Recent Patents on Anti-Cancer Drug Discovery, 2007, 2, 73-78


New Perspectives in the Treatment of Melanoma: Anti-Angiogenic and Anti-Lymphangiogenic Strategies Floriana Facchetti, Elena Monzani and Caterina A.M. La Porta1,* Department of Biomolecular Science and Biotechnology, University of Milan, Milan 20133, Italy Received: December 27, 2005; Accepted: September 22, 2006; Revised: October 31, 2006

Abstract: Melanoma is a significant, worldwide growing public health burden. Single-agent chemotherapy or immunotherapy remains the treatment of election for this disease when systemic therapy is offered. Malignant melanoma of the skin is distinguished by its capability to early metastatic spread by means of lymphatic vessels to regional lymph nodes. Herein new accomplishments on the role of lymphangiogenesis and of angiogenesis in cutaneous melanoma will be discussed, together with the possible application of these discoveries in developing prognostic and therapeutic tools in melanoma metastasis. Furthermore, the present review will summarize the main angiogenic inhibitors reported in the recent patents (2003-2005), with special emphasis on the aspects which have important implications for the prognosis and the treatment of human melanomas.

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Keywords: Melanoma, angiogenesis, lymphangiogenesis. INTRODUCTION Malignant melanoma incidence is increasing in the US, Europe and Australia [1-4]. Surgery remains the cornerstone of treatment for patients with loco-regional disease. However, only a few patients with advanced disease may be cured by surgery, and the majority of patients die [5, 6].

oxygen and nutrients for malignant tumor growth, invasion, and metastasis [12]. Whereas blood vessel growth is tightly controlled under physiological conditions, tumor progression is frequently associated with the acquisition of an angiogenic phenotype, which in turn is associated with a switch in the balance of pro- and antiangiogenic factors. These factors may be specific for distinct tumor types and tumor localizations, and may be altered during tumor progression [13].

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Bayer describes dacarbazine, which belongs to the group of drugs called alkylating agents, used as standard of melanoma care for many years. Response rates of 7-13% have been reported in recent large phase III trials, with a further 15-28% of patients having stable disease [7,8]. However, few responses are longstanding.

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A number of randomised trials failed to show a survival advantage for combination therapy over single-agent treatment [9-11]. Combination therapy is associated with an increased response rate, but also significantly increased toxicity resulting in increased numbers of hospital admissions. Immunotherapy continues to be evaluated in metastatic disease such as interferon (IFN)-alpha 2b and IL-2.

In conclusion, the majority of patients with advanced malignant melanoma requiring systemic therapy, singleagent treatment remains the treatment of choice. However, combination therapy may be warranted in certain circumstances such as when significant tumor shrinkage is a primary aim. ANTI-ANGIOGENIC AGENTS The induction of angiogenesis- the generation of new capillary blood vessels from pre-existing vessels- is generally considered as essential to ensure the supply of

*Address correspondence to this author at the Department of Biomolecular Science and Biotechnology, Celoria 26, 20133, Milan, Italy; E-mail: [email protected]

1574-8928/07 $100.00+.00

New blood vessel formation is a prominent feature of human cutaneous melanomas, indicating that these tumors have angiogenic activity [14]. The observation that cutaneous melanoma cells acquire the capacity to actively induce the growth of new blood vessels dates back to the earliest days of tumor angiogenesis research [15-17]. The clinical and prognostic significance of tumor angiogenesis for melanoma progression and metastasis, however, has remained controversial [18]. Contradictory results might be explained by the non-standardized assessments of tumor vascularity and by the variety of detection methods used to visualize tumor-associated blood vessels. Moreover, recent evidence has shown that the extent of vascularization does not discriminate between benign premalignant and malignant epithelial experimental and human skin tumors [19-21]. Importantly, none of the studies published on melanoma blood vessel quantification have included the - recently discovered - molecular markers that can be used to specifically detect blood vessels and lymphatic vessels in tissue sections [22, 23]. Many angiogenic factors were demonstrated to be synthesized by melanoma cells, including VEGF, bFGF, IL8, PDGF. The specific biological function of several of these factors has been evaluated in both in vitro angiogenic models and in xenograft models. For instance knockdown of VEGFR-2 and Tie-2 with an intrabody was demonstrated to reduce tumor growth and angiogenesis in a human melanoma xenograft model [24] and a different modulation © 2007 Bentham Science Publishers Ltd.


Recent Patents on Anti-Cancer Drug Discovery, 2007, Vol. 2, No. 1

of cytokines such as TGFbeta 1 or matrix-metalloproteinase such as gelatinase A has been shown to occur in a different manner between black and white metastasis [25]. Recently, a highly patterned system of vascular channels, lined externally by tumor cells, was observed in some aggressive human uveal and cutaneous melanomas [26]. This feature, termed “vasculogenic mimicry” was also observed after injection of melanoma cells into an ischemic micro environment that was surgically induced in the hind limbs of nude mice [27]. Formation of tubular networks were created in vitro by growing melanoma cells in three-dimensional cultures [28]. Multiple proangiogenic factors are produced by primary cutaneous melanoma cells such as VEGF whose expression appears to be increase during the transition from horizontal to vertical growth phase or metastasis [29-32], bFGF detected in metastatic and primary invasive melanomas [33], IL-8 that was found to be absent in normal epidermis and in benign melanocytic lesions, but was expressed in high levels of the majority of cutaneous melanoma [34]. Furthermore, down-regulation of endogenous angiogenesis inhibitors has been observed in several epithelial cancers, and it has been proposed that it might enhance tumor progression [34]. Thalidomide has anti-angiogenic and immunomodulatory proprieties and has been used successfully in the treatment of Kaposi’s sarcoma, myeloma and renal cancer [35,36]. Recent trials in melanoma, in which thalidomide was added to temozolomide (describes by Schering Corporation) reported a trend toward superior response rates and survival when the combination is compared with temozolomide monotherapy [37,38]. Temozolomide exerts its anticancer activity through the methylation of DNA at the O6 position of guanine residues. Considering the increase in efficacy with no increase in toxicity, temozolomide-thalidomide was recommended for further study.

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lymphatic vessels and the discovery of molecules that can drive lymphatic vessel growth [46-52]. Vascular remodelling associated with lymphangiogenesis and angiogenesis seems to involve a similar process. In response to molecular mediators, both lymphatic and vascular endothelial cells proliferate and migrate toward a stimulus as the extracellular matrix is degraded, followed by association of the endothelial cells into tube-like structures [53]. New production and realignment of the extracellular matrix and controlled apoptosis at appropriate sites are required for blood vascular and lymphatic system formation. Besides using similar processes of remodelling, blood and lymphatic vessels are closely associated in vivo. Process in understanding lymphangiogenesis has been hampered by the very similar characteristics of blood and lymphatic vessels in tissue section and it is made difficult by the lack of lymphatic-specific markers [54]. Furthermore, more accurate and simplified lymphatic vessel identification has recently been made possible by the discovery of molecules that are specifically expressed by lymphatic endothelium. Vascular endothelial growth factor receptor-3 (VEGFR-3) is predominantly expressed on lymphatic endothelium in normal adult tissue [55, 56] (Fig. 1). In particular, VEGF-C and VEGF-D members of VEGF family of secreted glycoproteins have been identified as regulators of lymphangiogenesis in mammals [56] (Fig. 1). The receptor for VEGF-C and -D is VEGFR-3 [57] (Fig. 1). The lymphatic receptor for hyaluronan, LYVE-1, has been reported to be a specific marker of lymphatic vessels and is thought to function in transporting-hyaluronan from the tissue to the lymph [58, 59, 60]. The transcription factor Prox 1 although required for lymphatic vessel development and expressed on lymphatic endothelium [61], is also expressed in other cell types and tissues, including hepatocytes and liver [62] and lens tissue [63], and is therefore of limited use immunohistochemically to identify lymphatic vessels. Podoplanin and desmoplakin have been reported as markers for lymphatic endothelium, but they also react with other cell types [6469]. In summary, a more extensive range of markers for lymphatic endothelium is now available: it should be of aid in defining the role of lymphatic vessels in tumor biology.

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Lenalidomide (CC-5013) or Revlimid described by Calgene Corporation is a potent analogue of thalidomide that produces T-cell stimulation and has shown single-agent activity in melanoma [39,40].

MEDI-522 is a humanised monoclonal antibody to alphaVbeta3 integrin [41,42], and a randomised phase II trial of dacarbazine and MEDI-522 has completed accrual and the results are awaited. Semaxanib (SU5416) is a selective inhibitor of VEGF receptor 2 (VEGFR-2) and kit receptor tyrosine kinase. A recent phase II study of 31 patients with melanoma showed that it is well tolerate [43]. Bevacizumab or Avastin described by Genentech is a monoclonal antibody against VEGF that has shown a significant survival advantage when combined with chemotherapy in advanced colorectal cancer [44]. A phase II trial in melanoma is ongoing and preliminary results described minimal toxicity with tumor responses [45]. LYMPHANGIOGENESIS AND MELANOMA The growth of lymphatic vessels, lymphangiogenesis, received considerable attention in the last two years, due to the identification of proteins specifically expressed on

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The metastatic spread of tumor cells is underlying cause of most cancer-related deaths and both clinical and pathological evidence confirm that the metastatic spread of tumors via lymphatic vessels to local/regional lymph nodes is an early event in metastatic disease, for many solid human tumors. In particular, the use of sentinel lymph nodes has been developed as a promising method for the diagnosis and staging of such diseases as breast cancer and melanoma [70]. An interesting open question is how tumor-associated lymphangiogenesis is regulated and whether tumor-associated lymphatic could be formed by direct vessel co-option, by sprouting and/or splitting from pre-existing lymphatic vessels in surrounding tissues or by recruitment of lymphatic endothelial cells progenitors from bone marrow. Tumor cells or emboli have to overcome a series of barriers to establish metastasis in distant organ. Multiple molecular and cellular responses initiated by a combination of various stimuli may be required for the metastatic event. These sequential processes are thought to include induction of angiogenesis

New Perspectives in the Treatment of Melanoma

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Fig. (1). VEGFs and their receptors. VEGFR-1 (Flt-1) and VEGFR-2 (KDR) have seven extracellular immunoglobulin homology domains, but in VEGFR-3 (Flt-4), the fifth immunoglobulin domain is cleaved on receptor processing into disulfide-linked subunits. VEGFR-1 and VEGFR-2 mediate angiogenesis, whereas VEGFR-3 is involved mainly in lymphangiogenesis.

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and/or lymphangiogenesis, detachment from surrounding tumor cell mass and access to blood or lymphatic vessels, survival in the circulation, random or specific arrest in the microvasculature of target organs, exit from the vessels and growth and invasion into the organs to form a metastatic focus. Since lymphatic vessels have a discontinuous basement membrane and lack of tight intraendothelial junctions [71], it is believed that it would be easier for tumor cells to enter into the lymphatic vessels rather than the blood circulation. However the importance of tumor-induced lymphangiogenesis for the spread of lymphatic melanoma is unclear. Recent experimental and clinical evidence strongly suggest that active lymphan-giogenesis is induced by tumor types, including cutaneous melanoma, and that it plays an important role in lymphatic tumor dissemination [72]. The extent of tumor-associated lymphangiogenesis can serve as a powerful prognostic tool for the evaluation of primary cutaneous melanomas. Thereby a better understanding of the lymphatic system may provide new insight into the biology of tumor metastasis as well as novel prognostic and therapeutic tools in metastatic disease. Transgenic mice overexpressing VEGF-C or xenotran-plantation of VEGF-C expressing tumor cells into immuno-deficient mice have demonstrated a role for VEGF-C in tumor lymphangiogenesis and the subsequent formation of lymph node

metastasis [73]. However, there is at present little evidence for lymphangiogenesis in human tumors, which is at variance with the data obtained in animal’s models. Nonetheless, the striking correlation between levels of VEGF-C in primary tumors and lymph node metastasis exists. This suggests that VEGF-C may activate pre-existing lymphatics which then become actively involved in tumor cell chemotaxis, intralymphatic intravasation and distal dissemination. The role of VEGF-C in human tumor metastasis is therefore likely to involve lymphoangiogensis as well as its capacity to induce activation of pre-existing lymphatic endothelium. Interestingly, overexpression of VEGFR-3-Ig by stable transfection of a human lung cancer cell line selected for a highly metastatic phenotype expressing high levels of endogenous VEGF-C was demonstrated to inhibit tumor lymphangiogenesis and lymph nodes metastasis when the cells were grown as tumors in immunodeficient mice [74,75]. On the other hand, preexisting lymphatics were not affected by the VEGFR-3-Ig treatment, suggesting that newly formation vessels are necessary for lymphatic metastasis [76]. VEGF-D expression was shown to be up-regulated in human melanomas compared with melanocytes [76]. The incidence of intratumoral lymphatics (LYVE positive) was significantly higher in metastatic melanomas and correlated with poor-disease-free


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survival [76]. Many questions remain, however, to be addressed. Firstly, is to study how tumor-associated lymphangiogenesis is regulated. Tumor-associated lymphatics could be formed by direct vessels co-option, by sprouting and/or splitting from pre-existing lymphatic vessels in surrounding tissues or by recruitment of lymphatic endothelial cells (LEC) progenitors from bone marrow. The existence of LEC progenitors has been suggested in avian embryogenesis [77]. VEGFR-3+/CD34+ endothelial precursors have also recently been identified from human foetal liver and blood and upon culture they were shown to express both vascular and lymphatic EC markers [78]. Considering that the lymphatic vessels have a discontinuous basement membrane and lack tight intraendothelial junctions, it is believed that it would be easier for tumor cells to enter the lymphatic vessels rather than the blood circulation lymphatic onces. Experimental evidences have been obtained suggesting that LECs could attract tumor cells by secreting chemokines and therefore actively promote lymphatic metastasis. Secondary lymphoid chemokine (CCL21) is highly expressed in lymph nodes specifically in endothelial cells of high endothelial venules and T cell-rich areas and also in the lymphatic endothelium of multiple organs [79]. CCL21 has been shown to be chemotactic for naïve T cells and it is implicated in T lymphocyte homing and in the migration of antigen-stimulated dendritic cells into secondary lymphoid organs [79]. It has been shown recently that CCR7 and CXCR4 receptors of CCL21 and CXCL12 respectively are highly expressed in human breast cancer cells. Their ligands exhibit peak levels of expression in regional lymph nodes, bone marrow, lung and liver which represent the first destinations of breast cancer metastasis [80]. Furthermore the overexpression of CCR7 by B16 murine melanoma cells enhanced the incidence of lymph node but not lung metastasis when the tumor cells were implanted into the footpads of mice. CCR7 mediated increase of lymphatic metastasis was also shown to be completely suppressed by treatment with neutralizing anti-SLC antibodies [81].

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lymphatic endothelium and VEGF-C induces proliferation migration and invasion [87-89]. CURRENT & FUTURE DEVELOPMENTS Melanoma represents a significant and growing public health burden worldwide. However, single-agent chemotherapy or immunotherapy remains the treatment of election choice when systemic therapy is offered. Malignant melanoma of the skin is distinguished by their propensity for early metastatic spread by way of lymphatic vessels to regional lymph nodes. we think that the topic of the present review, in which are discussed the new acknowledgments regarding to the role of lymph-angiogenesis and of angiogenesis in cutaneous melanoma and the possible use of these discoveries in prognostic and therapeutic tools in melanoma metastasis, have important implications for the prognosis and the treatment of human melanomas in the near future. REFERENCES [1]


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Potential inhibitors of the VEGFR-3 include mAbs that block the binding of VEGF-C and VEGF-D to VEGFR-3. A neutralising VEGF-D mAb that blocks binding to both VEGFR-2 and VEGFR-3 was demonstrated to inhibit angiogenesis, lymphangiogenesis and metastatic spread via the lymphatics in a mouse tumor model that secreted recombinant VEGF-D [82]. Another approach would be to sequester VEGF-C and VEGF-D with a soluble version of the extracellular domain of VEGFR-3 [83]. An attracting approach for inhibiting VEGFR-3 signalling pathway would involve identification of orally active small molecules that interfere with the binding of VEGF-C/D to this receptor [84]. Small molecule inhibitors of the tyrosine kinase catalytic domain of VEGFR-3 could be useful for blocking this signalling pathway, showing promise anti-angiogenic effect [85, 86]. Recently inhibitors of the VEGFR-3 signalling pathway may be useful anti-cancer therapeutics via mechanisms other than blocking lymphangiogenesis. For example, Kaposi’s sarcoma is characterized by the presence of a core of spindle-shaped cells that may be derived from

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Facchetti et al.

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