Date of Award

2021

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Vincent Sollars, Committee Chairperson

Second Advisor

Dr. Piyali Dasgupta

Third Advisor

Dr. Emine Koc

Fourth Advisor

Dr. Wei Li

Fifth Advisor

Dr. William McCumbee

Abstract

The ability for species to evolve new features in response to changing circumstances in order to survive and propagate is a ubiquitous observation on both the macroscopic and microscopic levels of living systems. It should be no surprise, then, that diseases such as cancer utilize their own forms of adaptation to perpetuate themselves when exposed to external threats. Indeed, concepts drawn from Darwinian evolution are now widely accepted to help explain certain aspects of carcinogenesis and malignant progression, the sum of which have come to be known as the theory of tumor evolution. Since metastasis and drug resistance are features that manifest toward the late stages in the disease after withstanding numerous selective pressures, cancer cells harboring these features can be viewed as the most evolutionarily fit. Just as many forms of life rely on common adaptive mechanisms to promote their survival during dramatic shifts in their environment, metastatic and drug resistant cancers may rely upon common cellular mechanisms to promote their survival when faced with untenable circumstances. We hypothesize that one of the oldest genes in the human genome, HSP90, functions as a link between metastatic and drug resistant behavior of cancer. We believe this occurs through HSP90’s relationship in supporting the function of gene products that define the cancer hallmarks and clinical evidence suggesting HSP90 is important in progressing cancer into advanced stages. In the following chapters we discuss HSP90 and its role in orchestrating evolution of metastatic and drug resistant phenotypes. We use the clinically relevant HSP90 inhibitor, AUY922, to explore our assertions in vitro in the context of non-small cell lung cancer (NSCLC), which is prone to evolving metastatic and drug resistant phenotypes. We examine the implications for our findings, future directions, and new possibilities for utilizing HSP90 inhibitors to treat cancer.

Subject(s)

Cancer -- Research.

Lungs -- Cancer -- Research.

Medical genetics -- Research.

Genomics -- Research.

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