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- All Subjects: adaptive therapy
Description
Adaptive therapy utilizes competitive interactions between resistant and sensitive cells by keeping some sensitive cells to control tumor burden with the aim of increasing overall survival and time to progression. The use of adaptive therapy to treat breast cancer, ovarian cancer, and pancreatic cancer in preclinical models has shown significant results in controlling tumor growth. The purpose of this thesis is to draft a protocol to study adaptive therapy in a preclinical model of breast cancer on MCF7, estrogen receptor-positive, cells that have evolved resistance to fulvestrant and palbociclib (MCF7 R). In this study, we used two protocols: drug dose adjustment and intermittent therapy. The MCF7 R cell lines were injected into the mammary fat pads of 11-month-old NOD/SCID gamma (NSG) mice (18 mice) which were then treated with gemcitabine.<br/>The results of this experiment did not provide complete information because of the short-term treatments. In addition, we saw an increase in the tumor size of a few of the treated mice, which could be due to the metabolism of the drug at that age, or because of the difference in injection times. Therefore, these adaptive therapy protocols on hormone-refractory breast cancer cell lines will be repeated on young, 6-week old mice by injecting the cell lines at the same time for all mice, which helps the results to be more consistent and accurate.
ContributorsConti, Aviona (Author) / Maley, Carlo (Thesis director) / Blattman, Joseph (Committee member) / Seyedi, Sareh (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Life history theory offers a powerful framework to understand evolutionary selection pressures and explain how adaptive strategies use the life history trade-off and differences in cancer defenses across the tree of life. There is often some cost to the phenotype of therapeutic resistance and so sensitive cells can usually outcompete resistant cells in the absence of therapy. Adaptive therapy, as an evolutionary and ecologically inspired paradigm in cancer treatment, uses the competitive interactions between drug-sensitive, and drug-resistant subclones to help suppress the drug-resistant subclones. However, there remain several open challenges in designing adaptive therapies, particularly in extending this approach to multiple drugs. Furthermore, the immune system also plays a role in preventing and controlling cancers. Life history theory may help to explain the variation in immune cell levels across the tree of life that likely contributes to variance in cancer prevalence across vertebrates. However, this has not been previously explored. This work 1) describes resistance management for cancer, lessons cancer researchers learned from farmers since adaptive evolutionary strategies were inspired by the management of resistance in agricultural pests, 2) demonstrates how adaptive therapy protocols work with gemcitabine and capecitabine in a hormone-refractory breast cancer mouse model, 3) tests for a relationship between life history strategy and the immune system, and tests for an effect of immune cells levels on cancer prevalence across vertebrates, and 4) provides a novel approach to improve the teaching of life history theory. This work applies lessons that cancer researchers learned from pest managers, who face similar issues of pesticide resistance, to control cancers. It represents the first time that multiple drugs have been used in adaptive therapy for cancer, and the first time that adaptive therapy has been used on hormone-refractory breast cancer. I found that this evolutionary approach to cancer treatment prolongs survival in mice and also selects for the slow life history strategy. I also discovered that species with slower life histories have higher concentrations of white blood cells and a higher percentage of heterophils, monocytes and segmented neutrophils. Moreover, larger platelet size is associated with higher cancer prevalence in mammals.
ContributorsSeyedi, Seyedehsareh (Author) / Maley, Carlo (Thesis advisor) / Blattman, Joseph (Committee member) / Anderson, Karen (Committee member) / Wilson, Melissa (Committee member) / Huijben, Silvie (Committee member) / Gatenby, Robert (Committee member) / Arizona State University (Publisher)
Created2023
Description
Adaptive therapy utilizes competitive interactions between resistant and sensitive cells by keeping some sensitive cells to control tumor burden with the aim of increasing overall survival and time to progression. The use of adaptive therapy to treat breast cancer, ovarian cancer, and pancreatic cancer in preclinical models has shown significant results in controlling tumor growth. The adaptive therapy model comes from the integrated pest management agricultural strategy, predator prey model, and the unique intra- and inter-tumor heterogeneity of tumors. The purpose of this thesis is to analyze and compare gemcitabine dose response on hormone refractory breast cancer cells retrieved from mice using an adaptive therapy strategy with standard therapy treatment. In this study, we compared intermittent (drug holiday) adaptive therapy with maximum tolerated dose therapy. The MCF7 resistant cell lines to both fulvestrant and palbociclib were injected into the mammary fat pads of 8 weeks old NOD/SCID gamma (NSG) mice which were then treated with gemcitabine. Tumor burden graphs were made to track tumor growth/decline during different treatments while Drug Dose Response (DDR) curves were made to test the sensitivity of the cell lines to the drug gemcitabine. The tumor burden graphs showed success in controlling the tumor burden with intermittent treatment. The DDR curves showed a positive result in using the adaptive therapy treatment method to treat mice with gemcitabine. Due to some fluctuating DDR results, the sensitivity of the cell lines to gemcitabine needs to be further studied by repeating the DDR experiment on the other mice cell lines for stronger results.
ContributorsConti, Aviona Christina (Author) / Maley, Carlo (Thesis advisor) / Blattman, Joseph (Committee member) / Anderson, Karen (Committee member) / Arizona State University (Publisher)
Created2022
Description
A big part of understanding cancer is understanding the cellular environment itthrives in by analyzing it from a microecological perspective. Humans and other species
are affected by different cancer types, and this highlights the notion that there may be a
correlation between specific tissues and neoplasia prevalence. Research shows that
humans are the most susceptible to adenocarcinomas and carcinomas which include the
following tissues: lungs, breast, prostate, and pancreas. Furthermore, research shows that
adenocarcinoma accounts for 38.5% of all lung cancer cases, 20% of small cell
carcinomas, and 2.9% of large cell carcinoma. The incidence of the most common cancer
types in humans is consistently increasing annually. This study analyzes trends of tissue-specific cancers across species to examine possible contributors to vulnerability to
cancer. I predicted that adenocarcinomas would be the most prevalent cancer type across
the tree of life. To test this hypothesis, I reviewed over 130 species that reported equal to
or greater than 50 individual necropsy pathology records across 4 classes (Mammalia,
amphibia, Reptilia, Aves) and ranked them by neoplasia prevalence. This information was
then organized in tables in descending order. The study’s resulting tables and data
concluded that the hypothesis was correct. I found that across all species
adenocarcinomas were the most common cancer type and account for 30.4% of
malignancies reported among species. Future research should investigate how organ size
contributes to neoplasia prevalence.
ContributorsPERAZA, ASHLEY (Author) / Maley, Carlo (Thesis advisor) / Boddy, Amy (Thesis advisor) / Baciu, Cristina (Committee member) / Arizona State University (Publisher)
Created2022
Description
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and exhibits a male-bias in occurrence and mortality. Previous studies have provided insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and mortality. This study uses pathway analysis to add insight into the biological processes that drive sex-differences in HCC etiology as well as a provide additional framework for future studies on sex-biased cancers. Gene expression data from normal, tumor adjacent, and HCC liver tissue were used to calculate pathway scores using a tool called PathOlogist that not only takes into consideration the molecules in a biological pathway, but also the interaction type and directionality of the signaling pathways. Analysis of the pathway scores uncovered etiologically relevant pathways differentiating male and female HCC. In normal and tumor adjacent liver tissue, males showed higher activity of pathways related to translation factors and signaling. Females did not show higher activity of any pathways compared to males in normal and tumor adjacent liver tissue. Work suggest biologic processes that underlie sex-biases in HCC occurrence and mortality. Both males and females differed in the activation of pathways related apoptosis, cell cycle, signaling, and metabolism in HCC. These results identify clinically relevant pathways for future research and therapeutic targeting.
ContributorsRehling, Thomas E (Author) / Buetow, Kenneth (Thesis advisor) / Wilson, Melissa (Committee member) / Maley, Carlo (Committee member) / Arizona State University (Publisher)
Created2021
Description
Cooperative cellular phenotypes are universal across multicellular life. Division of labor, regulated proliferation, and controlled cell death are essential in the maintenance of a multicellular body. Breakdowns in these cooperative phenotypes are foundational in understanding the initiation and progression of neoplastic diseases, such as cancer. Cooperative cellular phenotypes are straightforward to characterize in extant species but the selective pressures that drove their emergence at the transition(s) to multicellularity have yet to be fully characterized. Here we seek to understand how a dynamic environment shaped the emergence of two mechanisms of regulated cell survival: apoptosis and senescence. We developed an agent-based model to test the time to extinction or stability in each of these phenotypes across three levels of stochastic environments.
ContributorsDanesh, Dafna (Author) / Maley, Carlo (Thesis director) / Aktipis, Athena (Committee member) / Compton, Zachary (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2021-12
Description
The representation of a patient’s characteristics as the parameters of a model is a key component in many studies of personalized medicine, where the underlying mathematical models are used to describe, explain, and forecast the course of treatment. In this context, clinical observations form the bridge between the mathematical frameworks and applications. However, the formulation and theoretical studies of the models and the clinical studies are often not completely compatible, which is one of the main obstacles in the application of mathematical models in practice. The goal of my study is to extend a mathematical framework to model prostate cancer based mainly on the concept of cell-quota within an evolutionary framework and to study the relevant aspects for the model to gain useful insights in practice. Specifically, the first aim is to construct a mathematical model that can explain and predict the observed clinical data under various treatment combinations. The second aim is to find a fundamental model structure that can capture the dynamics of cancer progression within a realistic set of data. Finally, relevant clinical aspects such as how the patient's parameters change over the course of treatment and how to incorporate treatment optimization within a framework of uncertainty quantification, will be examined to construct a useful framework in practice.
ContributorsPhan, Tin (Author) / Kuang, Yang (Thesis advisor) / Kostelich, Eric J (Committee member) / Crook, Sharon (Committee member) / Maley, Carlo (Committee member) / Bryce, Alan (Committee member) / Arizona State University (Publisher)
Created2021
Description
All multicellular organisms are susceptible to developing cancer, but some organisms have varying sensitivities to the disease. One such organism is the Trichoplax adhaerens which has no documented case of cancer development. T. adhaerens cancer resistance was studied by observing physiological and morphological changes of the organism after radiation treatment. Preliminary experiments suggested that this organism is able to survive exposure to 160 gray radiation treatment almost as well as untreated organisms. The T. adhaerens have two genes, TriadG6402 and TriadG5479, similar to the human genes TP53 and MDM2 respectively. TP53 and MDM2 are the two main genes associated with apoptosis in humans: an important cell regulatory checkpoint involved in cancer prevention. PCR analysis, done after radiation treatment, showed an overexpression of the ortholog gene MDM2 in the T. adhaerens. This may suggest that T. adhaerens block apoptosis from occurring and that their ortholog gene is involved in DNA repair. It is significant to study the gene expression of TriadG6402 and TriadG54791 in T. adhaerens because these genes are well conserved in humans. Future studies of these genes in the T. adhaerens can be used to understand the evolution of the function of these genes in more complex organisms and be used for human cancer prevention.
ContributorsKulkarni, Arathi (Author) / Fortunato, Angelo (Thesis director) / Maley, Carlo (Committee member) / Department of Economics (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05