Title: Targeting stress pathways for prostate cancer treatment
1. Purpose: The aim of this project is to evaluate the potential of interfering with stress signaling pathways in prostate cancer (PCa) cells as a novel form of therapy. In that context, we aim to evaluate the therapeutic potential of several key factors that regulate stress pathways in prostate cancer, as well as test the efficacy of a small molecule stress signaling inhibitor and a nutritional supplement as agents that can block disease progression and drug resistance. Our earlier studies have shown that these strategies are effective to inhibit PCa progression in vitro and in vivo using immune-deficient animal models. In this project, we will extend these results to syngeneic PCa model, which features full murine immunity and comprehensive stroma environment for tumor progression.
2. Distress: This project includes surgical procedures such as castration and intra-prostatic injection which can cause severe post-surgical pain and distress to animals. In addition, some engineered tumor cells may have metastatic potential that can cause severe distress to animals.
3. Expected benefit: Our hypothesis is that the key regulators of stress pathways (including heat shock response (HSR) and unfolded protein response (UPR) pathways) will serve as therapeutic targets in mouse models of PCa; when we inhibit their expression by gene knockout or knockdown, we will see significant decrease in tumor take rate and tumor growth. In addition, we hypothesize that small molecule inhibitors and a novel nutritional supplement that we will utilize will decrease tumor burden in the same model system. To test the validity of our hypothesis, we will use syngeneic mouse models that have a complete and functional immune system, which is particularly relevant when studying the process of tumor progression and drug response. In this project, engineered murine prostate cancer cell lines MyC-CaP, TRAMPC-1, RM-1, TRAMP-C2, or RM-9 will be allografted (subcutaneously or orthotopically) to FVB/N and C57BL/6 mice respectively, followed by anti-cancer drugs treatment (alone or in combination) and monitoring of tumor progression. In addition, we will explore the potential role of the UPR and HSR pathways as regulators of castration-resistant PCa (CRPC), the advanced form of PCa, using castrated FVB/N mouse model (allografted with MyC-CaP cells). We expect that the results generated in this project will significantly improve our understanding about the roles of stress pathways in PCa progression and may provide proof-of-principle for novel PCa therapies.
4. Number of animals, and what kind: This project will use 2081 male FVB mice, 780 C57BL/6, and 190 male NSG mice.
5. How to adhere to 3R: The number and use of the animals are planned and designed strictly following the guidelines of 3R principles to minimize the use of animals. The experimental procedures may cause moderate distress and temporal severe pain to the animals. To enhance the animal welfare and minimize the severity, we will use enrichment in cages, clinical/severity score sheet, appropriate analgesic treatment and appropriate anesthesia.
2. Distress: This project includes surgical procedures such as castration and intra-prostatic injection which can cause severe post-surgical pain and distress to animals. In addition, some engineered tumor cells may have metastatic potential that can cause severe distress to animals.
3. Expected benefit: Our hypothesis is that the key regulators of stress pathways (including heat shock response (HSR) and unfolded protein response (UPR) pathways) will serve as therapeutic targets in mouse models of PCa; when we inhibit their expression by gene knockout or knockdown, we will see significant decrease in tumor take rate and tumor growth. In addition, we hypothesize that small molecule inhibitors and a novel nutritional supplement that we will utilize will decrease tumor burden in the same model system. To test the validity of our hypothesis, we will use syngeneic mouse models that have a complete and functional immune system, which is particularly relevant when studying the process of tumor progression and drug response. In this project, engineered murine prostate cancer cell lines MyC-CaP, TRAMPC-1, RM-1, TRAMP-C2, or RM-9 will be allografted (subcutaneously or orthotopically) to FVB/N and C57BL/6 mice respectively, followed by anti-cancer drugs treatment (alone or in combination) and monitoring of tumor progression. In addition, we will explore the potential role of the UPR and HSR pathways as regulators of castration-resistant PCa (CRPC), the advanced form of PCa, using castrated FVB/N mouse model (allografted with MyC-CaP cells). We expect that the results generated in this project will significantly improve our understanding about the roles of stress pathways in PCa progression and may provide proof-of-principle for novel PCa therapies.
4. Number of animals, and what kind: This project will use 2081 male FVB mice, 780 C57BL/6, and 190 male NSG mice.
5. How to adhere to 3R: The number and use of the animals are planned and designed strictly following the guidelines of 3R principles to minimize the use of animals. The experimental procedures may cause moderate distress and temporal severe pain to the animals. To enhance the animal welfare and minimize the severity, we will use enrichment in cages, clinical/severity score sheet, appropriate analgesic treatment and appropriate anesthesia.