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Bladder Cancer: New Subtype Discovery May Offer Better Treatment Options

Cedars-Sinai Finding May Help Target New Therapies and Predict Which Treatments Are Most Beneficial for Patients

Cedars-Sinai investigators have identified a subtype of cancer cells that could help predict how bladder cancers respond to certain therapies. Their findings likely will guide physicians toward the most effective treatment for patients with that cancer type and potentially pave the way to discover new drug therapies. The research was published online recently by Nature Communications.

Of the roughly 83,000 cases of bladder cancer diagnosed in the U.S. each year, about 25% are muscle-invasive, meaning the cancer has spread to muscles in the bladder wall and is more likely to spread farther to lymph nodes and other organs. While the five-year average survival rate for bladder cancer that is confined to the bladder is about 69%, that figure drops to 37% or below if the cancer spreads.

In recent years, the gold-standard treatment for muscle-invasive bladder cancers has been neoadjuvant chemotherapy, which helps shrink the tumors prior to surgical removal of the bladder. Immune checkpoint therapy—using the patient’s own immune cells to battle tumors—has emerged as another therapeutic option for patients whose cancer has spread beyond the bladder or who can't tolerate chemotherapy, or major surgery.

"Neoadjuvant chemotherapy and immune checkpoint therapy have revolutionized bladder cancer management," said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and co-senior author of the study. "However, determining which patients would benefit most from each type of therapy remains a major challenge."

With other types of cancer, particularly breast cancer, classifying whole tumors according to their genetic fingerprints has helped physicians choose targeted treatments that improve outcomes, Theodorescu explained. But this type of stratification has been less satisfactory for bladder cancer.

"When you do genetic profiling of a whole tumor, you're looking at all the proteins that are expressed," said Theodorescu, PHASE ONE Foundation Distinguished Chair and professor of Surgery and Pathology and Laboratory Medicine at Cedars-Sinai. "That tissue includes cancer cells, immune cells, cells from the connective tissue and the lining of blood vessels, and others. My hypothesis was that if we looked at the expression of individual cells within the bladder tumor, we could develop more effective tools to guide treatment and perhaps even find novel targets for future therapies."

Theodorescu’s research team used single-nucleus RNA sequencing—a novel method of profiling gene expression in cells using isolated nuclei, rather than whole tissues—to look at the genes expressed by each individual cell in aggressive muscle-invasive bladder cancers from 25 patients. They then performed additional analysis to map the positions of the individual cells within the tissue samples.

"This process allowed us to look at different cell types in the tumor and study interactions between those cells," said Simon Knott, PhD, associate director of the Center for Bioinformatics and Functional Genomics and associate professor of Biomedical Sciences at Cedars-Sinai, and co-senior author of the study.

The research team identified a previously unclassified type of cell in the bladder lining that expressed high levels of a protein called Cadherin 12, or high-CDH12. Patients who had tumors with large concentrations of high-CDH12 cells were more likely to experience poor outcomes following surgery, with or without neoadjuvant chemotherapy. However, these patients were also more likely to respond to immune checkpoint therapy, a type of immunotherapy that unmasks cancer cells to be attacked by the patient’s own immune system.

The investigators also found a type of immune cell, called T cells, positioned near groups of high-CDH12 cells, thus providing insight into why tumors with a high concentration of high-CDH12 might respond well to immune checkpoint therapy.

"These high-CDH12 cells appear to paralyze the immune system by drawing T cells to them and then exhausting them," Knott said. "While this protects the cancer cells from immune-mediated killing, it does make them vulnerable to immune checkpoint blockade, which reinvigorates the nearby T cells and causes them to destroy the cancer."

Also positioned near the high-CDH12 cells were connective-tissue cells called fibroblasts, which play an essential role in wound healing and could serve to shield tumor cells from chemotherapy. It is possible that a test using high-CDH12 cells as a biomarker could one day guide clinicians in choosing the correct treatment for patients with muscle-invasive bladder cancers, Theodorescu explained.

The investigators are planning studies of tumor samples obtained before and after chemotherapy and immunotherapy so that they can observe the reactions of the high-CDH12 cells to these treatments.

"For this study, we didn't have the types of samples that would allow us to do that," Knott said. "But looking at before-and-after tissues would let us see how these cells change their signals. If they are exposed to chemotherapy, do they increase their signaling to fibroblasts? If they are exposed to checkpoint inhibitors, do they decrease signaling to T cells? I would predict ‘yes,’ but we don't know for certain."

Research for this study is supported by the National Cancer Institute under Award Number CA075115.

Disclosures: Co-authors Kenneth Gouin, Nathan Ing, Charles Rosser, Simon Knott and Dan Theodorescu have filed a provisional patent (Application No. 63/197,129 Use of cancer cell expression of Cadherin 12 and Cad-Herin 18 to treat muscle invasive and metastatic bladder cancers) based on the biomarker features of the CDH12 population defined in this work.

Read more on the Cedars-Sinai Blog: The Weapon Inside