Researchers at Weill Cornell Medicine and the New York Genome Center have uncovered new insights into the genetic mechanisms that fuel bladder cancer, potentially paving the way for more effective treatments. The study, published on October 9 in Nature, identifies the role of antiviral enzymes in driving early bladder cancer mutations and highlights how chemotherapy can contribute to genetic changes that make the cancer harder to treat.
The study focused on urothelial carcinoma, the most common form of bladder cancer, and used advanced whole-genome sequencing to map DNA mutations and structural changes in tumor cells. Researchers found that mutations caused by APOBEC3 enzymes, which normally target viral DNA, are an early driver of bladder cancer. They also discovered that chemotherapy, particularly platinum-based drugs like cisplatin, leads to additional mutations that help cancer cells survive treatment.
“These findings define new fundamental mechanisms driving bladder cancer evolution – mechanisms that we can now think about targeting with therapies,” said co-senior author Dr. Bishoy Faltas, a leading oncologist at Weill Cornell Medicine.
A clearer picture of bladder cancer resistance
One of the study’s major discoveries was the role of circular DNA structures, known as extra-chromosomal DNAs (ecDNAs), in promoting cancer resistance to therapy. These ecDNAs, which contain multiple copies of genes that drive cancer growth, persist and evolve in tumor cells even after chemotherapy. Researchers demonstrated that one such gene, CCND1, promotes treatment resistance when arranged in this circular form.
“Traditionally, we’ve used methods that analyze only a tiny fraction of tumor DNA, but this study shows that sequencing all the DNA provides a much clearer picture of cancer’s development and resistance mechanisms,” said co-author Olivier Elemento, director of the Englander Institute for Precision Medicine at Weill Cornell Medicine.
The findings suggest that targeting ecDNAs or the enzymes responsible for early mutations could offer new therapeutic strategies for urothelial carcinoma, a cancer that is often diagnosed in its later stages and is difficult to treat effectively.
Implications for treatment
Bladder cancer affects approximately 80,000 people each year in the U.S., and while early-stage cancer can often be cured with surgery, more advanced cases are much harder to manage. The study’s findings on how chemotherapy spurs additional mutations could influence future treatment approaches, including personalized therapies aimed at targeting specific genetic changes in tumors.
The researchers are also exploring the potential of using a recently FDA-approved drug that targets the HER2 receptor, commonly found in breast cancer, to treat bladder cancer patients whose tumors show strong signs of ERBB2 ecDNAs.
The study, funded by institutions including the National Cancer Institute and the Department of Defense, underscores the importance of genetic research in understanding cancer progression and developing more effective treatments. The researchers plan to continue investigating how single-cell DNA sequencing and gene activity analyses can deepen our understanding of bladder cancer biology.
By exploring new ways to block the formation and maintenance of ecDNAs, the team hopes to develop strategies to counteract the resistance mechanisms that make bladder cancer so difficult to treat in its advanced stages.
FingerLakes1.com is the region’s leading all-digital news publication. The company was founded in 1998 and has been keeping residents informed for more than two decades. Have a lead? Send it to news@fingerlakes1.com.