Author ORCID Identifier
0000-0003-2334-2612
Date of Graduation
8-2020
Document Type
Dissertation (PhD)
Program Affiliation
Experimental Therapeutics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Joya Chandra
Committee Member
Min Gyu Lee
Committee Member
Andrew Gladden
Committee Member
Michael Curran
Committee Member
Candelaria Gomez-Manzano
Abstract
Regulation of chromatin accessibility is a key mechanism of cellular identity, allowing different tissues to develop using the same DNA template. Cancers will often hijack these epigenetic pathways, reactivating developmental genes to drive growth and deactivating tumor suppressor and immune recognition genes. Chromatin-modifying proteins deposit and remove chemical moieties from histone tails to aid in governing gene expression, and these proteins have become a new therapeutic target in cancer. Traditional chemotherapeutics aim to damage DNA, dysregulate cell division, or block hormonal growth signals, but epigenetic therapy can target vulnerabilities specific to cancer cells and broadly change gene expression patterns that may aid new modalities such as immunotherapy. Pediatric high-grade gliomas (pHGGs) often possess mutations in histone coding genes that cause aberrant histone methylation and gene expression. Cells derived from these patient’s tumors display growth inhibitory sensitivity to epigenetic drugs targeting histone deacetylases and methyltransferases, but other epigenetic targets remain unexplored in this cancer. The histone demethylase LSD1 (also known as KDM1A, BHC110, and KIAA0601) has been revealed as a promising target in leukemias and viii pediatric sarcomas, but its validity as a cancer target in pediatric glioma is unknown. LSD1 can be inhibited by small molecules with unique mechanisms of action, binding to either the catalytic site directly, or to an allosteric interface region. These LSD1 inhibitors produce differing effects in various cell types, dependent on LSD1-interacting proteins and how these interactions are disrupted by inhibitor binding. Through testing of a suite of catalytic and scaffolding LSD1 inhibitors, I have revealed LSD1 as an immune-regulatory target in pHGG, and as a potential mediator of metabolism and redox balance in natural killer (NK) cells. Furthermore, using bioinformatics approaches, I reveal differences in pHGG immune infiltrate by tumor location that may govern future treatment with LSD1 inhibitors or other immunostimulatory agents. This thesis collectively demonstrates that LSD1 is a valid therapeutic target in pHGG, and that inhibiting distinct structural domains of LSD1 boosts innate immune reactivity in pHGG and modulates the metabolism and oxidative stress of NK cells. My work sets the stage for clinical translation of a combination pHGG therapy using an LSD1 inhibitor with NK cell infusion.
Keywords
LSD1, NK cell, metabolism, pediatric glioma, tumor microenvironment