Elucidating the mechanism of a novel chemotherapy regimen for soft tissue sarcomas
Creators: name: Gutierrez, Wade R.
Publisher: name: University of Iowa
Year: 2024
Subjects: Cancer
Decitabine
Gemcitabine
Mouse models
Sarcoma
Medicine
Chemotherapy

description: Sarcomas are a diverse group of mesenchymal tumors with limited treatment options. Over 100 histological subtypes of sarcomas have been identified to date. The rarity of individual subtypes and the heterogeneity of these cancers present unique challenges in the study and development of novel therapies. The current standard of care for advanced or metastatic disease was developed over four decades ago and has only a 15% response rate. There is a critical need to develop new, efficacious chemotherapy regimens to treat these deadly malignancies.
description: The work presented in this dissertation focuses on a novel chemotherapy regimen for the treatment of soft tissue sarcomas. This combination therapy consists of two FDA-approved chemotherapies, gemcitabine and decitabine, and was recently tested in a Phase 1 clinical trial (NCT02959164). In Chapter 1, I discuss the history of chemotherapy in cancer treatment and highlight the development, mechanisms, and clinical uses of gemcitabine and decitabine. I also explore the various subtypes of sarcomas and outline current treatment options and outcomes. Finally, I discuss the utility of animal models in the study of sarcoma biology and in preclinical drug studies.
description: Chapter 2 details the development and validation of two new allograft models of undifferentiated pleomorphic sarcoma and rhabdomyosarcoma, two of the most common forms of adult and pediatric soft tissue sarcoma, respectively. Tumor growth kinetics, histology, and immune infiltration are analyzed and compared between the primary genetically engineered tumor models and their syngeneic allograft counterparts. These data lay a foundation for the in vivo studies discussed in the following chapter.
description: In Chapter 3, I explore the efficacy and therapeutic mechanism of gemcitabine and decitabine combination therapy. Using the models of undifferentiated pleomorphic sarcoma discussed in Chapter 2, I demonstrate that the combination therapy has superior efficacy compared to monotherapy and that its therapeutic mechanism is immune-independent. Additional in vitro studies uncover a sequence-dependent mechanism wherein gemcitabine primes cells for treatment with decitabine, resulting in cell cycle arrest and apoptosis. Initial inhibition of ribonucleotide reductase by gemcitabine bolsters the effectiveness of decitabine by increasing the ratio of decitabine to endogenous deoxycytidine triphosphate. These findings demonstrate that gemcitabine and decitabine therapy is a novel effective treatment option for soft tissue sarcomas and highlights a new role for decitabine in augmenting cytotoxic chemotherapy.
description: In Chapter 4, I discuss some of the potential cellular and molecular mechanisms by which gemcitabine and decitabine may be promoting cell cycle arrest and apoptosis. I also consider why the regimen displays varying levels of efficacy across different sarcoma and carcinoma cell lines. I end this chapter and dissertation by outlining drugs that could be used in place of gemcitabine or decitabine and those that could be combined as a third member of the regimen to further increase its therapeutic benefit.