Abstract
Treatment of patients with gynecologic malignancies diagnosed at advanced stages remains a therapeutic challenge. Survival rates of these patients remain significantly low, despite surgery and chemotherapy. Advances in understanding the role of the immune system in the pathogenesis of cancer have led to the rapid evolution of immunotherapeutic approaches. Immunotherapeutic strategies, including targeting specific immune checkpoints, as well as dendritic cell (DC) immunotherapy are being investigated in several malignancies, including gynecological cancers. Another important approach in cancer therapy is to inhibit molecular pathways that are crucial for tumor growth and maintenance, such as the insulin-like growth factor-1 (IGF1) pathway. The IGF axis has been shown to play a significant role in carcinogenesis of several types of tissue, including ovarian cancer. Preclinical studies reported significant anti-proliferative activity of IGF1 receptor (IGF1R) inhibitors in gynecologic malignancies. However, recent clinical studies have shown variable response rates with advanced solid tumors. This study provides an overview on current immunotherapy strategies and on IGF-targeted therapy for gynecologic malignancies. We focus on the involvement of IGF1R signaling in DCs and present our preliminary results which imply that the IGF axis contributes to an immunosuppressive tumor microenvironment (TME). For the long term, we believe that restoring the TME function by IGF1R targeting in combination with immunotherapy can serve as a new clinical approach for gynecological cancers.
Highlights
Treatment of Gynecologic Malignancies: Current AdvancesEndometrial cancer is the most common gynecological malignancy in the developed world and the second most common in developing countries [1, 2]
This study provides an overview on current immunotherapy strategies and on Insulin-Like Growth Factor (IGF)-targeted therapy for gynecologic malignancies
We focus on the involvement of IGF1 receptor (IGF1R) signaling in dendritic cell (DC) and present our preliminary results which imply that the IGF axis contributes to an immunosuppressive tumor microenvironment (TME)
Summary
Endometrial cancer is the most common gynecological malignancy in the developed world and the second most common in developing countries [1, 2]. The mTOR inhibitors everolimus and temsirolimus demonstrated antitumor activity in endometrial cancer, with greatest sensitivity in cells with PIK3CA or PTEN mutations [4, 5]. Another important agent is bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), which was shown to be effective in endometrial cancer [6]. Recent Phase 3 studies found that adding bevacizumab to standard chemotherapy improved overall survival and progression-free survival in women with advanced, metastatic, or recurrent cervical cancer [10]. Barroilhet and Matulonis provides an updated overview regarding this concept which is based on tumor gene sequencing, in order to match agents targeted against specific tumor mutations regardless of the involved organ [21]
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