Johns Hopkins researchers make progress in the development of noninvasive urine test for prostate cancer

Researchers at the Johns Hopkins Kimmel Cancer Center have made significant progress toward development of a simple, noninvasive liquid biopsy test that detects prostate cancer from RNA and other specific metabolic chemicals in the urine.

A description of their findings appears in the Feb. 28 issue of the journal Scientific Reports.

The investigators emphasize that this is a proof-of-principle study for the urine test, and it must be validated in additional, larger studies before it is ready for clinical use.

The researchers used RNA deep-sequencing and mass spectrometry to identify a previously unknown profile of RNAs and dietary byproducts, known as metabolites, among 126 patients and healthy, normal people. The cohort included 64 patients with prostate cancer, 31 with benign prostatic hyperplasia and prostatitis diseases, and 31 healthy people with none of these conditions. RNA alone was not sufficient to positively identify the cancer, but addition of a group of disease-specific metabolites provided separation of cancer from other diseases and healthy people.

"A simple and noninvasive urine test for prostate cancer would be a significant step forward in diagnosis. Tissue biopsies are invasive and notoriously difficult because they often miss cancer cells, and existing tests, such as PSA (prostate-specific antigen) elevation, are not very helpful in identifying cancer," says Ranjan Perera, Ph.D., the study's senior author. Perera is also the director of the Center for RNA Biology at Johns Hopkins All Children's Hospital, a senior scientist at the Johns Hopkins All Children's Cancer & Blood Disorders Institute and the Johns Hopkins All Children's Institute for Fundamental Biomedical Research, and an associate professor of oncology at the Johns Hopkins University School of Medicine and Johns Hopkins Kimmel Cancer Center member.

We discovered cancer-specific changes in urinary RNAs and metabolites that -- if confirmed in a larger, separate group of patients -- will allow us to develop a urinary test for prostate cancer in the future."  Bongyong Lee, Ph.D., study's first author and a senior scientist at the Cancer & Blood Disorders Institute.

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Researchers identify new prevention strategy for type 1 diabetes

A protein newly identified as important in type 1 diabetes can delay onset of the disease in diabetic mice, providing a new target for prevention and treatment in people, according to research led by scientists at the U.S. Department of Energy's Pacific Northwest National Laboratory and Indiana University School of Medicine. Because type 1 diabetes is incurable and has serious lifelong health consequences, prevention is a major research goal.

The key to the new study, published online January 9, 2020, in the journal Cell Metabolism, is a technique called mass spectrometry, which can comprehensively detect proteins that are found at extremely low levels in the body, but can have large effects on health.

The multidisciplinary research team of physicians and biochemists used a new strategy to pinpoint proteins in beta cells, a subset of pancreatic islets that increase or decrease in response to immune system attack. Beta cells normally regulate blood sugar levels in the pancreas. In people susceptible to type 1 diabetes (previously called insulin-dependent or juvenile diabetes) these cells are slowly destroyed by the body's own immune system. Here, the researchers focused on how islets respond to inflammation.

The researchers treated human pancreatic islets with substances produced by the body and thought to be involved in the diabetes disease process. They identified a total of 11,324 proteins, with 387 affected by the treatment. Of these 387, they narrowed their focus to one: growth differentiation factor 15 (GDF15).

We wanted to identify proteins that can intervene in the diabetes disease process. We became interested in GDF15 because the protein level was suppressed by 70 percent after treatment. Ernesto Nakayasu, a biomedical scientist at PNNL and co-lead author of the study      

              GDF15 is known for its protective effects in different types of cells in the human body but it had never been studied in islets. When the researchers measured levels of GDF15 in pancreas tissue from people with diabetes, they found the protein was depleted in their malfunctioning islet cells.

But the key piece of evidence emerged when the scientists treated non-obese diabetic mice withGDF15, and it reduced development of diabetes by 53%. Non-obese diabetic mice are a common model for testing type 1 diabetes treatments because they spontaneously develop autoimmune diabetes with many similarities to the human disease. 

"We hypothesized that reduced GDF15 was not a good thing for islet survival, and indeed that was the case," said Raghu Mirmira, a study principal investigator. "This work opens the way for us to consider these sorts of 'islet protective factors' as therapies to prevent or reverse type 1 diabetes." 

Mirmira until recently served as professor of pediatric diabetes and director of the Center for Diabetes and Metabolic Diseases at Indiana University School of Medicine. He is now a professor of medicine in the Section of Endocrinology, Diabetes & Metabolism at the University of Chicago

"This approach differs substantially from current thinking that targets the immune system. While GDF15 may be one new therapy, we identified other proteins that may work in conjunction with GDF15, so this work really represents a treasure-trove of information that can be mined for new therapies," said Mirmira.PNNL's Tom Metz, the co-principal investigator and an expert in mass spectrometry-based proteomics of islets, agreed, adding:

This study illustrates the power of non-reductionist, comprehensive approaches, such as proteomics, for discovering new information in complex systems. The protective role of GDF15 against islet destruction and its ability to delay onset of type 1 diabetes in the mouse model would have been very difficult to discover without performing the initial comprehensive proteomics analysis of stressed human islets.

The researchers are now working on the idea that low levels of GDF15 in islets may somehow be playing a proactive role in instigating the autoimmune attack that ultimately kills them.This thinking is somewhat counterintuitive in the type 1 diabetes field, but it is this kind of out-of-the-box thinking that may lead to therapies we never thought of previously.Raghu Mirmira, a study principal investigator.

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