Browsing School, Graduate by Subject "Oncology"
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Beyond Efficacy, Toxicity, and Cost: Patients Define Cancer Care Value in the United StatesPer-capita health-care costs in the United States outpace those of all other countries. Oncology care is particularly expensive, with costs that have nearly doubled over the past twenty years. Cancer care costs are expected to continue to grow exponentially and comprise a considerable proportion of overall health spending costs. While there have been some “blockbuster” or “game changing” treatments, many others offer seemingly minimal benefits. As such, there has been a heightened focus on the concept of cancer care “value,” with multiple organizations promulgating value frameworks designed to assess the perceived value of medications derived from various health economics perspectives. Yet, value is an elusive target, and there is not consensus regarding the dimensions that should be included in such assessments. Value frameworks have the potential to impact patient access to care, yet it is unclear to what extent patient preferences, values, and goals have been incorporated into the value assessments. This study explores how cancer patients and survivors define the concept of “value” in cancer care and if those definitions align with current value frameworks and assessments. This research study was conducted through primary data collection and sought to describe and clarify experiences (such as receiving a cancer diagnosis, engaging in treatment decision making, and moving forward throughout survivorship) as they have unfolded in the lives of cancer patients and survivors. Findings will be used to inform the future direction of value assessments and ultimately, policies that impact the lives of cancer patients and their families.
Burden and Mental Health of Family Caregivers of Cancer Patients: The Impact of SpiritualityBackground: As the primary source of care for individuals with cancer, family caregivers are relied on for treatment support and emotional care during the cancer trajectory. Studies on caregiver burden and psychological sequelae among cancer caregivers have been conducted cross-sectionally. Spirituality has been suggested as a potential buffer between burden and sequelae. Yet, there have been very few longitudinal studies addressing burden, depression, and spirituality, and there is limited information on psychometric properties of the spirituality measures in cancer caregivers. Purpose: The aims of this study were to: 1) evaluate validity of the Spiritual Perspective Scale (SPS) and explore differences in spirituality across caregiver and patient characteristics, 2) describe caregiver burden during active cancer treatment and explore caregiver and patient factors influencing caregiver burden, and 3) examine changes in caregiver burden, spirituality, and depression and explore the moderating effect of spirituality on burden-depression relationship over time. Methods: A secondary analysis of data from a longitudinal study of cancer caregivers from the NIH Clinical Center was conducted. Caregivers completed measures, including the Spiritual Perspective Scale (SPS), Caregiver Reaction Assessment (CRA), and NIH Toolbox and PROMIS® measures. Structural equation modeling and linear mixed modeling were used for testing study aims. Results: The SPS was found to have satisfactory psychometric properties in cancer caregivers. Adjusting for a direct effect of race did not alter the pattern of results, and caregivers who were older, female, racial/ethnic minorities, less educated, affiliated with a religion, and who provided care to anyone other than the patient reported higher levels of spirituality. Baseline mutuality between the caregiver and patient was negatively associated with initial burden. Changes in caregiver burden were related to being spouse caregivers, sole caregivers, and income. Scores on total burden, spirituality, and depression remained stable over time. Caregivers’ spirituality moderated the link between burden and depression (-1.26, p = .025). Conclusions: Higher levels of spirituality may act as a protective factor in the relationship between burden and depression during active cancer treatment. Identified factors related to burden and strategies to strengthen spirituality should be considered to improve caregiver mental health.
Developing Therapies to Overcome Immunosuppressive Myeloid Cells in the Tumor MicroenvironmentMyeloid cells in the tumor microenvironment represent significant barriers to the development of successful cancer immunotherapies. A multi-kinase inhibitor, Regorafenib (Reg), and a DNA-PK inhibitor, NU7441 (NU) were shown in a previous study to reduce expression of immunoinhibitory proteins in adaptive immune cells while increasing stimulatory MHC-I on cancer cells. In this study, we explored whether these drugs could reverse the suppressive activity of myeloid-derived suppressor cells (MDSCs) and alternatively activated macrophages. To test this idea, we used splenocytes from tumor-bearing mice and a human monocytic cell line differentiated into suppressive macrophages and assessed Arginase activity, their ability to suppress effector T cells, and mRNA expression of immunosuppressive and activating markers. We showed that Reg/NU decrease arginase activity and increase immunoactivating markers. These data demonstrate that treatment of suppressive myeloid cells with Reg/NU confers a less suppressive phenotype and leads to the generation of a more activating phenotype.
The Design and Development of Dual MCL-1/BCL-2 and HDM2/Bcl-2 Protein Family Inhibitors Using a Polypharmacology ApproachApoptosis, a cellular process that leads to cell death, is a vital signaling pathway for maintaining homeostasis. Intracellular-activated apoptosis is regulated by the B-cell lymphoma 2 (BCL-2) family of proteins, which encompasses two classes of proteins: the pro-apoptotic and anti-apoptotic members. Apoptosis is controlled by a protein-protein interaction (PPI) between the two members. Specifically, the anti-apoptotic proteins’ surface hydrophobic binding groove binds to the α-helical Bcl-2 homology 3 (BH3) domain of the pro-apoptotic proteins, thus inhibiting apoptosis. During apoptotic conditions, BH3 activator proteins are expressed and disrupt the PPI, initiating apoptosis. During tumorigenesis, the anti-apoptotic proteins are overexpressed and capture the activator proteins before they can act, progressing tumor development. A strategy developed to overcome this oncogenic transformation is BH3 mimicry, the design of small molecules that behave like BH3 activators to free the pro-apoptotic proteins. Though potent BH3 mimetics have been synthesized, cytotoxic and resistance issues have arisen. Specifically, BCL-XL inhibition causes thrombocytopenia within patients and BCL-2 inhibition causes resistance mechanisms to emerge that involve the upregulation of MCL-1. Presently, there are no potent dual inhibitors of BCL-2 and MCL-1 to overcome these issues. Additionally, p53 has been shown to regulate apoptosis through the Bcl-2 family by either direct interactions or increasing their expression. P53 is rapidly degraded due to the overexpression of HDM2, a ubiquitin ligase, within cancer cells. The PPI between p53 and HDM2 resembles the PPI between the members of the Bcl-2 family. Also, Venetoclax (BCL-2 inhibitor) and idasanutlin (HDM2 inhibitor) act synergistically in combination therapies. Thus, we followed a polypharmacology approach to synthesize dual BCL-2/MCL-1 and dual HDM2/Bcl-2 family inhibitors. We were able to create potent dual MCL-1/BCL-2 indazole inhibitors (Ki MCL-1 < 1.50 µM, BCL-2 < 0.050 µM, BCL-XL > 10.00 µM), dual HDM2/Bcl-2 family pyrazole and imidazole inhibitors (Ki MCL-1 < 0.050 µM, HDM2 < 25.00 µM), HSQC-confirmed nicotinate-based MCL-1 inhibitors (Ki MCL-1 < 3.00 µM) and a new alpha-helix mimetic scaffold for disrupting PPIs. Further optimization of these inhibitors is planned, along with cell viability studies. Overall, these inhibitors can serve as starting points for future experiments and polypharmacology designs.