The Oncologist, Vol. 5, Suppl 1, 28-31,
April 2000
© 2000 AlphaMed Press
The Role of Vascular Endothelial Growth Factor (VEGF) in AIDS-Related Kaposi's Sarcoma
Keikawus Arastéha,
Alison Hannahb
a Auguste-Viktoria-Krankenhaus, Berlin, Germany;
b SUGEN, Inc., South San Francisco, California, USA
Correspondence:
Keikawus Arastéh, M.D., Auguste-Viktoria-Krankenhaus, II. Innere Abteilung, Rubensstrasse 125, D-12157 Berlin, Germany. Telephone: 011-49-30-79-03-2609; Fax: 011-49-30-79-03-2005; e-mail: arasteh{at}avk.b.shuttle.de
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Abstract
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Kaposi's sarcoma (KS) is the most common neoplasm associated with human immunodeficiency virus-1 (HIV-1) infection. KS involves the skin and mucous membranes as well as other organs and can lead to tumor-associated edema and ulcerations. Despite therapy with highly active antiviral agents, most patients with HIV-1-related KS eventually develop disseminated disease. In the treatment of KS, a strong rationale exists for the use of agents that inhibit vascular endothelial growth factor (VEGF). Angiogenesis appears to be an important feature of this disease, and recent experimental studies have demonstrated the role of VEGF and its receptors in the pathogenesis of KS. Thus, therapeutic agents that target the VEGF pathway may be an effective strategy in reducing the tumor growth and edema associated with KS. Phase I study results with SU5416, a synthetic low molecular-weight inhibitor of the VEGF-Flk-1/KDR receptor tyrosine kinase, demonstrate that this agent is well tolerated.
Preliminary results show that in a majority of patients with autoimmune deficiency syndrome (AIDS)-related disease, SU5416 clearly has biological activity (it flattens, shrinks, or dissolves lesions and reduces or resolves edema) or stabilizes the disease. Angiogenesis inhibition with SU5416 is a promising therapeutic approach in treating patients with KS, and further clinical evaluation is currently under way.
Key Words. AIDS-related Kaposi's sarcoma • VEGF • VEGF-Flk-1/KDR receptor • Angiogenesis • Angiogenesis inhibitor • Phase I clinical studies
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Introduction
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Kaposi's sarcoma (KS), the most common tumor associated with human immunodeficiency virus-1 (HIV-1) infection, develops in ~30% of patients infected with HIV-1 [1]. The lesions of this multicentric vascular neoplasm are usually purplish patches, plaques, or nodules. The tumor most frequently involves the skin and mucous membranes and can lead to tumor-associated edema and ulceration. Visceral involvement, which often leads to mortality, occurs in nearly half of KS patients [2]. Although highly active antiretroviral therapy can prolong the time to treatment failure in patients with KS [3], almost all patients with HIV-1-related (also known as epidemic) KS eventually develop disseminated disease. Progression often occurs in an orderly fashion from a few localized or widespread mucocutaneous lesions to more numerous lesions and generalized skin disease with involvement of lymph nodes, gastrointestinal tract, lungs, and other organs. Pleuropulmonary KS is an ominous sign that usually occurs late in the course of the disease, especially in those patients whose death is directly attributed to KS [4, 5].
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Pathological Characteristics of KS Lesions
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Pathologically, at least three components characterize KS lesions: A) neoangiogenesis and proliferation of spindle-shaped cells of endothelial and macrophage origin; B) cellular infiltrate represented by macrophages, lymphoid cells, mast cells, and neutrophils, and C) infection of spindle and mononuclear cells with the human herpesvirus-8 (HHV-8), also known as KS-associated herpesvirus [6]. The spindle-shaped autoimmune deficiency syndrome (AIDS)-KS cells play important roles in the development of KS lesions and are considered the "tumor cells" [7]. However, there is no direct evidence that these "tumor cells" are autonomously growing neoplastic cells rather than hyperproliferating normal cells [8]. In addition to the typical cells present, both AIDS-related and classical KS are characterized by extensive tissue edema [9]. The role of HHV-8 in the causation of KS is not completely clear. The consistent presence of this virus, which is not ubiquitous in the population as a whole, suggests its key etiological role in AIDS-related as well as classical KS lesions [8]. This virus is also associated with another unusual syndrome in AIDS patients, primary effusion lymphomas, which grow as lymphomatous effusions in the absence of an identifiable contiguous tumor mass.
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Rationale for Targeting the VEGF Signal Transduction Pathway in KS
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Angiogenesis is one of the most important features of AIDS-related KS. The spindle-shaped AIDS-KS cells have been shown to contain and secrete large amounts of vascular endothelial growth factor (VEGF) [7]. VEGF is a major regulator of both physiological and pathological neovascularization. VEGF, a relatively specific mitogen for vascular endothelial cells, elicits a pronounced angiogenic response in a variety of in vivo models. The production of VEGF by various tumor types has been demonstrated in lung [10], uterine cervix [11], head and neck [12], breast [13, 14], colorectal [15, 16], and prostate cancer [17] and in renal cell carcinoma [18]. VEGF may play a major role in the tumorigenicity and metastatic potential of these tumor types. Interestingly, VEGF was initially identified as a potent tumor-secreted vascular permeability factor [19], and recent studies have shown that two effects, stimulation of endothelial cell growth and induction of vascular permeability, may be mediated through different mechanisms [20].
Evidence suggests that VEGF and its interaction with its receptor VEGFR-2 (Flk-1/KDR) play a critical role in the pathogenesis of KS (Table 1
) [21-25]. It has been shown that VEGF is a growth factor in vitro for KS cells and that blocking the VEGF-Flk-1/KDR interaction can abolish VEGF-induced growth [24]. In this study, VEGF was found to be capable of causing a dose-responsive mitogenic and motogenic reaction in an immortal cell line derived from a KS lesion. The stimulation of these cells with a mutant VEGF that was incapable of activating Flk-1/KDR produced no proliferative response and a weak motogenic stimulation, suggesting that Flk-1/KDR is essential in transducing a proliferative signal in these cells. Further, the study demonstrated that Flk-1/KDR cooperates with another VEGF receptor, VEGFR-3, in inducing cell migration in these cells [24].
The expression of the Flk-1/KDR and VEGFR-1 (Flt-1) mRNA in small stromal vessels in and around tumors also suggests that VEGF may be an important regulator of the edema and angiogenesis seen in KS [22]. AIDS-KS cells expressed high levels of Flt-1 and Flk-1/KDR, while the normal skin of the same patients showed no expression of these receptors. In vitro, VEGF antisense oligonucleotides that block VEGF mRNA inhibited KS cell growth in a dose-dependent manner [1]. Additionally, the involvement of activated endothelial cells expressing the VEGF receptor in tumor angiogenesis and KS tumor growth is supported by studies with VEGF-derived toxins in mice. Chimeric toxins produced by the fusing of VEGF165 or VEGF121 to diptheria toxin were highly toxic to proliferating endothelial cells in vitro and substantially retarded the growth of KS tumors in mice [26].
Agents that interfere with VEGF signal transduction may also block the angiogenic activities of the Tat protein of HIV-1. This protein is released from infected T cells and appears to be angiogenic in vivo in nude and transgenic mice. Tat can mimic VEGF by specifically binding to and activating the Flk-1/KDR tyrosine kinase receptor [21, 27], a result that is consistent with the finding that VEGF does not synergize with Tat in vivo in the induction of angioproliferative KS-like lesions in nude mice [28]. In transgenic mice, Tat-induced angiogenesis is blocked by agents blocking the Flk-1/KDR receptor [21].
Recent evidence on the role of HHV-8 in the pathogenesis of KS suggests an upregulation of Flk-1/KDR in endothelial cells [23]. Infection of human primary endothelial cells with HHV-8 particles causes long-term proliferation and survival of these cells. Given that only 1%-6% of the endothelial cells in each culture were positive for the viral genome, the mechanism for the proliferative and survival advantage was determined to be an HHV-8-induced paracrine upregulation of Flk-1/KDR, causing both infected and uninfected cells to respond to VEGF [23].
Lastly, VEGF has been implicated in the mediation of tumor-associated edema [25], which can be a disabling symptom of patients with the disease. In this study, cultured AIDS-KS spindle cells and conditioned medium (AIDS-KS-CM) were tested for the ability to induce vascular hyperpermeability in animals. The AIDS-KS spindle cells and AIDS-KS-CM induced vascular hyperpermeability that was histamine independent, and this activity was blocked by anti-VEGF neutralizing antibody [25].
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Clinical Trials with Angiogenesis Inhibitors
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In clinical trials, angiogenesis inhibitors have demonstrated activity against KS. Thalidomide, a specific inhibitor of endothelial cell growth, produced a 35% partial response rate in a phase II study [29], although more than one-third of the patients discontinued the study because of toxicity. TNP-470, an antiangiogenic fumagillin analog, demonstrated an 18% partial response rate in patients with early-stage KS in a phase I study [30]. However, this intravenously administered drug has a very short half-life, with wide interpatient and intrapatient variability in pharmacokinetic studies.
Agents that interrupt the VEGF-mediated signaling pathway may be expected to have a more significant therapeutic effect in patients with KS, since these agents would be expected to interrupt the VEGF-induced pathway as well as the Tat-induced angiogenesis. Additionally, through inhibition of the vascular permeability activity, these agents may be able to specifically abrogate the KS-associated edema. SU5416, a novel synthetic compound, is a potent and selective inhibitor of the Flk-1/KDR receptor tyrosine kinase. SU5416 is under clinical evaluation for the treatment of human cancers. In mice, SU5416 was shown to decrease tumor vascularization and inhibit the growth of tumor cells derived from various tissues [31]. Phase I testing has been completed in patients with advanced malignancies and has demonstrated that SU5416 is well tolerated for chronic administration at biologically active dose levels, with a maximum tolerated dose of 145 mg/m2 [32]. In this study, patients with various advanced tumors, including KS and other malignancies, showed stable disease after being treated for six months [32].
A multicenter, dose-escalating study of SU5416 in patients with cutaneous AIDS-related KS is currently under way. The primary objective is to evaluate the safety and tolerability of escalating doses of SU5416 in patients with AIDS-related KS. The secondary goals are to establish pharmacokinetic and virological interactions with other HIV therapies as well as to evaluate the antitumor effects. Plasma levels of SU5416 and its metabolites, protease inhibitor levels, serial CD4+ counts, and virological loads will be measured in all patients. The study plans to enroll 30 HIV-positive adults of either gender with biopsy-proven KS that has not responded to or has progressed with standard therapy (Table 2). Patients must have five measurable lesions (
10 mm), KS-related generalized edema, or edema of the extremities without evidence of active lesions. Patients with symptomatic pulmonary KS are not eligible for the study. SU5416 will be administered intravenously twice weekly, with successive cohorts to receive 65-145 mg/m2 (Table 3). Measurements of lesion size, and extent of edema, as well as investigator and patient global assessments are performed at four-week intervals; response categorization is based on standard AIDS Clinical Trial Group (ACTG) criteria together with clinical parameters of response (such as decreased edema or improved performance status). To date, 20 patients with KS have been enrolled in the study. Among the first 18 assessable patients, 11 showed evidence of biological activity that includes flattening, shrinkage, or dissolution of lesions and reduction or dissolution of edema [33]. Pain reduction and increased mobility were reported by individual patients showing response. With the current doses, no dose-limiting toxicity was observed. Individual patients treated at the higher doses reported headaches, which decreased after multiple doses.
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Conclusions
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The reviewed data provide clear evidence that VEGF plays a major role in the pathogenesis of AIDS-related KS. Preliminary results of a phase I study indicate that SU5416, a novel selective inhibitor of Flk-1/KDR receptor tyrosine kinase, appears to have significant biological activity in treatment-refractory AIDS-related KS. SU5416 is well tolerated at doses of 145 mg/m2, with no dose-limiting toxicities at that level. These results support the progression of SU5416 into phase II studies in patients with therapy-refractory AIDS-related KS.
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accepted for publication February 19, 2000.
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Abstract
Introduction
