DOI

https://doi.org/10.25772/1FMW-H372

Defense Date

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

David A. Gewirtz

Second Advisor

Hisashi Harada

Third Advisor

Katherine Nicholson

Fourth Advisor

Antonio Abbate

Fifth Advisor

Edward Ishac

Abstract

Abstract

Although great strides have been made over the decades in development and optimization of anti-cancer therapies, even highly effective drugs often fail to completely eliminate tumors. Residual tumor cells can enter into a state of dormancy for prolonged periods of time but eventually are able to regain proliferative capacity and reemerge as chemotherapy-resistant disease. Because recurrent disease is a leading contributor to patient’s mortality, it is paramount to identify strategies for effectively destroying residual tumor cells.

Cytotoxic drugs and ionizing radiation are used as standard therapies in a variety of cancers. These modalities induce apoptosis, autophagy and senescence. Senescence is a state of prolonged growth arrest, which cells are able to eventually escape regaining proliferative capacity.

Autophagy is generally considered to be a protective mechanism; however, it can take non-protective or even cytotoxic form in response to anti-cancer treatments. Furthermore, chemotherapy or radiation induced autophagy was shown to be a contributor to the immune response against tumor cells.

Using a model of Triple Negative Breast Cancer, we were able to show increased immunosurveillance of tumor cells after enhanced autophagy was achieved by combining epigenetic remodeling with chemotherapy.

Alternatively, we were able to achieved effective clearance of tumor cells induced into senescence by chemotherapy or radiation by the senolytic drug ABT-263 (Navitoclax). In summary, autophagy and senescence alone or in concert, can be induced by conventional anti-tumor modalities. Those processes can be modulated independently to achieve clearance of residual tumor cells following anti-cancer therapies.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-5-2019

Available for download on Friday, December 04, 2020

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