Author ORCID Identifier
Semester
Summer
Date of Graduation
2024
Document Type
Dissertation
Degree Type
PhD
College
School of Medicine
Department
Not Listed
Committee Chair
Weimin Gao
Committee Co-Chair
Christopher Cifarelli
Committee Member
Christopher Cifarelli
Committee Member
David Clump
Committee Member
Constantinos Hadjipanayis
Committee Member
Paul Lockman
Abstract
Lung cancer remains the most frequently diagnosed malignant neoplasm shared in men and women worldwide, second only to the sexually dimorphic prostate cancer in men and breast cancer in women. Overall, lung cancer was responsible for 12.5% of new cancer cases globally in the year 2022. Of these cases, 80-85% are non-small cell lung cancer (NSCLC), a highly genotypically diverse sub-type of lung cancer. Over the past three decades, extraordinary improvement in screening, smoking cessation, early diagnosis and targeted therapy have been made, improving NSCLC survival markedly. However, as patients are surviving their primary disease better, there is a temporal relationship with increased incidence of morbidity and mortality of secondary sequelae stemming from NSCLC. One major contributor to this burden is lung cancer brain metastases (LCBM) of NSCLC. The magnitude of this problem is made evident by the fact that most common brain tumor in adults is not attributable to a primary brain malignancy, but rather metastases of lung cancer. Historically, nearly 50% of NSCLC patients acquire LCBM at some point during the natural history of their disease and up to two thirds will have multifocal CNS disease. LCBM from NSCLC portends poorer prognoses a median overall survival of only 12 months following initial diagnosis. This poor survival is largely perpetuated by primary and acquired therapy resistance. Considering the current landscape of care, new therapies and treatment paradigms should be developed to improve the survival and function of patients suffering from LCBM. Such strategies include identification of new targets, combination therapies with synergistic agents, and development of therapies based on unique tumor dynamic and kinetic characteristics. Beyond the classical barriers to brain tumor treatment, one significant hurdle in the implementation of these strategies is the evolution of the NSCLC lesion as it is treated and disseminates. Considerations must be made for: 1) the tumor’s new environment, 2) the acquisition of therapy resistance, and 3) the internal cellular environment that allows NSCLC to thrive in its new environment. Previously regarded as discrete clinical entities, resistance and metastasis may not be as exclusive to one another as once suggested. In fact, for LCBM there are many overlaps in the co-permissive factors that constellate into metastatic/resistant (MR) phenotype which fosters growth and development within neural tissue. Examining these changes, both in the transcriptome and the proteome, of these lesions have revealed targetable nexi that relieve the cells of the MR phenotype. This dissertation aims to explore these commonalities and leverage the exploitation of these pathways to help improve survival in LCBM patients by addressing both metastasis and resistance.
Recommended Citation
Marshall, Kent L., "Translational Approaches to Address the Metastatic/Resistant (MR) Phenotype of Non-Small Cell Lung Cancer Brain Metastases" (2024). Graduate Theses, Dissertations, and Problem Reports. 12596.
https://researchrepository.wvu.edu/etd/12596
Embargo Reason
Publication Pending
Included in
Neoplasms Commons, Nervous System Diseases Commons, Neurosciences Commons, Neurosurgery Commons, Oncology Commons