Investigating couplet strategies incorporating 4 pillars of cancer therapy
This dissertation, and accompanying research, is the work of studies designed to rationalize combination strategies to combat cancer. Among central “pillars” of cancer therapy, chemotherapy, molecularly targeted therapy, radiation therapy, and immunotherapy are the focus in this research. From a comparative and translational perspective, these research aims include not only the treatment of companion animals with cancer, but also forge the development of strategies that may provide benefit for human cancer patients. While the translation of our findings into people is not eminent, this mindset for potential translation helped shape our research investigations with integrated methodology to enhance the likelihood of benefiting companion animals with cancer, and possibly even people. Chapter I entails a review of the past and current literature regarding target-based radiosensitization strategies. Here we also present some of the clinical presentations of companion animal cancers that are commonly treated with radiotherapy and highlight the utility of companion animal models for improving the predictive value of radiotherapy investigations. The material reviewed in this section creates a solid foundation for the current knowledge surrounding combination strategies involving radiotherapy and helps prelude our use of radiotherapy in some of the subsequent chapters. Chapter II addresses the issue of disease stratification in dogs with urothelial carcinomas. In male dogs specifically, uroepithelial cancers include invasive urothelial carcinoma and prostate carcinoma. The inability to distinguish invasive urothelial carcinoma involving the prostate from prostate carcinoma results in indiscriminate clinical management strategies that could be suboptimal as first-line chemotherapy options differ in people. Here we investigate if prostate specific membrane antigen (PSMA) can be used to differentially characterize uroepithelial tumors in dogs. Chapter III introduces the procaspase-3 activator, PAC-1, which can selectively induce apoptosis in cancerous cells by leveraging the overexpression of procaspase-3. Exploiting procaspase-3 overexpression by cancer cells is thought to explain why PAC-1 can synergize with chemotherapeutics, which has been demonstrated in several prior original research articles. This chapter focuses on the clinical application of a promising combination of PAC-1 with a conventional chemotherapeutic, doxorubicin, for managing canine pulmonary metastatic osteosarcoma. We have also sought to rationalize the exploration of PAC-1 with radiotherapy in Chapter IV. The effect of PAC-1 on proteins involved in DNA damage response and repair are investigated and procaspase-3 expression is assessed in canine cancers that are commonly treated with radiotherapy. Chapter V investigates immune-stimulating radiotherapy in combination with a TLR9 agonist (CpG ODN 2395), an innate immune system stimulant, in the context of canine osteosarcoma. Here we aim to elicit radiation-induced immunogenic cell death and induce an in situ vaccine effect by administering CpG ODN 2395 intratumorally. The resultant immune response may then exert body-wide immunosurveillance to delay or prevent metastatic progression.
Cancer, Chemotherapy, Targeted Therapy, Radiotherapy, Immunotherapy
University of Illinois - Urbana-Champaign
Networked Digital Library of Theses and Dissertations
University of Illinois at Urbana-Champaign