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BIOTEK2021-Bioteknologi for verdiskaping

Development of novel drugs for prostate cancer therapy

Alternative title: Utvikling av nye legemidler for prostatakreft terapi

Awarded: NOK 6.4 mill.

Prostate cancer is the most common male cancer and the second most common cause of cancer related death in men. While early detection has reduced mortality from prostate cancer, there is no cure for advanced disease. Consequently, 1 in 6 men is diagnosed with prostate cancer and 1 in 30 men are expected to die from metastatic PCa in the western world. Furthermore, current treatment modalities have significant side effects. Thus, prostate cancer constitutes a major health problem, as well as a big economic challenge and novel therapeutic approaches are urgently needed. The goal of this project has been to optimize two candidates for prostate cancer therapy that were recently discovered in our laboratory and conduct studies to establish that they work in cell culture and in mouse models of human prostate cancer. The work is based on inhibiting the expression of two genes that are essential for prostate cancer growth based on our previous work. This is achieved by using nanoparticles, small spheres about 50 nm (nm is one billionth of a meter), containing small RNA molecules (siRNAs) that target the two genes. These nanoparticles are then injected directly into the circulation through a vein, or intraperitoneally, circulate in the body and find the tumors, and then deliver their contents which kill cancer cells. During this project, we have established and optimized the nanoparticle based system in our laboratory, and applied it towards two potential drug targets that we previosly identified. Through a novel screening protocol, we have found several siRNAs for each gene with greatly improved ability to target the two genes both in cell culture but also in mice against human tumors. We also found that these optimized siRNAs in nanoparticles, targeting both genes, may increase the efficacy of some treatments that are in the clinic for prostate cancer in cell culture studies. These findings now form the basis for potential development of intellectual property rights and translational applications.

Prostate cancer (PCa) remains a significant medical burden in the western world and a major cause of morbidity and mortality. In men, it is the most commonly diagnosed noncutaneous cancer and the second most common cause of cancer-related death. While ear ly detection has reduced mortality from PCa, there is no curative treatment for advanced disease. Consequently, 1 in 6 men is diagnosed with PCa and 1 in 30 men are expected to die from metastatic PCa in the western world. Furthermore, current treatment m odalities have significant side effects. Thus, PCa constitutes a major health problem, as well as a big economic challenge and novel therapeutic approaches are urgently needed. The goal of this project is to optimize two lead therapeutic agents for PCa an d to complete proof of principle studies to secure IPR which can then form the basis of preclinical in vivo proof of concept studies. The product of this project is a drug formulation composed of one or two nanoliposomal siRNAs against KLK4 and/or STAMP2. Based on our current findings, each one of these alone is expected to profoundly inhibit PCa tumor survival in vivo in preclinical models of human PCa, as well as sensitizing PCa tumors to drugs currently used in the clinic. Furthermore, we expect that c ombinatorial use of the siRNAs against these two genes will be even more effective for these end points. To our knowledge, there are no reported targets in PCa which can be knocked down by nanoliposomal siRNA delivery for a favourable biological response. Thus, both our targets and the system of delivery are unique and may afford benefits over the currently available modalities. This project will firmly assess the robustness of this proof of principle and optimize the deliverables for a possible proof of concept study.

Funding scheme:

BIOTEK2021-Bioteknologi for verdiskaping