open access: Integrin Inhibitors as a Therapeutic Agent for Ovarian Cancer (note also reference to Avastin)

Introduction

Ovarian cancer is a highly metastatic disease characterized by widespread peritoneal dissemination and ascites and is the leading cause of death from gynecologic malignancies. It is often diagnosed at a late stage after tumor cells are disseminated within the peritoneal cavity. Despite aggressive treatments which consist of surgical cytoreduction and chemotherapy, more than two-thirds of all patients succumb to the disease within 5 years [1]. The initial step of ovarian cancer metastasis is that cancer cells, detached from the ovarian surface epithelium, attach to the layer of mesothelial cells that line the inner surface of the peritoneum. Several integrins have been identified as important mediators of ovarian carcinoma metastasis to the mesothelium, suggesting that integrin inhibitors could be a new therapeutic strategy to prevent cancer cells from attaching onto the peritoneal cavity. During the last 10 years, novel insights into the mechanisms that regulate cell survival as well as cell migration and invasion have led to the development of novel integrin inhibitors for cancer treatments [2]. In this short review, we describe the critical roles of integrins during the metastatic process of ovarian carcinoma and discuss the potential of integrin inhibitors as a new therapeutic agent for the treatment of ovarian cancer.

2. Biology of IntegrinThe role of integrins in cell migration and invasion is one of their most studied functions in tumor biology [3, 4].....

    Table 1: Candidate integrin inhibitors for ovarian cancer treatment.

6. Conclusion:

Recognition of the need for cytoreduction along with the evolution of surgical techniques and the establishment of chemotherapy regimens through multiple clinical trials allows a majority of ovarian cancer patients to achieve “disease-free” status after the initial treatment. One of the major disappointments with the current ovarian cancer treatments is failure to achieve a complete cure, even in optimally debulked or chemosensitive patients. The establishment of efficacious consolidation or maintenance therapies would be a powerful tool for improving the miserable outcomes of patients with advanced-stage disease.The biological behavior of ovarian carcinoma is unique, differing from the classic and well-studied pattern of hematogenous metastasis found in most other cancers. Once ovarian cancer cells have detached as single cells or clusters from the primary ovarian tumor, they are carried by the physiological movement of peritoneal fluid and finally metastasize to the peritoneum and omentum, suggesting that the attachment of cancer cells onto the mesothelial cells covering the basement membrane is the initial key step in metastasis. Bevacizumab has already shown significant utility in ovarian cancer treatment not only in combination with current chemotherapy but also as a single agent, indicating that antiangiogenic therapy has considerable promise. Given that targeting integrins can affect not only the diverse functions of tumor cells, including adhesion, migration, invasion, proliferation, and survival, but also tumor microenvironments, especially the angiogenic endothelial cells, integrin inhibitors obviously have the potential for clinical use in the near future. Unfortunately, although several clinical trials have been attempted against ovarian cancer, no integrin inhibitor has shown sufficiently promising efficacy to progress to further clinical investigation; the agents targeting only a single integrin, such as αvβ3 and α5β1, failed to show evident clinical benefits in metastatic cancer treatment. In cancer progression, more than one integrin pathway is involved. For example, even if inhibition of the function of α5β1-integrin as a fibronectin receptor could be adequately achieved, the other integrins, such as αvβ3 or α3β1, would eventually compensate for its function. Therefore, a combination of different integrin receptor pathways is likely to be more effective in the clinical setting and should be explored for the future clinical application.
Collectively, although there remain many questions and challenges, integrin-targeted therapies continue to be a promising approach to improve the outcomes of women with ovarian cancer.