Multimodality Targeting of Glioma Cells

Glioma is the most common malignant primary tumor in the central nervous system, accounting for about 80% of total malignant brain tumors. The World Health Organization (WHO) classification divides glioma into 4 grades according to the degree of malignancy: anaplastic astrocytoma (WHO grade III) and well-differentiated astrocytoma (WHO grade I/II) have various median survivals from 2 to 7 years ; glioblastoma (GBM; WHO grade IV), which constitutes 54.9% of all gliomas, is the most serious and malignant form of glioma, with a median overall survival of 12 to 15 months.

Despite the aggressive standard-of-care treatment, which includes surgical resection, fractionated radiation, and temozolomide-based chemotherapy, the relapse of high-grade glioma is essentially universal, and the 5-year survival rate of patients with GBM is less than 10%. Multiple mechanisms contribute to treatment inefficacy: complete surgical removal is nearly impossible because of its location and infiltrative nature; the use of fractionated radiation is restricted because of the potential damage to normal brain tissue; the blood-brain barrier (BBB) blocks most chemotherapy drugs; and glioma cells develop primary and acquired resistance to chemotherapy. Therefore, the development of new therapies is urgently needed.

Angiogenesis, the formation of new blood vessels, plays a critical role in the growth and spread of cancer. Antiangiogenic therapy that primarily targets vascular endothelial growth factor (VEGF) has been an efficient therapeutic strategy in treating non–small cell lung, colorectal, renal, and ovarian cancers. Glioma is among the most vascularized tumors in humans. Recent studies show that bevacizumab, a monoclonal antibody against VEGF, increased progression-free survival (PFS) but not overall survival (OS) in newly diagnosed GBM, which may indicate some initial therapeutic efficacy that did not translate to long-term outcomes. In contrast, targeted molecular therapy has recently achieved remarkable success in various cancer types, including non–small cell lung cancer, breast cancer, and leukemia. Recent advances in identifying oncogenic signal pathways and deciphering metabolic, genomic, and epigenetic regulation in glioma cells have provided deep insights into the molecular pathogenesis of the malignancy, and more importantly, have shed light on the development of new targeted therapies in patients with glioma. This chapter discusses the potential targets of glioma therapy and their clinical efficacy, the potential therapeutic barriers, and the new direction and promise, with a focus on antiangiogenic and targeted molecular therapies.

Antiangiogenic therapy

Therapeutic Targets and Treatment Efficacy

Angiogenesis proceeds by endothelial cell (EC) sprouting and outgrowth from existing vessels. This process is subjected to spatiotemporal regulation: triggered by binding of angiogenic factors to their receptors and executed by sequent activation of downstream signal pathways. These signaling events eventually induce Rho GTPase–mediated and phosphatidylinositol 3-kinase (PI3K)–mediated cell migration and invasion, and lead to genetic and metabolic reprogramming to promote cell growth and proliferation. These ligands, receptors, kinases, and transcriptional factors in the regulatory network can serve as potential targets for antiangiogenic therapy ( Fig. 5.1 ).

Angiogenic factors

The most widely preferred approach for antiangiogenesis currently is the blockade of the pathways of angiogenic factors, including VEGF, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor/scatter factor (HGF/SF), and angiopoietins. Several of these factors are described here.

Vascular endothelial growth factor

VEGF and its receptor VEGFR2 have served as the primary therapeutic targets for antiangiogenic therapy in last 3 decades. Bevacizumab, the most widely used humanized VEGF antibody, has been approved for treating metastatic colorectal carcinoma, non–small cell lung cancer, metastatic renal cell carcinoma, breast cancer (in the European Union [EU]), ovarian cancer (in the EU), and recurrent GBM. Ranibizumab is another neutralizing antibody against VEGF, with a similar binding affinity. Bevacizumab, used as monotherapy or in combination with chemotherapy, slightly improved PFS but not OS in most clinical trials including patients with GBM. Ziv-aflibercept is a recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of VEGF1/2, therefore binding to circulating VEGF like a trap. Ziv-aflibercept has approximately 100-fold higher affinity than either bevacizumab or ranibizumab, showing markedly more potent blockade of VEGFR-1 or VEGFR-2 activation. Clinical trials showed that Ziv-aflibercept plus FOLFIRI (folinic acid, fluorouracil and irinotecan) improved PFS and OS in metastatic colorectal carcinoma with a median OS of 13.5 months, compared with a median OS of 12.06 months with FOLFIRI alone. The efficacy of Ziv-aflibercept needs further evaluation in patients with glioma.

Basic fibroblast growth factor

bFGF/fibroblast growth factor receptor (FGFR) induces angiogenesis by promoting extracellular matrix degradation, altering intercellular adhesion, enhancing cell motility, and stimulating cell growth in ECs. Pazopanib is a second-generation tyrosine kinase inhibitor that targets FGFR, VEGFR, platelet-derived growth factor receptor (PDGFR), and c-Kit. Pazopanib has been approved by the US Food and Drug Administration (FDA) for treating soft tissue sarcoma. Pazopanib did not prolong PFS but showed in situ biological activities indicated by radiographic responses in a phase II trial for patients with recurrent GBM. The combination of pazopanib and lapatinib (epidermal growth factor receptor [EGFR] inhibitor) was evaluated in a phase I/II trial, but was terminated early because of the poor 6-month PFS rate. Other clinical trials are ongoing to evaluate the combination of pazopanib with temozolomide in newly diagnosed GBM ( NCT02331498 ) and the combination of pazopanib with topotecan in recurrent GBM ( NCT01931098 ).

Platelet-derived growth factor

Aberrant activation of PDGF/PDGFR signaling is one of the hallmarks of glioma biology. Overexpression of PDGF/PDGFR has been found in glioma cells and surrounding ECs; coexpression of ligand receptor in these cells allows both autocrine and paracrine forms of activation, resulting in vessel formation and glioma cell migration, survival, and invasion. Both sorafenib and sunitinib are multitargeted angiogenesis inhibitors that target PDGFR, VEGFR, mast/stem cell growth factor (c-Kit) and FMS-like tyrosine kinase 3 (FLT-3). They have been approved for the treatment of multiple cancer types, including renal cell carcinoma, hepatocellular carcinoma, pancreatic neuroendocrine tumor, and gastrointestinal stromal tumors. A phase II trial of sunitinib alone in recurrent anaplastic astrocytoma and recurrent GBM failed to show significant antitumor activity; no partial responses (PRs) or complete responses (CRs) were observed in the cohort. A phase I trial of the combination of sorafenib with temozolomide and radiation therapy showed that sorafenib was well tolerated. Combination of sorafenib and temsirolimus (mammalian target of rapamycin [mTOR] inhibitor) showed poor efficacy with a 6-month PFS rate of 0%. Further clinical trials of different combinations of sorafenib with other agents are now under study ( NCT01434602 , NCT01817751 ).

Hepatocyte growth factor

HGF is often highly expressed in GBM, which may lead to increased glioma cell invasion. HGF/c-Met also stimulates EC proliferation and migration and induces angiogenesis. Cabozantinib is an orally bioavailable inhibitor that targets HGF, c-Met, rearranged during transfection (RET), and VEGFR2. Cabozantinib has been approved for treating medullary thyroid cancer. A phase I trial of cabozantinib with temozolomide and radiotherapy in newly diagnosed patients with GBM showed that cabozantinib was well tolerated at a dose of 40 mg daily. Several phase II trials of cabozantinib in patients with malignant gliomas were completed ( NCT01068782 , NCT00704288 ), but the results have not been published yet.

Angiopoietins

Angiopoietins and their receptor Tie2 are important for angiogenesis induction. Regorafenib is an oral multikinase inhibitor that targets several protein kinases, including those involved in the regulation of tumor angiogenesis (VEGFR, Tie2, PDGFR, and FGFR) and oncogenesis (c-Kit, RET, rapidly activated fibrosarcoma 1 (RAF1), BRAF, and BRAF ^V600E ). Regorafenib has been approved for treating metastatic colorectal cancer and gastrointestinal stromal tumor. Large randomized clinical trials revealed that regorafenib provides a significantly improved PFS in metastatic gastrointestinal stromal tumors. Although the antitumor efficacy of regorafenib in malignant glioma cells was shown in a preclinical study, the clinical effects of regorafenib have not been validated in patients with glioma.

Antivascular agents

Thalidomide and its derivatives, lenalidomide and pomalidomide, are synthetic derivatives of glutamic acid with multiple properties, including immunomodulatory, antiinflammatory, and antiangiogenesis effects. These agents can inhibit EC proliferation, block biological functions induced by proangiogenic factors such as VEGF and bFGF, and induce antitumor activity. They have been approved for treating multiple myeloma. Clinical trials revealed that thalidomide had a limited efficacy in patients with recurrent or newly diagnosed GBM. Combinations of thalidomide with irinotecan or carmustine or conventional therapy have also failed to achieve sufficient efficacy in several phase II trials. Furthermore, phase I trials showed that lenalidomide was tolerable in both pediatric and adult patients with glioma. A phase II trial is ongoing to evaluate the antitumor effects of lenalidomide in patients with glioma ( NCT01553149 ). Pomalidomide shows effective anticancer activities in hematologic malignancies such as multiple myeloma and acute myeloid leukemia, but the efficacy of pomalidomide in malignant glioma has not been fully investigated. A phase I trial of pomalidomide in recurrent gliomas is ongoing ( NCT02415153 ). The antiangiogenic effects of these agents in gliomas needs further evaluation in clinical trials.

Potential Therapeutic Barriers

Antiangiogenic therapy, albeit initially groundbreaking, has encountered difficulties and failures in most malignant cancers. Current angiogenic therapies that mainly target VEGF pathways fail to produce a permanent response in most patients, usually showing a transient response initially with impressive radiographic responses followed by tumor regrowth and disease progression. Moreover, certain patients show no response after the antiangiogenic treatment in multiple cancer types, including GBM, suggesting both primary (intrinsic) and acquired (treatment-induced) mechanisms existing for the treatment resistance.

Primary resistance

Angiogenic pathway redundancy

There is a plethora of proangiogenic factors expressed in solid tumors inducing persistent, simultaneous activation of multiple RTK-mediated signal pathways. This abundance may explain why current therapies that target VEGF or several other angiogenic factors, such as PDGF and bFGF, individually have limited efficacy. This limited efficacy may be overcome by a combination of multiple angiogenic inhibitors. Molecular diagnosis that examines the activation panel of signal pathways specific to vascular ECs of tumor biopsy samples may further ensure the success of the combined therapies in individual patients.

Microenvironment-dependent protection

It has become increasingly recognized that the stromal cells including circulation-derived progenitor cells and myeloid cells in the tumor microenvironment contribute to the treatment resistance in ECs. CD11b ⁺ Gr1 ⁺ myeloid cells that express proangiogenic factors and other cytokines can infiltrate the tumor, which is critical for the anti-VEGF resistance in ECs. Studies show that targeting these cells by either antibody-based deletion or PI3K inhibition significantly reverses the treatment resistance in immunocompetent preclinical models of RT2 primitive neuroectodermal tumor and other murine cancers. Recent studies showed that macrophages are a critical determinant for glioma progression. These results suggest that targeting tumor-associated macrophage may serve as a promising strategy to sensitize antiangiogenic treatment in glioma.

Vascular transformation

Our recent work reveals that GBM-associated ECs undergo mesenchymal transformation to acquire fibroblast phenotypes, including enhanced cell migration and proliferation, leading to aberrant angiogenesis. This new concept is different from the previously proposed endothelial-mesenchymal transition in a breast cancer model: instead of EC generation of tumor-associated fibroblasts de novo, transformed ECs still retain vascular functions, including vessel formation and absorption of acylated low-density lipoprotein (acLDL). More importantly, transformation-induced downregulation of VEGFR2, and possibly its downstream signaling, renders the EC resistant to anti-VEGF treatment. Therefore, this newly identified mechanism may provide an explanation for primary resistance to anti-VEGF therapy and serve as an alternative target for antiangiogenic therapy in gliomas.

Acquired resistance

Compensatory activation of angiogenic pathways

Among other cancer types, GBM relapse after antiangiogenic therapy with the VEGFR inhibitor cediranib was associated with the reactivation of tumor angiogenesis, suggesting the tumor development of resistance mechanisms to evade the VEGF/VEGFR2 blockade. Compensatory upregulation of the other angiogenic factor pathways may contribute to this resistance, as indicated by increased bFGF/FGFR system in experimental tumor models and in patients with cancer. Therefore, an efficient antiangiogenic therapy may require the temporally precise targeting of multiple angiogenic pathways.

Pericyte-mediated vessel protection

Pericytes play a critical role in supporting EC function under physiologic conditions and inducing vascular abnormalities in cancer settings. Previous studies show that VEGF inhibition reduces vascularity and selectively eliminates the ECs that have no pericyte coverage, suggesting a protective role for pericytes. A further study reveals that tumor-associated pericytes secrete angiogenic factors, including VEGF, to support EC survival after antiangiogenic treatment. As such, targeting pericytes seems to enhance the efficacy of antiangiogenic therapy in a mouse model of pancreatic islet cancer, which needs to be clinically evaluated in patients with glioma.

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