76)(77). Therefore, the evaluation of antiangiogenic and anti-VEGF agents in GBM is highly needed.…”

Section: Inhibition Of Angiogenesis In Gbmmentioning

confidence: 99%

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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: Inhibition Of Angiogenesis In Gbmmentioning

confidence: 99%

Section: Inhibition Of Angiogenesis In Gbmmentioning

confidence: 99%

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

et al. 2017

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“…Antiangiogenic treatment has become an integral part of modern cancer therapy, targeting the vasculature of numerous aggressive malignancies including glioblastoma (Kerbel and Folkman, 2002;Norden et al, 2008a). This tumour entity is paradigmatic for and clinically determined by profoundly increased pathological angiogenesis and invasive growth (Louis, 2006).…”

Section: Introductionmentioning

confidence: 99%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.Oncogene advance online publication, Word Count:5,868 words Condensed title:Radiation-enhanced mTOR inhibition in glioblastomaWeiler et al. 2 AbstractA relevant mode of resistance to antiangiogenic and radiotherapy appears to be promotion of tumour cell motility and invasiveness in various cancer types, a process commonly referred to as 'evasive resistance' that may underlie progressive disease and complicates further treatment. Hence, a logical advancement in current oncology consists in optimizing antiangiogenic regimens by identifying suitable complementary strategies, ideally targeting cell motility. Here we report that clinically relevant radiation-enhanced inhibition of the mTOR complexes 1 and 2 exercises such a dual control of angiogenesis and invasiveness independent from PTEN/AKT activation in glioblastoma, a tumour entity that is paradigmatic for both excessive vascular proliferation and cell invasion. This is due to a concerted disrupture of the VEGF/VEGFR-2 signalling axis and likewise suppression of RGS4, which we identified to be a key driver of glioblastoma invasiveness. This combined antiangiogenic/antiinvasive approach might be a promising therapeutic option and warrants further clinical investigation in upfront glioblastoma therapy.Weiler et al.3

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“…Other antiangiogenic agents that are being evaluated in this setting are small-molecule TK inhibitors that are targeted to growth factor receptors like vascular endothelial growth factor receptor or platelet derived growth factor receptor (reviewed in ref. 58). Noteworthy, antiangiogenic therapy is associated with both reduced vascular permeability and perilesional edema as shown by a drastic reduction of steroid requirements.…”

Section: Current Therapeutic Options For Glioblastomamentioning

confidence: 99%