Angiogenesis

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Folkman first postulated that angiogenesis (the formation of new blood vessels from the preexisting vascular bed) is required for tumor progression.93 Initially, malignant cells derive their nutrients from the normal host vessels by diffusion, but tumor growth is limited beyond 1 to 2 mm without new blood vessel growth.94 Neovascularization is initiated by increased permeability of preexisting vessels in response to vascular endothelial growth factor (VEGF) produced by the tumor; this allows for the extravasation of plasma proteins that lay down the matrix upon which activated growth factor-secreting endothelial cells migrate. Proteolytic degradation of the extracellular matrix and basement membrane then enables endothelial cells to form new capillaries. Normally, perivascular cells are attracted and form basal lumina around the vessels, thus limiting endothelial cell proliferation and decreasing their dependence on VEGF-A. However, in tumors, pericytes have a decreased association with new blood vessels, which as a consequence are leaky due to an imbalance of appropriate proangiogenic and antiantigenic controls that control the so-called angiogenic switch. Hypoxia stimulates the tumor cells to generate proangiogenic factors, including vascular endothelial growth factor (VEGF), fibro-

blast growth factor (FGF), transforming growth factor-beta (TGF-p), and tumor necrosis factor-alpha (TNF-a). VEGF and FGF are considered the most important factors for tumor angiogenesis.

Tumor vascularization has been found to correlate with growth and metastatic potential in some tumor types, and microvessel density has been shown to be an adverse prognostic factor of distant disease and survival.95 Consequently, antiangiogenesis has been a new strategy for the development of anticancer treatment. The characterization of natural inhibitors and promoters of angiogenesis has led to the development of novel compounds that potentially interfere with various steps required for angiogenesis (Table 5.6, Figure 5.4). In principle, these approaches involve either targeting the endothelial cell, targeting activators of angiogenesis, or targeting the extracellular matrix.

Targeting the Endothelial Cell (Thalidomide, TNP-740, Endostatin, Angiostatin)

Thalidomide has been found to have immunomodulating and antiangiogenic properties by impeding VEGF- and bFGF-dependent angiogenesis through inhibition of TNF, inter-leukin (IL)-12, and IL-6 and stimulation of IL-2, interferon, and CD8+ T cells. Clinical activity has been seen in refractory multiple myeloma, myelodysplasia, Kaposi's sarcoma, renal cell cancer, colorectal cancer, and recurrent glioblas-tomas. No benefit has been demonstrated in Phase III trials of metastatic breast and head and neck malignancies. The thalidomide analogue, CC-5013, has increased potency and efficacy with less sedation, constipation, and neuropathy and has demonstrated promising activity in Phase I trials of patients with advanced solid cancers.96

TNP-470 is a potent endothelial inhibitor in vitro, and animal models have demonstrated the broadest anticancer range of any known agent. In clinical trials, TNP-470 has shown evidence of antitumor effect both as monotherapy with responses observed in relapsed or refractory malignan-cies97 and in combination with chemotherapy.98

The clinical observation that the removal of the primary tumor can lead to the rapid growth of previously dormant micrometastases led to the discovery of angiostatin and endostatin, two potent endogenous antiangiogenic agents. Endostatin is a 20-kDa C-terminal fragment of collagen XVIII found in vessel walls and basement membranes. Recombinant human endostatin inhibited endothelial cell proliferation and tumor growth in preclinical studies, and in a subsequent Phase II trial there were 23 patients with stable disease and 2 with minor responses of the 37 evaluable patients.99 Angiostatin is a 38-kDa internal fragment of plasminogen, which has subsequently been shown to induce dormancy and regression of tumor models. Angiostatin binds to ATP synthase on the surface of human endothelial cells, induces apoptosis in endothelial cells and tumor cells, inhibits endothelial migration and tubule formation, and inhibits matrix-enhanced plasminogen activation. A Phase I trial in patients with advanced cancer demonstrated that it was well tolerated, with some patients (7 of 24) achieving long-term stable disease.100

Targeting Activators of Angiogenesis

Vascular endothelial growth factor (VEGF-A), a critical regulator of physiologic angiogenesis during embryogenesis and skeletal growth, is also important in the pathologic angiogenesis of tumor growth. VEGF-A is a multifunctional cytokine expressed by many tumor cells, promoting microvascular permeability, endothelial cell migration, division, and survival, and inhibiting apoptosis. Oxygen tension/hypoxia, growth factors, oncogenes, inflammatory cytokines, and various hormones regulate the level of VEGF-A. The effects of VEGF are mediated in part by two receptor tyrosine kinases (RTKs), VEGFR-1 (flt-1) and VEGFR-2 (flk-1), which are expressed on endothelial cells. The level of VEGF-A expression in cancer cells has been found to correlate with tumor size, metastasis, poor disease free-survival (DFS), and overall survival (OS).101 Consequently, VEGF and its receptors

FIGURE 5.4. Inhibitors of angiogenesis.

FIGURE 5.4. Inhibitors of angiogenesis.

have been investigated for antiangiogenesis therapies in various malignancies. Different strategies have been designed to inhibit VEGF function, including inhibition of endogenous tumor VEGF secretion (antisense), neutralizing VEGF in the microcirculation, or preventing VEGF binding to its receptor (antibodies), and targeting subsequent signal transduction by VEGF (small molecule receptor tyrosine kinase inhibitors) (see Figure 5.4).

Ribozymes are RNA molecules that can recognize RNA sequences and cleave specific sites on other RNA molecules. Angiozyme, a synthetic ribozyme that targets the VEGFR-1 mRNA, was well tolerated in a Phase I/II study of patients with refractory solid tumors,102 and further trials are in progress. Bevacizumab (avastin) is a recombinant anti-VEGF humanized MAb,103 which, in patients with untreated metastatic colorectal cancer given in combination with chemotherapy, showed a significant increase in response rate and time to progression compared with chemotherapy alone, with a 4.7-month prolongation of overall survival.104 This result represents the first clinical validation for antiangio-genesis therapy as an effective cancer treatment, and recent similar studies in untreated advanced non-small cell lung cancer have demonstrated improved response rates and time to progression with the addition of bevacizumab.105 Finally, several different small molecules targeting VEGF receptor tyrosine kinases have been developed, each with a different selectivity profile (Table 5.7); these include SU5416 (intravenously administered), SU6668, SU11248, and PTK 787.106'107

Targeting the Extracellular Matrix

The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that mediate degradation of extracellular matrix expressed by tumor cells or stroma.108 They are synthesized as inactive zymogens (pro-MMP) and activated by proteinase cleavage. Their activity is regulated by endogenous inhibitors such as p2-macroglobulin, throm-bospondin-2, tissue inhibitors of metalloproteinases (TIMPs), and small molecules with TIMP-like domains. MMPs can promote tumor progression by increasing cell growth, migration, invasion, metastasis, and angiogenesis. Several different approaches have been developed to inhibit the activity of MMPs, including antisense mRNA or ribozyme technol-ogy.109 Integrins are a group of heterodimeric transmembrane receptors that mediate cell-cell and cell-ECM interactions. Vitaxin, a humanized derivative of a mouse LM609 MAb, was developed to inhibit the MMP-2 interaction with integrin avp3, although its instability precluded further development.110 Cilengitide (EMD 121974) is a synthetic cyclic pen-tapeptide small molecule inhibitor of avp3 and avp5, which in a Phase I trial gave prolonged stable disease in 3 of 37 patients.111 Finally, MMP enzymatic inhibitors (MMPI) have been developed. Marimastat was the first orally available MMPI and has been tested in several phase III trials in glioblastoma, breast, ovarian, and small and non-small cell lung cancers. These trials were discontinued because marimastat failed to demonstrate superiority over placebo or standard chemotherapy. However, in a Phase III placebo-controlled trial in patients with advanced gastric cancer, marimastat showed significant improvement in OS (2-year survival, 5% versus 18%) and PFS over placebo-treated patients. These benefits remained significant even after longer follow-up.112 Other MMPIs in development are listed in Table 5.7.

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