At a Glance
Ovarian cancer is the fifth leading cause of female cancer deaths in the United States. Patients with ovarian cancer face nonspecific early symptoms, late diagnosis and high rates of recurrence following chemotherapy. This project sought to identify genomic biomarkers through non-invasive biofluid analysis that may be used for monitoring disease recurrence and predicting resistance. To do so, the researchers developed patient-derived organoid models from ovarian cancer ascites and established infrastructure for cell-free DNA isolation. The ability to easily assess risk of resistance in patients would potentially eliminate the use of ineffective therapy and serve as a signal for determining when second-line therapies should be explored.
The Challenge
Ovarian cancer accounts for five percent of all cancer deaths in females in the United States. Patients with ovarian cancer nearly always face recurrence and resistance to platinum-based chemotherapy, which is the current standard of care. Outcomes are highly dependent on rapid detection and determination of the optimal course of therapy at the time of recurrence. However, currently the only way to determine if a patient is responsive to chemotherapy is to treat them and wait up to six months to determine response. Moreover, few targeted biological therapies exist for patients, and treatment options are limited once tumors become platinum-refractory.
Project Goals
The overarching goal of this project was to determine if the features of platinum-based chemotherapy resistance, previously identified in models, can be identified in samples from patients with ovarian cancer. This goal was addressed through two specific aims:
- Genomic and functional comparison of subpopulations of tumor cells in ascites from ovarian cancer patients.
- Comparison of genomic alterations and epigenetic markers in ascites and plasma cell-free DNA and primary tumor DNA.
Results
The research team collected 17 tumor cell-containing abdominal fluid (ascites) samples from ovarian cancer patients. They grew samples as patient-derived organoids, which allowed for more robust and reproducible downstream analysis. The organoids developed were used to determine stemness markers and chromatin states predictive of therapeutic resistance, which has the potential to generate new prognostics signatures for ovarian cancer patients. The researchers also collected 100 paired plasma samples and extracted cell-free DNA from both plasma and ascites samples. They prepared libraries for sequencing and analysis training is underway. Future work will involve examining cell-free DNA fragmentation patterns between ascites and plasma and assessing how these relate to the tumors from which they derive.
