Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model

<p>Abstract</p> <p>Background</p> <p>Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions <it>in vitro </it>in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays.</p> <p>Methods</p> <p>One family of peptides with high activity is derived from the α-fibrils of type IV collagen. Based on the results from the <it>in vitro </it>screening, we have evaluated the ability of a 20 amino acid peptide derived from the α5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed <it>in vivo </it>angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line.</p> <p>Results</p> <p>Pentastatin-1 decreased the invasion of vessels into angioreactors <it>in vivo </it>in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density <it>in vivo </it>in a small cell lung cancer xenograft model.</p> <p>Conclusions</p> <p>The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer.</p

Clinical Efficacy and Safety of Bevacizumab Monotherapy in Patients with Metastatic Melanoma: Predictive Importance of Induced Early Hypertension

Background: VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Methods and Findings: Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12–49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Conclusion: Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab

Lymphatic vessels regulate immune microenvironments in human and murine melanoma

Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment

A novel eGFP-expressing immunodeficient mouse model to study tumor-host interactions

A NOD/Scid mouse expressing enhanced green fluorescent protein (eGFP) is described, in which human and mouse tumors marked with red fluorescent protein can be established in vivo, both at subcutaneous and orthotopic locations. Using light microscopy as well as multiphoton confocal microscopy techniques, we visualized in detail the intricate colocalization of tumor and host cells in situ. Moreover, using fluorescence-activated cell sorting (FACS), we were able to completely separate the host cells from the tumor cells, thus providing a system for detailed cellular and molecular analysis of tumor-host cell interactions. The fact that tumor and host cells can be reliably identified also allowed us to detect double-positive cells, possibly arising from cell fusion events or horizontal gene transfer. Similarly, the model can be applied for the detection of circulating metastatic cells and for detailed studies on the vascular compartments within tumors, including vasculogenic mimicry. Thus, the model described should provide significant insight into how tumor cells communicate with their microenvironment.—Niclou, S. P., Danzeisen, C., Eikesdal, H. P., Wiig, H., Brons, N. H. C., Poli, A. M. F., Svendsen, A., Torsvik, A., Enger, P. Ø., Terzis, J. A., Bjerkvig, R. A novel eGFP-expressing immunodeficient mouse model to study tumor-host interactions

Baseline Demographic and Clinical Characteristics of Patients.

<p>Abbreviations: LDH, lactate dehydrogenase; ULN, upper limit of normal; WHO, World Health Organization.</p

Patterns of response to treatment with bevacizumab monotherapy in metastatic malignant melanoma patients.

<p>Panel A shows the best overall response for 32 patients who had undergone at least one tumor assessment measured as the change from baseline in the sum of the largest diameters of each target lesion. Three patients progressed clinically and/or biochemically before first tumor assessment, and are not shown. Negative values indicate tumor shrinkage, and the dashed lines indicate the threshold for a partial response (PR) and progressive disease (PD), respectively. Panel B shows the duration and characteristics of the responses in each patient.</p

Computed tomography showing partial responses in three different patients at baseline and at 12 months.

<p>Panel A shows ovarian metastases in a 43 years old woman. Panel B shows lung metastases in a 50 years old man. Panel C shows liver metastases and pleural effusion (*) in a 70 years old man. Arrows show the largest diameter of the lesions.</p

Study flow diagram.

<p>Between April 2005 and August 2009, 52 patients with metastatic melanoma were screened. Thirty-five of those patients were eligible according to inclusion criteria and received the study drug.</p