Pharmacogenomic Signatures That Predict Drug Response and Resistance in High-Grade Serous Ovarian Cancer Using Patient-Derived Organoids and Their Exosomes
Abstract
Ovarian cancer is the fifth leading cause of cancer-related death among women and has the highest fatality rate among gynecologic cancers. In the United States, more than 20,000 new cases and 13,000 deaths from ovarian cancer occurred in 2017. High-grade serous ovarian carcinoma (HGSC) is the most common and the most lethal subtype of ovarian cancer. Although the 5-year survival rate has improved for patients diagnosed with advanced-stage HGSC, the long-term survival rate (>5 years) remains very low at 30%. This low overall survival is largely due to the advanced stage at diagnosis and a high rate of relapse due to the emergence of platinum resistance with few effective next-line treatments in platinum-resistant patients. Currently, designing therapeutic strategies for an individual patient is limited due to difficulty in obtaining post-therapy tumor samples and limited knowledge of early markers of evolving drug resistance. Tumor sampling is also an invasive approach and fails to account for the biologic adaptability of malignancies, including tumor heterogeneity, stress response under the pressure of chemotherapy, and the evolution of drug resistance. Better models are critically needed to identify patients that may develop chemotherapy resistance during treatment in order to make progress in treating patients with ovarian cancer. High-throughput cancer cell line screening assays have been fundamental tools to evaluate drug sensitivity patterns and pharmacogenomics profiling that may guide early-phase clinical trials of novel agents and rational cancer therapeutic strategies. The application of physiologically relevant patient-derived organoid (PDO) cultures as a new generation of test platforms for future drug discovery efforts has enormous potential to bridge the gap between primary 2D cell-based screening and animal and human trials. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for preclinical evaluation of new drugs. This may explain why standard treatment and overall survival of HGSC has not changed for decades. Exosomes are extracellular vesicles that bud from the membranes of all cells, including cancer cells, and are secreted into bodily fluids carrying tumor-specific biomolecules (mRNAs, miRNA, and proteins). Importantly, exosomes are stable in peripheral fluids, easily accessible and detectable, and have been proposed to be used as a liquid biopsy enabling patient-specific assessment of response to therapy, as well as to make decisions on which therapy should be used when the patient becomes resistant to the current therapy. We propose to develop drug screens utilizing PDOs from patients diagnosed with HGSC and to use these models to develop signatures that predict response to a particular drug based on the expression of molecules in the organoid as well as their exosomes. We have developed organoids from HGSC tumors and performed small-scale drug testing. In addition, we have successfully isolated exosomes and their miRNA cargo from PDO cultures of several ovarian cancer patient samples. This study aims to utilize PDOs to develop drug resistance signatures that predict tumor response, as well as an miRNA signature that can serve as a liquid biopsy to monitor resistance over the course of a patient’s treatment. While several PDO drug screens have been performed in other cancers, none to date have expanded their analysis of drug response beyond that of the organoid itself. The analysis of the organoid and the miRNA cargo from the exosomes they secrete is truly innovative and adds an additional layer of complexity and information gained from the 3D model that is crucial for the development of accurate drug response signatures. Results from this study will allow validation and standardization of the technology for PDO models in drug screening for HGSC, the expansion of these screens to newly developed novel therapeutics to trea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910096
Entities
People
- Kelsi Andrade
Organizations
- United States Army
- University of Oklahoma Health Sciences Center