Conditional Reprogramming of Urine Cultures for Bladder Cancer
A research team led by investigators from Georgetown University Medical Center and Fudan University in China has devised a noninvasive and individualized technique for detecting and treating bladder cancer. Their findings were published by Jiang et al in Protein & Cell.
The method uses a urine specimen instead of invasive tumor sampling and a method developed and patented by Georgetown to culture cancer cells that can reveal the molecular underpinnings of each patient’s unique bladder cancer. Their study sets forth a cost-friendly, simple, and painless technique that can determine the best treatment for each person’s bladder tumor; monitor the progress of treatment; predict or detect cancer recurrence early; and identify new drugs that are may show activity in this malignancy.
“This is the first study to show, using patient samples, that a ‘living liquid biopsy’ from urine can help determine treatment. This work also suggests that we might be able to grow and test cancer cells for treatment from other ‘living biomarkers’ found in blood and saliva. We are just at the beginning of this new diagnostic innovation,” said the study co-senior author, Xuefeng Liu, MD, Professor of Pathology and Oncology and member of the Center for Cell Reprogramming at Georgetown University and Georgetown Lombardi Comprehensive Cancer Center.
Conditional Reprogramming
Patient-derived cells from urine using a technique called conditional reprogramming can grow indefinitely without genetic manipulation, said Dr. Liu. Before this technique, which is less than a decade old, normal cells could not grow in lab culture, and cancer cells acquired numerous genetic mutations using previous culturing techniques. In the short time that investigators worldwide have been using conditional reprogramming, the method has proven useful in basic and clinical research in many kinds of cancers.
“Functional analyses using patient-derived models such as conditional reprogramming are urgently needed for precision oncology,” said Dr. Liu. Currently, the percentage of U.S. patients with cancer who benefit from genome-driven oncology treatment is less than 10%, he added.
Methods
The study compared tumor biopsies from 70 patients with individual urine specimens, both processed through conditional reprogramming cultures. Primary cells isolated from urine and tumor samples both rapidly formed conditional reprogramming cultures and representative three-dimensional compact spheroids. The overall success rate of culturing urine conditional reprogramming cultures was about 84%.
“Similarly, the analysis of the mutation ratio for both patient tissue and corresponding conditional reprogramming cultures confirmed that both single nucleotide variants and DNA insertions and deletions were retained during the culturing,” said Dr. Liu.
“We also identified some mutations not identified in the original tumor biopsies, suggesting that the urine cell cultures better reflect overall tumor diversity than a single biopsy,” he said. “The conditional reprogramming culture technique may also expand our understanding of how low frequency mutations help lead to bladder cancer development and progression. Overall, conditional reprogramming cultures may identify new actionable drug targets and help explain why this cancer is so often resistant to treatment.”
After determining that the urine colonies and tumor tissue samples had matching molecular characteristics and genetic alterations, the researchers tested urine-based conditional reprogramming cultures cancer cells with 64 clinical oncology drugs. They found that, overall, the urine-based cancer cells were resistant to more than half of the drugs. They also discovered that many of the urine cancer cells were highly sensitive to bortezomib, which is currently being tested for use in urothelial cancer.
Investigators also showed that as tumors progress, they change to become more molecularly diverse. “In our study, we can obtain urine samples at any time before and after treatment, which provides the possibility to obtain real-time pathological conditions,” explained Dr. Liu. In fact, for some patients, researchers compared urine culture–based drug sensitivities with a patient’s clinical responses to traditional treatment, as well as to computed tomography and positron emission tomography follow-up images. They discuss how this analysis on seven patients matched the patient’s clinical history and their urine-based conditional reprogramming cultures findings, “which confirms and supports use of urine conditional reprogramming in clinical practice,” the researchers said.
“We successfully built up a novel, convenient model of conditional reprogramming cultures that faithfully retains the molecular characteristic and genetic landscapes of the original tumor,” the study authors wrote. “The high success rate and rapid proliferation of urine conditional reprogramming cultures imply they are suitable for large-scale drug testing.”
Dr. Liu added that the proven ability to form three-dimensional tumor spheroids from conditional reprogramming cultures will allow them to study the tumor microenvironment. “This novel in vitro bladder cancer system opens [up] new avenues for predicting patient-specific drug responses and turning the promise of personalized medicine into a reality,” he concluded.
Disclosure: For full disclosures of the study authors, visit link.springer.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
