Dissertation
Elucidating the mechanism of a novel chemotherapy regimen for soft tissue sarcomas
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007525
Abstract
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.
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.
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.
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.
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.
Details
- Title: Subtitle
- Elucidating the mechanism of a novel chemotherapy regimen for soft tissue sarcomas
- Creators
- Wade R. Gutierrez
- Contributors
- Rebecca D. Dodd (Advisor)David J. Gordon (Committee Member)Jon C. Houtman (Committee Member)Dawn E. Quelle (Committee Member)Christopher S. Stipp (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cancer Biology)
- Date degree season
- Spring 2024
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007525
- Number of pages
- xiii, 140 pages
- Copyright
- Copyright 2022 Wade R. Gutierrez
- Language
- English
- Date submitted
- 11/01/2022
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 122-140).
- Public Abstract (ETD)
Sarcomas are a group of tumors that develop in connective tissues such as muscle, fat, and bone. Sarcomas are difficult cancers to study and treat. There are over 100 different types of sarcomas, and some types are very rare, making it challenging to conduct large-scale clinical trials. Many sarcomas are initially treated with surgery and radiation. If the cancer recurs or spreads, chemotherapy is used. Unfortunately, little progress has been made in developing new chemotherapy treatments for sarcomas. The most effective chemotherapy treatment currently available was developed over four decades ago and only works in 15% of patients.
This dissertation outlines my work investigating a new chemotherapy regimen for soft tissue sarcomas. The treatment is a combination of two chemotherapies, gemcitabine and decitabine, that are FDA-approved and already used in the clinic. I tested the combination therapy in various mouse models of sarcoma and found that the combination is more effective than either drug alone. I also studied how the combination therapy works on a cellular level and found that gemcitabine must be given before decitabine for the treatment to work. I discovered that gemcitabine increases the effectiveness of decitabine by promoting its utilization within cancer cells. This work is a step forward in the development of new, effective chemotherapy treatments for soft tissue sarcomas and highlights a new use for decitabine in improving chemotherapy treatment.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984647258202771
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