Phase I/II Trial of the Safety and Efficacy of AE-941 (Neovastat®) in the Treatment of Non–Small-Cell Lung Cancer

Latreille, Jean; Batist, Gerald; Laberge, Francis; Champagne, Pierre; Croteau, David; Falardeau, Pierre; Levinton, Carey; Hariton, C.; Evans, William K.; Dupont, Éric

doi:10.3816/clc.2003.n.003

Cited by 54 publications

(31 citation statements)

References 14 publications

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“…[68][69][70] Some clinical trials have had promising results in gastric cancer and nonsmall cell lung cancer. 71,72 Patients with limited musculoskeletal symptoms have had improved survival in recent studies. 68 A clinical trial of MMP inhibitors in head and neck cancer has not been published, but reports in other cancers imply that broad-spectrum inhibitors will have limited clinical benefit (Table 2) because of dose-limiting musculoskeletal symptoms.…”

Section: Matrix Metalloprotease Inhibitors In Clinical Trialsmentioning

confidence: 99%

Matrix metalloproteases in head and neck cancer

Rosenthal¹,

2006

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Matrix metalloproteases (MMPs) are a collection of enzymes capable of cleaving extracellular matrix components, growth factors, and cell-surface receptors. MMPs modulate most aspects of tumorigenesis and are highly expressed in cancer compared with normal tissues. Preclinical studies have demonstrated that head and neck squamous cell carcinomas (HNSCCs) express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in mouse models decreases invasion and metastasis. However, the clinical trials for MMP inhibitors have failed to demonstrate a significant survival advantage in most cancers. The disparity between preclinical and clinical studies has led to the reevaluation of how MMP functions in cancer and the design of clinical trials for molecularly targeted agents. Mouse model data and analysis of HNSCC tumor specimens suggests that membrane type-1 MMP (MT1-MMP) may be a critical enzyme in tumor cell invasion and survival in vivo. This accumulated data provide evidence for development of selective MT1-MMP inhibitors as therapy in HNSCC.Keywords matrix metalloprotease inhibitor; MMP; extracellular matrix; head and neck cancer; squamous cell carcinoma; membrane type-1 MMP; drug development; proteases The hallmark of cancer remains regional and distant metastases. Regional metastasis in head and neck squamous cell carcinoma (HNSCC) decreases survival by almost 50%, and invasion beyond the lymph node capsule further decreases survival. 1 For tumor cells to invade and metastasize they must: (1) develop motility, (2) alter cell-cell and cell-matrix adhesion, and (3) remodel the extracellular matrix. 2 It was recognized in the 1980s that matrix metalloprotease (MMP) could degrade extracellular matrix (ECM) components and that this could potentiate local tumor invasion and metastasis. 3 A significant amount of effort has been funneled into the development of MMP inhibitors (MPIs) promote tumor angiogenesis by mobilizing or activating factors such as basic fibroblast growth factor, vascular endothelial growth factor, or transforming growth factor-beta. 15,16,18 Second, the complexity of cell types expressing MMPs in the tumor mass was appreciated ( Figure 1 ASSESSMENT OF MATRIX METALLOPROTEASES IN HEAD AND NECK CANCERMMPs consistently found overexpressed in head and neck cancer include MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, and MMP-14 (Table 1). However, MMP-1, MMP-2, MMP-9, and MT-1 MMP are most commonly identified in HNSCC and associated with disease progression. With the understanding that conflicting reports are abundant and negative studies unlikely to be published, it is possible to summarize the extensive MMP findings in HNSCC. Although most studies evaluate only one or two MMPs within a given head and neck site, studies have examined expression of multiple TIMPs and MMPs in oral cavity SCC. 12,22 Interestingly, these studies commonly identify upregulation of TIMP-1, which is associated with a poor survival. Levels of TIMP-2 are often unchanged between t...

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Section: Matrix Metalloprotease Inhibitors In Clinical Trialsmentioning

confidence: 99%

Matrix metalloproteases in head and neck cancer

Rosenthal¹,

2006

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Section: Introductionmentioning

confidence: 99%

“…Compounds that inhibit any of these steps are expected to be candidates of anti-metastatic and/or anti-invasive agents. Hence, the clinical efficacy of such invasive inhibitors in cancer chemotherapy are extensively exploited [2,3].In the screening for anti-invasive compounds from natural products, myxochelin A (1) was found to inhibit the in vitro tumor cell invasion. Herein, we describe the isolation, structure determination, synthesis and biological properties of 1.…”

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confidence: 99%

Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861†

et al. 2006

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In the screening of antitumor compounds from microbial secondary metabolites, myxochelin A was isolated from a culture broth of Nonomuraea pusilla TP-A0861. The absolute configuration was determined to be S by synthesizing both enantiomers from an L-or D-lysine derivative and comparing their specific rotations. Both enantiomers of myxochelin A showed remarkable inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells at non-cytotoxic concentrations. Keywords myxochelin A, invasion, antitumor, Nonomuraea IntroductionTumor invasion is the major cause of treatment failure and death in cancer patients. The process of invasion into the basement membrane is a cascade of sequential complex steps, mainly consisting of tumor cell adhesion, enzymatic degradation of extracellular matrix proteins, and migration [1]. Compounds that inhibit any of these steps are expected to be candidates of anti-metastatic and/or anti-invasive agents. Hence, the clinical efficacy of such invasive inhibitors in cancer chemotherapy are extensively exploited [2,3].In the screening for anti-invasive compounds from natural products, myxochelin A (1) was found to inhibit the in vitro tumor cell invasion. Herein, we describe the isolation, structure determination, synthesis and biological properties of 1. Results and Discussion Screening and Structure DeterminationThe screening method employed in this study is based on the experimental model of tumor cell invasion using Transwell cell culture chamber and Matrigel, the reconstituted basement membrane [4]. This bioassay enables the detection of compounds that inhibit cell adhesion, enzymatic degradation of extracellular matrix, or migration. While screening for anti-invasive compounds from our natural products library, significant activity was shown by myxochelin A (1, Fig. 1

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“…AE-941 (Neovastat) is derived from shark cartilage and inhibits MMP-2, -9 and -12 [90,91]. Dalteparin is a low-molecular weight heparin and inhibitor of MMP-9 [92].…”

Section: Clinical Potential Of Extracellular Matrix Research In Digesmentioning

confidence: 99%

The Extracellular Matrix in Digestive Cancer

Worthley

Giraud

Wang

2010

Cancer Microenvironment

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The extracellular components of the cancer microenvironment play a critical role in tumor initiation, progression and invasion. In this review we examine the normal formation and function of the basement membrane and extracellular matrix. We characterize the interactions between the matrix and the epithelium and explore the causes and consequences of the extracellular remodeling that accompanies carcinogenesis. Finally, we address the therapeutic possibilities of incorporating matrix as well as epithelial strategies in the management of digestive cancer.

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Phase I/II Trial of the Safety and Efficacy of AE-941 (Neovastat®) in the Treatment of Non–Small-Cell Lung Cancer

Cited by 54 publications

References 14 publications

Matrix metalloproteases in head and neck cancer

Matrix metalloproteases in head and neck cancer

Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861†

The Extracellular Matrix in Digestive Cancer

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