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- All Subjects: adaptive therapy
- Creators: Blattman, Joseph
- Creators: Anderson, Karen S
Description
The majority of non-small cell lung cancer (NSCLC) patients (70%) are diagnosed with adenocarcinoma versus other histological subtypes. These patients often present with advanced, metastatic disease and frequently relapse after treatment. The tumor suppressor, Liver Kinase B1, is frequently inactivated in adenocarcinomas and loss of function is associated with a highly aggressive, metastatic tumor (1). Identification of the mechanisms deregulated with LKB1 inactivation could yield targeted therapeutic options for adenocarcinoma patients. Re-purposing the immune system to support tumor growth and aid in metastasis has been shown to be a feature in cancer progression (2). Tumor associated macrophages (TAMs) differentiate from monocytes, which are recruited to the tumor microenvironment via secretion of chemotaxic factors by cancer cells. We find that NSCLC cells deficient in LKB1 display increased secretion of C-C motif ligand 2 (CCL2), a chemokine involved in monocyte recruitment. To elucidate the molecular pathway regulating CCL2 up-regulation, we investigated inhibitors of substrates downstream of LKB1 signaling in A549, H23, H2030 and H838 cell lines. Noticeably, BAY-11-7082 (NF-κB inhibitor) reduced CCL2 secretion by an average 92%. We further demonstrate that a CCR2 antagonist and neutralizing CCL2 antibody substantially reduce monocyte migration to NSCLC (H23) cell line conditioned media. Using an in vivo model of NSCLC, we find that LKB1 deleted tumors demonstrate a discernible increase in CCL2 levels compared to normal lung. Moreover, tumors display an increase in the M2:M1 macrophage ratio and increase in tumor associated neutrophil (TAN) infiltrate compared to normal lung. This M2 shift was significantly reduced in mice treated with anti-CCL2 or a CCR2 antagonist and the TAN infiltrate was significantly reduced with the CCR2 antagonist. These data suggest that deregulation of the CCL2/CCR2 signaling axis could play a role in cancer progression in LKB1 deficient tumors.
ContributorsFriel, Jacqueline (Author) / Inge, Landon (Thesis advisor) / Lake, Douglas (Thesis advisor) / Blattman, Joseph (Committee member) / Arizona State University (Publisher)
Created2015
Description
Non-small cell lung cancer (NSCLC) has become the leading cause of cancer-related deaths in the United States with a combined 5-year survival rate of only 16%. Even with advancements in aggressive chemotherapeutics, there has been little improvement in patient survival. LKB1 (liver kinase B1)/STK11 (serine-threonine kinase 11) is a tumor suppressor gene mutated in ~30% of NSCLC adenocarcinomas and loss of LKB1 is associated with a more aggressive cancer phenotype. In LKB1-deficient NSCLC, we observe significantly elevated expression and secretion of the chemokines CCL2, CCL5, and CCL20, which are involved in macrophage recruitment. Numerous studies have shown that high infiltration of a unique subset of macrophages called tumor-associated macrophages (TAMs) is associated with poor prognosis in patients with various cancers. mTORC1-HIF1-α and NFκB are two pathways that have been shown to regulate chemokine secretion and are often up-regulated in the absence of LKB1. Dosing LKB1-null cell lines with inhibitors of mTOR and NFκB in addition to silencing HIF1-α gene expression demonstrate that NFκB but not mTORC1-HIF1-α signaling may play a role in regulating chemokine secretion in LKB1-deficient NSCLC. Collectively, these results provide insight into the mechanisms responsible for the aggressive phenotype associated with LKB1-deficient non-small cell lung cancer.
ContributorsO'Brien, Kelley Xiao-Fung (Author) / Blattman, Joseph (Thesis director) / Inge, Landon (Committee member) / Friel, Jacqueline (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / School of Life Sciences (Contributor)
Created2015-05
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
Resistance to existing anti-cancer drugs poses a key challenge in the field of medical oncology, in that it results in the tumor not responding to treatment using the same medications to which it responded previously, leading to treatment failure. Adaptive therapy utilizes evolutionary principles of competitive suppression, leveraging competition between drug resistant and drug sensitive cells, to keep the population of drug resistant cells under control, thereby extending time to progression (TTP), relative to standard treatment using maximum tolerated dose (MTD). Development of adaptive therapy protocols is challenging, as it involves many parameters, and the number of parameters increase exponentially for each additional drug. Furthermore, the drugs could have a cytotoxic (killing cells directly), or a cytostatic (inhibiting cell division) mechanism of action, which could affect treatment outcome in important ways. I have implemented hybrid agent-based computational models to investigate adaptive therapy, using either a single drug (cytotoxic or cytostatic), or two drugs (cytotoxic or cytostatic), simulating three different adaptive therapy protocols for treatment using a single drug (dose modulation, intermittent, dose-skipping), and seven different treatment protocols for treatment using two drugs: three dose modulation (DM) protocols (DM Cocktail Tandem, DM Ping-Pong Alternate Every Cycle, DM Ping-Pong on Progression), and four fixed-dose (FD) protocols (FD Cocktail Intermittent, FD Ping-Pong Intermittent, FD Cocktail Dose-Skipping, FD Ping-Pong Dose-Skipping). The results indicate a Goldilocks level of drug exposure to be optimum, with both too little and too much drug having adverse effects. Adaptive therapy works best under conditions of strong cellular competition, such as high fitness costs, high replacement rates, or high turnover. Clonal competition is an important determinant of treatment outcome, and as such treatment using two drugs leads to more favorable outcome than treatment using a single drug. Switching drugs every treatment cycle (ping-pong) protocols work particularly well, as well as cocktail dose modulation, particularly when it is feasible to have a highly sensitive measurement of tumor burden. In general, overtreating seems to have adverse survival outcome, and triggering a treatment vacation, or stopping treatment sooner when the tumor is shrinking seems to work well.
ContributorsSaha, Kaushik (Author) / Maley, Carlo C (Thesis advisor) / Forrest, Stephanie (Committee member) / Anderson, Karen S (Committee member) / Cisneros, Luis H (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