Reliable Cancer Therapies

Location: Catholic University of Leuven, Belgium
Collaboration: Prof. Dr. Vergote & Prof. Dr. Amant

Uterine cancer is the most frequent malignancy of the female genital tract and the fourth most frequent cancer in women in the developed world. At the moment, treatment modalities for uterine cancer include surgery, chemotherapy and radiotherapy, but these are limited for primary advanced and recurrent disease leading to a poor overall survival rate of these patients. Development of new treatment strategies for uterine cancer, including endometrial cancer and uterine sarcoma, is therefore crucial. To this end, the projects described below focus on identification of new therapeutic approaches in endometrial cancer.

1. PRE-CLINICAL EVALUATION OF PHARMACOLOGICAL EFFICACY IN ENDOMETRIAL CANCER

Pre-clinical evaluation of available targeted therapies based on identification of genes and pathways commonly affected in endometrial cancer

The precise etiology of endometrial carcinomas is still unknown, but multiple genetic alterations have already been reported, including PTEN gene inactivation, KRAS and p53 mutations. Moreover, information on the effect of genetic alterations on chemosensitivity and response to available targeted treatments in endometrial cancer is rather limited.
In the current project, the focus is on the identification of specific genetic changes (including mutations, amplifications and deletions) in endometrial cancer and their effect on the clinical outcome of the disease. To this end, primary cultures of endometrial cancer are established and their response to targeted drugs as well as to chemotherapeutic agents is correlated with the genetic profile of the primary cultures. Hereby, a system to predict the response of primary tumor cultures to different types of therapies will be developed. Furthermore, primary endometrial cancer cells are used to establish a pre-clinical tumor model in mice so that the in vitro findings can be validated in vivo.

Role of placental growth factor in endometrial carcinoma and preclinical evaluation of anti-placental growth factor in endometrial cancer

Tumor growth and metastasis require the formation of new blood vessels, a process called angiogenesis. One of the key angiogenic factors involved herein is Vascular Endothelial Growth Factor (VEGF), and antitumor strategies targeting the VEGF signaling pathway are currently used in several types of cancer. Placental Growth Factor (PlGF) is a homolog of VEGF and functions as a pleiotropic cytokine involved in several aspects of tumor growth and metastasis. Most importantly, in preclinical observations it has been demonstrated that anti-PlGF also enhances the efficacy of chemotherapeutic agents without evoking side effects as observed with anti-VEGF therapy. In the current project, the role for PlGF in endometrial cancer is evaluated and the efficacy of anti-PlGF therapy is investigated in pre-clinical tumor models of endometrial cancer.

2. DEVELOPMENT OF IMMUNOTHERAPY FOR ENDOMETRIAL CANCER

Dendritic cell vaccination

Tumor cells accumulate several alterations in their genetic material which allow the immune system to recognize these tumor cells as “aberrant”. Immunotherapeutic vaccination strategies aim to instruct the patient’s immune system to destroy the tumor. Herein, vaccination with tumor antigen loaded dendritic cells is particularly promising, because dendritic cells are professional antigen presenting cells capable of inducing naïve T cell responses and, more importantly, immunological memory. Since few tumor antigens are known in endometrial cancer, efforts are put in the identification of tumor antigens to be used as targets for the dendritic cell vaccine. However, also the use of total genetic material of the patient’s own tumor will also be evaluated. Subsequently, mRNA from defined tumor antigens or total tumor derived mRNA will be used to transfect dendritic cells together with immunostimulatory molecules to enhance the dendritic cell capacity. These genetically modified dendritic cells will first be used in vitro to induce tumor-specific T cell responses as proof-of-principle, followed by the application of autologous dendritic cell vaccines in endometrial cancer patients.

Immunomodulation

During the course of tumor growth tumors cells develop mechanisms to evade attack by the immune system and a tolerogenic, immunosuppressive tumor microenvironment is established. These immunosuppressive mechanisms constitute a major hurdle for effective anti-tumor vaccination. Therefore, we are exploring which immunosuppressive mechanisms are used by endometrial cancers. We are looking at various tumor-induced (STAT3, immunosuppressive mediators, IDO, etc.) as well as immune-related (regulatory [/no-glossary]T cells[/no-glossary], myeloid-derived suppressor cells, CTLA-4, PD-1, etc.) suppressive pathways. The idea is to select the most predominantly used mechanism in endometrial cancer for further development to combine with the dendritic cell vaccine. In addition, we will also investigate the endogenous anti-tumor immune response which has been demonstrated to be continuously induced and attenuated in a cyclical pattern. The underlying hypothesis is that the efficacy of treatment could potentially be enhanced by appropriate timing of treatment with regard to the endogenous anti-tumor immune cycle.