UBC Theses and Dissertations
A TRAMP-derived orthotopic prostate syngeneic (TOPS) cancer model for investigating oncolytic viral therapy and anti-tumor treatments Lardizabal, Justin James Lardizabal
Prostate cancer is the most common non-skin malignancy and the second leading cause of cancer-related death in North American men. Patients diagnosed with localized disease are usually treated with surgery or radiotherapy; however, many of patients are diagnosed with a more advanced disease. Patients with advanced prostate cancer are primarily treated with hormone ablation therapy. Initially, most of these patients respond well to treatment; however, over time the tumor becomes unresponsive and develops into castration resistant prostate cancer (CRPC). Current therapies for patients with CRPC, which include chemotherapy, have shown little effectiveness, therefore, alternative therapies that are more effective against advanced prostate cancer and CRPC are needed. Mouse models are essential for expanding our understanding of prostate cancer initiation, development, and progression. In addition, they are vital for the pre-clinical development of new treatments for advanced prostate cancer. We developed a TRAMP-derived orthotopic prostate syngeneic (TOPS) mouse model where cells derived from a TRAMP mouse express Luciferase and are orthotopically injected into immunocompetent mice. This established mouse model will be a valuable tool when developing and screening treatments for prostate cancer. This model produces mice with a functional immune system, tumor and metastases are reliably established, tumors can be monitored during their development and after exposure to potential therapeutics with bioluminescence imaging, and tumors are produced in a short period of time.Oncolytic viral therapy offers a novel treatment for patients with advanced prostate cancer and CRPC. An ideal tumor-specific virus can preferentially infect and replicate in a tumor cell, resulting in amplification of the virus and subsequent lysis of the tumor cell while leaving the normal cells unaffected. In this study, a transcriptionally and translationally controlled oncolytic herpes virus, AU27 was used in combination with Docetaxel. The combination acted synergistically against prostate cancer cells. AU27 replication was not affected by Docetaxel, however, the combination enhanced Docetaxel activity, determined by increased apoptosis. In vivo, AU27 was effective against TOPS mouse model tumors, reducing tumor size and increasing survival. The TOPS mouse model is a novel model that can be used to assess novel therapies against prostate cancer.
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