Dissertation
Integrated genomic approaches to characterize molecular responses to targeted therapies in low-grade serous ovarian cancer
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007945
Abstract
Low-grade serous ovarian cancer (LGSOC) is a unique subtype with distinct molecular and clinical characteristics. While this subtype is relatively rare (~5%) and has a low mortality rate, patients are typically younger at diagnosis and experience few (if any) disease-free intervals. Current standard chemotherapy is ineffective for LGSOC (<10% response rate), however, the presence of frequent genetic alterations in the mitogen-activated protein kinase (MAPK) pathway have led to targeted therapeutic clinical trials. Recent clinical trials utilizing inhibitors of mitogen-activated protein kinase kinase (MEK) (a key mediator of MAPK signaling), particularly trametinib or avutometinib/defactinib combination, have shown efficacy in patients with recurrent LGSOC. Unfortunately, after initial response, patients develop progressive disease, with no remaining treatment options. Here, we sought to characterize biological responses of LGSOC to MEK inhibition at the molecular level, and identify adaptive mechanisms of drug resistance, thereby establishing candidates for further exploration as therapeutic targets to prevent or reverse LGSOC progression.
Using integrated genomic approaches including pooled CRISPR screens, RNA sequencing, and Sleeping Beauty mutagenesis screens, we have shown that LGSOC responds to MEK inhibition by upregulating phosphoinositide 3-kinase (PI3K)- protein kinase B (AKT) signaling, thereby promoting cell survival and proliferation. Targeting the MAPK and PI3K-Akt pathways concurrently could be an effective treatment for patients with LGSOC to prevent or reverse progression. We have also identified potential mechanisms of MAPK pathway inhibition in LGSOC as either reactivation of the MAPK pathway or increasing expression of erythroblast transformation specific (ETS) family transcription factors and downstream genes involved in cell proliferation and survival.
Details
- Title: Subtitle
- Integrated genomic approaches to characterize molecular responses to targeted therapies in low-grade serous ovarian cancer
- Creators
- Rebekah Marie Peplinski
- Contributors
- Adam Dupuy (Advisor)Christopher Stipp (Committee Member)Benjamin Darbro (Committee Member)Tina Tootle (Committee Member)C. Andrew Frank (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007945
- Publisher
- University of Iowa
- Number of pages
- x, 86 pages
- Copyright
- Copyright 2025 Rebekah Marie Peplinski
- Language
- English
- Date submitted
- 04/21/2025
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 79-86).
- Public Abstract (ETD)
Ovarian cancer is the most lethal gynecologic cancer. Over half of patients with ovarian cancer will be diagnosed with late-stage disease. This is largely due to the delayed signs and symptoms of ovarian cancer and the lack of effective screening methods. Once diagnosed, treatment regimens include surgery and chemotherapy. Current therapies used are considered general, old-school chemotherapies and these first-line therapeutic options for ovarian cancer have not changed in the last 30 years.
Low-grade serous ovarian cancer (LGSOC) is rare subtype of ovarian cancer with a low mortality rate—but patients are typically younger at diagnosis and therefore live with symptomatic disease for longer. In addition, this subtype has a very low response rate to chemotherapy (less than 10%). One defining characteristic of LGSOC is frequent mutations within the MAPK pathway—a pathway associated with cell growth and survival. This pathway can be targeted therapeutically and has shown recent success in treating LGSOC. While these therapies are initially effective, majority of patients eventually develop progressive disease likely due to resistance to these chemotherapies.
The major objectives of my thesis project included (1) characterizing the molecular response to these targeted therapies, and (2) identifying the resistance mechanisms to these therapies. Together, these can ultimately aid in improving patient response and overall outcomes.
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984831125302771
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