Reining in protein production could have therapeutic effects on bladder tumors, according to new work published today in the journal JCI Insight. “This is the first time that it’s been shown that protein synthesis is necessary for efficient bladder cancer development,” said Dr. Andrew Hsieh, a Fred Hutchinson Cancer Research Center bladder and prostate cancer researcher and oncologist. Hsieh and Dr. Sujata Jana, the postdoctoral fellow in Hsieh’s lab who spearheaded the project, demonstrated that increasing protein synthesis expedited bladder cancer development and progression, while reducing protein synthesis slowed the process. They showed that an experimental drug that blocks protein synthesis — one which is already being evaluated in people with other cancers — slows bladder tumor progression and extends survival in mouse models of the disease. Similar drugs could have a wide impact: Jana and Hsieh also found that about a third of the patient tumor samples they surveyed have a molecular modification that could make the cancers vulnerable to drugs of this type. Though bladder cancer is the fourth-most common tumor type among U.S. men (and eighth most-common among women), it has historically garnered less research attention than other solid tumors. In 2021 in the U.S., over 80,000 people will be diagnosed with the disease, and more than 17,000 will die from it. It is primarily associated with exposure to certain toxic substances, including compounds in cigarette smoke. But while quitting smoking reduces a person’s risk for lung cancer, it doesn’t change their bladder cancer risk, Hsieh said. He became interested in studying bladder cancer as a young oncologist, taking on patients from a colleague after she moved to another practice. Most patients had prostate cancer, but a few had late-stage bladder cancer. “I just remember that within a year they all passed away,” Hsieh said. “It's a really terrible disease.” At the time, when Hsieh looked for studies that linked changes in protein synthesis (his area of study) to bladder cancer, he found none. Protein synthesis, also termed translation, is a fundamental process by which cells build the proteins that run every cellular process, from growth to migration. Sometimes, changes in this process promote cancer. When Hsieh started his own lab, he decided to include bladder cancer. “I wanted to dedicate my lab to a cancer that was understudied in the field of translation and needed more insight for the development of new therapeutics,” he said. Unlike many cancer researchers, Hsieh doesn’t focus on tumor DNA and the mutated genes that tumors use as instructions for making altered proteins. Instead, he studies a molecule in between DNA and protein, called messenger RNA, or mRNA. Because we only have two copies of each gene, but need many copies of each protein, our cells transcribe the information in a particular gene into many copies of mRNA, then “translate” that information to create proteins. Hsieh has found that changes in the process of translating mRNA into protein can underpin development and progression of tumors, including prostate tumors. When he started his own lab at the Hutch, Hsieh hoped to discover similar connections between mRNA translation and bladder cancer. Jana took up the project. Jana, Hsieh and their team first wanted to see if protein synthesis plays a role in bladder cancer formation. They used mice that have been genetically modified to reduce their production of proteins by about 60%. Though these mice have some abnormalities, the researchers saw no difference in bladder development and function compared to mice that synthesize proteins normally. They then compared bladder cancer formation in mice with reduced and normal protein synthesis. To induce bladder cancer, the researchers mimicked long-term carcinogen exposure, giving the mice a chemical found in cigarette smoke called BBN, short for N-butyl-N-(4-hydroxybutyl) nitrosamine, every day for 200 days, or about a quarter of a lab mouse’s natural lifespan. As the body attempts to flush out BBN, its carcinogenic effects get concentrated in the bladder, promoting tumor formation. The scientists saw that mice genetically engineered to have lowered protein synthesis lived 12% longer — a median difference in lifespan of about 30 days. “That was the linchpin for why we want to study this,” Hsieh said. “Having less protein synthesis seemed to protect from the carcinogenic effects of a smoking-related compound.” His team also found that BBN-caused bladder tumors produced new proteins at twice the rate of normal bladder tissue, further strengthening the link between mRNA translation and bladder cancer. Using tumor organoids, which mimic tumors growth in a lab dish, Jana was able to pinpoint a single molecule that appeared to be a key player in this process. Called eIF4E, it helps ensure that proteins can be produced by getting the mRNA-translation process started. She discovered bladder tumors had higher levels of a modified form of the eIF4E protein with enhanced function. Jana again found that reduced protein synthesis didn’t affect bladder development or function when she studied mice whose eIF4E gene had been altered to prevent this modification from occurring. When she treated mice with BBN, she saw that mice whose eIF4E couldn’t be modified by tumors lived 10% longer than mice with normal eIF4E. Their tumors were also significantly smaller. “It was striking evidence that eIF4E is very important for bladder cancer development through controlling protein synthesis,” Jana said, noting that it was surprising that a single modification could have such an effect on tumor development. She and Hsieh next turned to eFT508, an experimental drug — already being tested against several cancer types in clinical trials — that blocks the activity of enzymes that modify eIF4E. The researchers treated bladder cancer organoids made from tumors tissue that arose in mice treated with BBN and saw that it their growth, suggesting that eIF4E also plays a role in maintaining bladder tumors. Like many other tumor types, the molecular characteristics of different patients’ bladder cancer tumors can vary. Jana examined eIF4E in several patient-derived xenograft models, or PDX models, in which tumor tissue from a patient is implanted in a mouse. Five out of nine had high levels of modified eIF4E. When she compared the response of bladder tumor organoids made from patient-derived bladder tumors, she found that only the bladder tumors with high levels of the modification responded to drug treatment. When she treated PDX mice with the drug, it extended survival in the mice whose tumors carried high levels of modified eIF4E. As researchers, “we do experiments, we stand at the bench — but to see the effect in the whole organism, was a very exciting moment for me,” Jana said. Jana wanted to see how widespread this modification is in real-life patients. So she surveyed samples of bladder cancer tissues collected from 25 bladder cancer patients treated at the University of Washington. She found that 37% of patients whose tumors were invading the surrounding muscle had high levels of modified eIF4E, suggesting that a substantial number of patients have the potential to benefit from a drug that targets it. Each of the researchers’ survival studies of bladder cancer development or drug response took over a year for them to conduct. Hsieh noted that during this time, the field “exploded.” Several new classes of drugs have improved treatment options for bladder cancer patients. These include immunotherapies, including checkpoint inhibitors like Bavencio (avelumab) and antibody-drug conjugates that use immune proteins to concentrate cancer drugs in tumor tissue, as well as drugs that target a commonly overproduced protein. But many will still die after their disease spreads, and Hsieh and Jana hope that their work is a step toward offering patients another life-extending treatment. “The big question for me is, how does translation interface with these drugs?” Hsieh said. They aim to test eFT508’s potential as a combination therapy with other bladder cancer treatments, starting with mouse models of bladder cancer. They also hope to tease out whether eFT508’s anti-tumor effects come from reducing protein synthesis in bladder tumor cells themselves, or from effects on other cell types. Additionally, Jana is working to better understand how BBN treatment causes the increase in protein synthesis that facilitates tumor development, as well as untangling eIF4E’s role in bladder tumor development and progression. She’s also extending her focus to other regulators of protein synthesis. “There are very likely other ways bladder cancers use protein synthesis to promote aggressive disease,” she noted, pointing to the nearly two-thirds of patients whose tumors didn’t exhibit the eIF4E modification. “Hopefully [these results] garner interest in the clinical community to consider studying these things in clinical trials, perhaps using eFT508,” Hsieh said. “But there are also other companies that are developing translation inhibitors, and we're excited to be a part of that future.” This research was supported by the National Institutes of Health, a Burroughs Wellcome Fund Career Award of Medical Scientists, the Emerson Collective, the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, the Matthews family, Nancy and Dick Bernheimer, Dan Stinchomb, the Thomas and Patricia Wright Memorial Fund and eFFECTOR Therapeutics, Inc. Source
