Novel drug combination discovered to induce high rates of human beta cell proliferation

Harmine

Researchers at the Icahn School of Medicine at Mount Sinai have discovered a novel combination of two classes of drugs that, together, cause the highest rate of proliferation ever observed in adult human beta cells- the cells in the pancreas that produce insulin- without harming most other cells in the body. The result is an important step toward a diabetes treatment that restores the body's ability to produce insulin.

The finding involved one type of drug that is known to cause beta cells to proliferate and another that is already in widespread use in people with diabetes. Together, they caused the cells to proliferate at a rate of 5 to 6 percent per day. The study was published today in Science Translational Medicine online.

We are very excited about this new drug combination because for the first time ever, we are able to see rates of human beta cell replication that are sufficient to replenish beta cell mass in humans with diabetes."

Andrew Stewart, MD, Director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute and lead author of the study

Diabetes occurs when there are not enough beta cells in the pancreas, or when those beta cells secrete too little insulin, the hormone required to keep blood sugar levels in the normal range. Approximately 30 million people in the United States have diabetes and nearly 50 to 80 million more are living with prediabetes (also called "metabolic syndrome"). Diabetes can lead to major medical complications: heart attack, stroke, kidney failure, blindness, and limb amputation.

In type 1 diabetes, the immune system mistakenly attacks and destroys beta cells. A deficiency of functioning beta cells is also an important contributor to type 2 diabetes, the most common type of diabetes. Thus, developing drugs that can increase the number of healthy beta cells is a major priority in diabetes research.

According to Dr. Stewart, none of the diabetes drugs currently on the market can induce beta cell regeneration in people with diabetes. In parallel with the Mount Sinai work, other researchers are studying pancreatic transplantation, beta cell transplantation, and stem cell replacement of beta cells for people with diabetes, but none of these approaches is in widespread use.

"This is a very exciting discovery in the field of diabetes and is a key next step in drug development for this disease," said Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai. "This important work truly holds promise for so many people."

In 2015, Dr. Stewart and his team published a paper in Nature Medicine that showed that harmine, a drug that inhibits the enzyme dual specificity tyrosine-regulated kinase 1A (DYRK1A), induced multiplication of adult human beta cells. In that study, his team also discovered that harmine treatment led to normal control of blood sugar and proliferation in human beta cells in diabetic mice whose beta cells had been replaced with small numbers of transplanted human beta cells. While this was a major advance, the proliferation rate was lower than needed to rapidly expand beta cells in people with diabetes.

This current paper builds upon a study that Dr. Stewart and his team published in Cell Metabolism in December 2018 where they discovered that DYRK1A inhibitors combined with another drug that inhibits transforming growth factor beta superfamily members (TGFβSF), also known as a family of proteins with various biological processes such as growth, development, tissue homeostasis and immune system, could cause beta cells to proliferate at a rate of 5 to 8 percent per day. However, according to Dr. Stewart, TGFβSF's would likely have side effects on other organs in the body that would prevent clinical use.

The next challenge was developing ways to target regenerative drugs to the beta cells while avoiding other cells and organs in the body where they may elicit adverse effects.

In the study published today, titled "GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human beta cell regeneration," Dr. Stewart and his team combined DYRK1A inhibitors like harmine with a class of beta cell-targeting drugs, also known as GLP1R agonists, which are already in widespread use in people with type 2 diabetes. They showed-;in beta cells from normal people and people with type 2 diabetes, both in the tissue culture dishes and in human beta cells transplanted into mice-;that combining harmine (or any other DYRK1A inhibitor) with any of the many GLP1R agonist drugs currently on the market for diabetes yields high rates of human beta cell replication, and does so in a way that is highly selective for the beta cell.

The project arose from the PhD thesis of an Icahn School of Medicine graduate student, Courtney Ackeifi, now a postdoctoral fellow in Dr. Stewart's lab and first author of the paper, who explored a broad spectrum of potential drug partners that could enhance the beta cell regenerative efficacy and selectivity of harmine.

Said Dr. Ackeifi of the discovery, "The beauty here is that the combination of DYRK1A inhibitors with GLP1R agonists achieves the highest rate of human beta cell replication possible, and does so in a highly specific way. This is an important advance in the field of diabetes because we may have found a way to convert a widely used class of diabetes drugs into a potent human beta cell regenerative treatment for all forms of diabetes."

"We know that a critical pathway to drive a cure for type 1 diabetes includes transplanting insulin-producing beta cells into people or enticing their existing beta cells to start multiplying," explains Francis Martin, PhD, JDRF Director of Research. "It is exciting to learn from the work of Dr. Stewart and his team that GLP1R agonists could increase the effect of the recently discovered agents that promote multiplication. Using GLP1R offers a means to boost the effect while also improving the safety of this type of drug."

The next goals of the project are to perform long-term studies in animals transplanted with human beta cells, and to determine if any cells or organs in the body other than beta cells are affected by the new drug combination.

https://en.wikipedia.org/wiki/Harmine

https://en.wikipedia.org/wiki/Glucagon-like_peptide-1_receptor_agonist

Novel drug shows promise in treating metastatic kidney cancer

                    

Metastatic kidney cancer remains largely incurable. Despite a dozen treatments and several immunotherapies, survival rates beyond 5 years remain around 10 percent. A study published in the Journal of Clinical Oncology reports initial findings with a novel drug belonging to a new class of medicines called HIF-2a inhibitors that show promise in treating metastatic kidney cancer.

Among 51 patients with aggressive kidney cancer that had progressed through four prior treatments on average, PT2385, the first HIF-2a inhibitor to be evaluated in clinical trials, blocked tumor growth for at least 4 months in 40 percent of the patients. Furthermore, cancer growth was stopped for more than a year in 25 percent of the patients. In addition, side effects were minimal.

"The combination of activity and tolerability is very encouraging," said corresponding author Dr. Kevin Courtney, Assistant Professor of Internal Medicine at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center. "We treated multiple patients on this trial in the Kidney Cancer Program at UT Southwestern, more than at any other institution. In our experience, this HIF-2a inhibitor offers a combination of safety and potential activity that is unique compared to current treatments for advanced kidney cancer."

PT2385, developed by Peloton Therapeutics Inc., represents the culmination of two decades of research at UT Southwestern beginning with the discovery of HIF-2a by Dr. Steven McKnight, Professor of Biochemistry who holds the Distinguished Chair in Basic Biomedical Research, and Dr. David Russell, Vice Provost, Dean of Research, and holder of the Eugene McDermott Distinguished Chair in Molecular Genetics. Next was the finding of a vulnerability in HIF-2a by Dr. Richard Bruick, Professor of Biochemistry and the Michael L. Rosenberg Scholar in Biomedical Research, and Dr. Kevin Gardner, Professor of Biophysics. This research was followed by the identification of chemicals that exploit a crevice in HIF-2a to destroy its activity. These chemicals were then licensed to Peloton Therapeutics, in the UT Southwestern BioCenter at Southwestern Medical District, which developed the HIF-2a blocking drug.

In a manuscript published in Nature last year, Dr. James Brugarolas, Professor of Internal Medicine, showed that blocking HIF-2a successfully reduced the growth of 50 percent of kidney cancers that were transplanted from patients into mice. In fact, the HIF-2a drug had greater activity in this study and was better tolerated than sunitinib, the most commonly prescribed drug for kidney cancer.

Dr. Brugarolas, who directs the Kidney Cancer Program and is the Principal Investigator of one of only two Specialized Programs of Research Excellence (SPORE) in kidney cancer designated by the National Cancer Institute, is now working to identify patients who are most likely to benefit from treatment with PT2385. "One of the biggest challenges we face across all treatments for kidney cancer is pairing the right drug with the right patient," said Dr. Brugarolas, who also holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D.

"HIF-2a, which fuels cell growth, is the most important driver of kidney cancer and the development of a drug that is helping patients is a remarkable outgrowth of our research," said Dr. Russell.

UT Southwestern Medical Center owns stock in Peloton Therapeutics and has a financial interest in the clinical trial described in the Journal of Clinical Oncology article. Drs. Bruick, Gardner, and McKnight have financial interests related to consulting; and Drs. McKnight, Bruick, and Gardner related to investment.

http://www.utsouthwestern.edu/newsroom/articles/year-2017/kidney-cancer-drug.html

Novel drug shows promise in treating metastatic kidney cancer