Author ORCID Identifier
https://orcid.org/0000-0003-3302-8942
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Human and Molecular Genetics
First Advisor
J. Chuck Harrell
Abstract
Recent advancements in the genetic characterization of breast cancer subtypes provide critical insights into the molecular diversity of this malignancy and have led to more effective treatments for HER2-enriched and hormone receptor driven malignancies. Despite these advancements, triple-negative breast cancers (TNBCs) remain challenging to treat, due to limited options for targeted therapy. Carboplatin, a platinum-based chemotherapy agent, has emerged as a frontline therapy for TNBC. Unfortunately, the development of acquired resistance to carboplatin, remains a significant clinical challenge, demonstrating an increased need for better first and second line agents to treat TNBCs. This proposal aims to address this issue by identifying and targeting pathways that mediate carboplatin-resistance (CR). I hypothesize that pathways which are activated in CR disease are important for cancer cell survival and that inhibiting these pathways will increase cytotoxicity to cancer cells. This study will identify activated pathways which mediate carboplatin resistance and inhibit them. Additionally, we hope to potentiate the anti-cancer effects of the second-line therapy Sacituzumab govitecan (SG) through combination with inhibitors that exhibit cytotoxic activity; my hypothesis is that these combinations will be less toxic and more effective than mono-agent therapies.
To help address this challenge, I have developed isogenic pairs of carboplatin-sensitive (CS) and CR disease, derived from diverse TNBC patient-derived xenograft (PDX) models. Preliminary studies with these models show divergent responses to targeted therapeutics between CS and CR pairs, with CR models demonstrating reduced susceptibility to many common anti-cancer agents, similar to what is seen clinically in CR patients. We will utilize these models and a multi-omics approach to reveal unique genetic and proteomic profiles associated with acquired resistance to carboplatin. Defined expression and protein profiles associated with resistance will allow for identification of targetable pathways and therapeutic agents for the treatment of CR TNBC.
Antibody drug conjugates (ADCs) are a promising approach to targeted cancer treatment. SG, an ADC targeting trophoblast cell-surface antigen 2 (Trop-2), has gained approval as a second line therapy, treating advanced/metastatic TNBC. Interestingly, our initial studies showed decreased responsiveness to SG post-acquired resistance to carboplatin. This reflects a major obstacle for patients with TNBC as SG is often given following acquired resistance to standard chemotherapies. To address this challenge, this study will identify synergistic agents to heighten SG efficacy in CR models via high throughput drug screening. Extensive testing of drugs from a variety of cancer targeting pathways with SG will identify synergistic agents to help increase drug efficacy in CR TNBCs and aid in the elucidation of pathways involved in SG response.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-3-2025
Included in
Bioinformatics Commons, Cancer Biology Commons, Genetics Commons, Molecular Biology Commons, Molecular Genetics Commons