From Bench to Bedside Clinical Antiangiogenesis Trials

Numerous clinical studies have been initiated to test anti-angiogenic strategies on various malignancies employing synthetic as well as naturally occurring anti-angiogenic compounds. Over 80 anti-angiogenic agents are currently evaluated in clinical trials having enrolled over 10 000 patients [148]. Several of these trials recruit patients with brain tumors (at the time of writing this article an internet search revealed 14 ongoing trials; sources: http:// www.cancer.gov/clinical_trials; http://www.clinical-trials.gov; http://www.virtualtrials.org/index.cfm) targeting different pathways (see also Table 15.1) (see review [149]). Current reports from phase I and II clinical trials conclude that anti-angiogenic agents are well tolerated [150,151]. However, despite promising results obtained in experimental tumor models, none or only limited therapeutic effects have been reported from clinical trials. Differences in tumor vasculature in humans and animals as well as the use of tumor models established from cell lines which seldom resemble the molecular and morphological hetero-genous composition of primary tumors may be reasons for this discrepancy. The use of transgenic

FIGURE 15.1 Schematic representation summarizing current strategies for anti-angiogenic tumor therapy. The most promising approaches some of them in clinical trial (see Table 15.1) target the hypoxic tumor cell population by inhibition of different steps in the HIF signaling pathway as well as by inhibition of different angiogenic pathways in endothelial cells. See Plate 15.1 in Color Plate Section.

FIGURE 15.1 Schematic representation summarizing current strategies for anti-angiogenic tumor therapy. The most promising approaches some of them in clinical trial (see Table 15.1) target the hypoxic tumor cell population by inhibition of different steps in the HIF signaling pathway as well as by inhibition of different angiogenic pathways in endothelial cells. See Plate 15.1 in Color Plate Section.

tumor models may be one of the means to improve experimental testing of therapeutic approaches. Moreover, combination therapies with established conventional treatment regimens have been suggested to enhance therapeutic potential.

Combined Therapeutic Strategies in Anti-angiogenic Tumor Treatments

Several lines of evidence indicate that a multimodal approach is necessary to optimize clinical efficacy of anti-angiogenic treatments as resistance might develop over time in particular when used as monotherapies [152]. As outlined above, the regulation of tumor-associated angiogenesis involves a complex and intricate interplay of different molecular and cellular players. To increase the efficacy of anti-angiogenic strategies, these pathways need to be targeted simultaneously.

Moreover, although anti-angiogenic therapy targets genetically stable endothelial cells in the tumor vasculature, genetic alterations that decrease the vascular dependence of tumor cells can decisively influence the therapeutic response. Tumors represent heterogeneous cell populations as a consequence of genetic instability which is a hallmark of malignancy [153,154]. Accumulative acquisition of specific genetic alterations is implicated in tumor progression. Glioblastomas, for example, arise either de novo (primary glioblastoma) or by progression from a low-grade astrocytoma (secondary glioblastoma). Epidermal growth factor receptor overexpression and p53 mutations have been specifically associated with primary and secondary glioblastomas, respectively [155]. Interestingly, glioma progression in vivo

TABLE 15.1 Current Clinical Trials Employing Angiogenesis Inhibitors for Treatment of Malignant Gliomas

Mechanism

Therapeutic compound

Phase

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