Adaptive immune responses are capable to delete cancer cells by generating more specific tumor immunity and immunological memory. Toll-like Receptors (TLRs) play a key role in bridging innate and adaptive responses against cancer cells. Conversely, TLR stimulation leads the increased survival and proliferation in vitro and in vivo in a various cancer cell lines. Therefore, their role in cancer is still unresolved as there are many different studies showing contradictory results. However, other and our lab have obtained promising results by using TLR agonists in prostate cancer (PCa). PCa is the second most frequently diagnosed cancer among males worldwide and it is the sixth leading cause of cancer-related deaths. The recommended therapy nowadays for locally advanced PCa consists of surgery, long-term androgen deprivation therapy in combination with radiotherapy (RT). While RT is one of a mainstay option in treatment of prostate cancer (PC), radio-resistance (RdR) and relapse remain unsolved clinical problems. Then additional approaches are needed to determine the optimal combination of chemo-and radio-therapy whose synergistic effect culminate to tumor immune-rejection. To this purpose, the main task of the present research project is to demonstrate that TLR agonists and radiotherapy, all failing as mono-therapy in the most aggressive types of PCa, might synergistically work in a combination that is the final issue addressed in this project. Responsiveness to combined treatment of the aggressive androgen-resistant PCa cell lines PC3 and DU-145 will be investigated by clonogenic and MMT assays. Impaired repair of DNA double-strand breaks (DSBs) provides the best available correlation with radiosensitivity. Thus, genes related to severe DNA damage and repair (H2AX phosphorylation, Ku70, Rad51 and BRCA2) will be analyzed to detect the effects of radiation with or without TLR agonists pre-treatment.
The expected results of this combined treatment proposed may help to ameliorate the radiotherapy outcome in PCa, as it has been shown in other cancers (Cho JH Oncotarget 2017; Yuk JM Autophagy 2010) in the attempt to design innovative therapeutic strategies for PCa.
Radiotherapy failure of PCa results from a multifactorial and heterogeneous process including a wide variety of signalling and effectors molecules that often depend on the genetic and epigenetic background.
To improve the efficacy of treatments, there is an increasing interest in combining radiotherapy with novel targeted therapies. Due to a cellular heterogeneity and stroma complexity of prostate cancer, the development of successful combined therapy, which is the convergence of more than one anti-tumor mechanism, might help to overcome radiotherapy resistance especially occurring in vivo.