Effectiveness of an ADAM10 inhibitor as a radio-sensitizer to improve the treatment of cervical cancer

MSc (Applied Radiation Science and Technology), North-West University, Mahikeng Campus

Cervical cancer is the third most common type of cancer in women in developing countries with around 570 000 cases and 311 000 deaths recorded worldwide in 2018. In South Africa, over 90% of the cases are related to human papillomavirus (HPV) infection and annually, 5 743 new cases and 3 027 deaths are registered. Surgery, external beam therapy and chemotherapy are the standard treatments of cervical cancer, where combined therapy increases the survival rate of the patients. Though early stage cancer is curable, the median overall survival in cases of an advanced, recurrent disease is just over a year. Due to a lack of regular screening in developing countries, cervical cancer is often only detected at an advanced stage and therapy is not always available. Thus, there is an urgent need to improve current treatments and develop new strategies to treat cervical cancer. The goal of this dissertation was to determine the effectiveness of a disintegrin and metalloproteinase (ADAM10) inhibitor as a radiosensitizer for the treatment of cervical cancer. Inhibition of ADAM10 has been considered as a promising novel targeted cancer treatment strategy due to its role in the shedding off of a number of substrates that drive cancer progression. In addition, due to its role in the radiation response (RR) and Notch signaling pathway, blocking ADAM10 could enhance the effectiveness of radiation therapy (RT). In this dissertation, we successfully optimized the migration, apoptosis and invasion assay. Based on our results, we could conclude that the deregulation of ADAM10 activity by GI254023X (GI) had an effect on the migration of the Hela cells since it slowed down the gap closure. However, only one repeat was performed due to COVID 19 restriction. In contrast, no effect of GI on the invasion of the cervical cancer cells was seen. Results of the CSA assay were unclear and need to be repeated in the future to make a conclusion on the effect of GI on colony formation. Finally, a trend was seen to increase the apoptosis of Hela cells when control was compared to 2Gy+GI, which was not visible when control was compared with 2Gy only. However, when 2Gy was compared to 2Gy+GI, no significant differences were seen in living or apoptotic cells. Combined therapy of GI and RT had no increased inhibitory effects compared to single therapy in any of the assays studied. Therefore, based on our results, we could not conclude that GI254023X functions as a radiosensitizer for cervical cancer.

Masters