Good-Guy Bacteria May Help Cancer Immunotherapies Do Their Job

Individuals with certain types of bacteria in their gut may be more likely to respond well to cancer immunotherapy, researchers at the Harold C. Simmons Comprehensive Cancer Center found in a study of patients with metastatic melanoma.

The incidence of melanoma has been increasing over the past 40 years. Immunotherapies have dramatically improved the outlook for patients with metastatic melanoma in the past half-dozen years, but still only about half of these patients go into remission.

UT Southwestern cancer researchers analyzed the gut bacteria of 39 melanoma patients who were treated with immunotherapies and found a strong association between a good response and the presence of particular bacteria.

“Our research suggests there were certain good-guy bacteria that are needed to optimize the effectiveness of checkpoint inhibitors. These bacteria somehow prime your immune system so that it’s better able to attack cancer cells and kill them,” said senior author Dr. Andrew Koh, Associate Professor of Pediatrics and Microbiology with the Simmons Cancer Center.

Rick Spurr, former CEO of Zix, a company that provides email encryption services for banks and health care facilities, volunteered for the study that helped identify the link. The grandfather of six was diagnosed with metastatic melanoma, which was discovered on his lungs while he was fighting off a bout of pneumonia.

Mr. Spurr was treated with an every-other-week infusion of nivolumab, an immunotherapy drug that acts by lifting a brake on the immune system, allowing the body’s natural defenses to go into overdrive.

“I felt virtually no side effects from the treatment,” he said. “I started the treatment in the summer and I was skiing in November.”

Researchers found he had the beneficial gut bacteria and suspect this microbiome contributed to the outcome. As a group, patients who responded well to the immunotherapy had three specific bacteria:

  • Bacteroides thetaiotaomicron
  • Faecalibacterium prausnitzii
  • Holdemania filiformis

All three are common normal flora in the human intestinal tract.

After identifying the link, researchers looked for a potential reason for the association between the helper bacteria and immunotherapy effectiveness. “Is it something the bacteria are making? We examined metabolites in these subjects and found the strongest correlation between anacardic acid, present in cashews and mangoes, and the beneficial bacteria,” Dr. Koh said.

Researchers plan to follow up on the current research, which appears in the journal Neoplasia, with larger clinical studies.

“While these preliminary observations do not establish a firm causal connection between gut microbes and immunotherapy efficacy, they may lead eventually to a probiotic cocktail that could be given along with immunotherapy to enhance the chance of response,” said Dr. Koh, Director of Pediatric Hematopoietic Stem Cell Transplantation at UT Southwestern.

The research was supported by the Roberta I. and Norman L. Pollock Fund, the Melanoma Research Fund, the T. Boone Pickens Cancer Research Fund, the Cancer Prevention and Research Institute of Texas, and the National Institutes of Health.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 49 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.

CRI Scientists Discover Vitamin C Regulates Stem Cell Function and Suppresses Leukemia Development

Not much is known about stem cell metabolism, but a new study from the Children’s Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then regulates their function and suppresses the development of leukemia.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why. Our research provides part of the explanation, at least for the blood-forming system,” said Dr. Sean Morrison, the Director of CRI.

The metabolism of stem cells has historically been difficult to study because a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare. Techniques developed during the study, which was published in Nature, have allowed researchers to routinely measure metabolite levels in rare cell populations such as stem cells.

The techniques led researchers to discover that every type of blood-forming cell in the bone marrow had distinct metabolic signatures – taking up and using nutrients in their own individual way. One of the main metabolic features of stem cells is that they soak up unusually high levels of ascorbate. To determine if ascorbate is important for stem cell function, researchers used mice that lacked gulonolactone oxidase (Gulo) – a key enzyme that most mammals, including mice but not humans, use to synthesize their own ascorbate.

Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do. This gave CRI scientists strict control over ascorbate intake by the mice and allowed them to mimic ascorbate levels seen in approximately 5 percent of healthy humans. At these levels, researchers expected depletion of ascorbate might lead to loss of stem cell function but were surprised to find the opposite was true – stem cells actually gained function. However, this gain came at the cost of increased instances of leukemia.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said Dr. Michalis Agathocleous, lead author of the study, an Assistant Instructor at CRI, and a Royal Commission for the Exhibition of 1851 Research Fellow. “The epigenome is a set of mechanisms inside a cell that regulates which genes turn on and turn off.  So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

This increased risk is partly tied to how ascorbate affects an enzyme known as Tet2, the study showed. Mutations that inactivate Tet2 are an early step in the formation of leukemia. CRI scientists showed that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of leukemia.

These findings have implications for older patients with a common precancerous condition known as clonal hematopoiesis. This condition puts patients at a higher risk of developing leukemia and other diseases, but it is not well understood why certain patients with the condition develop leukemia and others do not. The findings in this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of Tet2. Our results suggest patients with clonal hematopoiesis and a Tet2 mutation should be particularly careful to get 100 percent of their daily vitamin C requirement,” Dr. Morrison said. “Because these patients only have one good copy of Tet2 left, they need to maximize the residual Tet2 tumor-suppressor activity to protect themselves from cancer.”

Researchers in the Hamon Laboratory for Stem Cell and Cancer Biology, in which Dr. Morrison is also appointed, intend to use the techniques developed as part of this study to find other metabolic pathways that control stem cell function and cancer development. They also plan to further explore the role of vitamin C in stem cell function and tissue regeneration.

Dr. Morrison is a Professor of Pediatrics at UT Southwestern, a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, and a Howard Hughes Medical Institute (HHMI) Investigator. He also holds the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern and the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern.

CRI and UTSW co-authors include Dr. Zhiyu Zhao, Assistant Professor at CRI and of Pediatrics at UT Southwestern; Dr. Weina Chen, Associate Professor of Pathology at UT Southwestern; Dr. Corbin Meacham, Dr. Rebecca Burgess, and Dr. Malea Murphy, postdoctoral researchers; and Dr. Ralph DeBerardinis, Associate Professor at CRI, of Pediatrics, and in the Eugene McDermott Center for Human Growth & Development. Dr. DeBerardinis, who holds the Joel B. Steinberg, M.D. Chair in Pediatrics and is a Sowell Family Scholar in Medical Research at UTSW, also is the Director of CRI’s Genetic and Metabolic Disease Program and Chief of the Division of Pediatric Genetics and Metabolism at UTSW.

The National Institutes of Health, HHMI, CPRIT, and donors to the Children’s Medical Center Foundation supported this work.

UT Southwestern Researchers Develop Potential Treatment for Fatal, Incurable Kidney Disease

Researchers at UT Southwestern Medical Center, working with a California biotech firm, have developed a potential drug to treat polycystic kidney disease – an incurable genetic disease that often leads to end-stage kidney failure.

The drug, now called RGLS4326, is in preclinical animal testing at San Diego-based Regulus Therapeutics Inc. An investigational new drug filing to pave the way for human clinical trials is expected later this year, said Dr. Vishal Patel, Assistant Professor of Internal Medicine at UT Southwestern.

Dr. Patel is senior author of a study describing research that led to the drug’s development, published online today in Nature Communications.

Affecting about 600,000 people in the U.S., autosomal dominant polycystic kidney disease (ADPKD) causes numerous fluid-filled cysts to form in the kidney. An affected kidney, normally the size of a human fist, sometimes grows as large as a football. As their numbers and sizes increase, these cysts eventually interfere with the kidney’s ability to filter blood and remove bodily waste. The cysts can quietly grow for decades until symptoms appear such as blood in the urine, Dr. Patel said. About half of those affected with ADPKD suffer kidney failure by age 60, according to the National Kidney Foundation.

“There isn’t a single drug on the U.S. market right now to treat the disease,” Dr. Patel said. “Once your kidneys fail, your only option for survival is to get a transplant or start dialysis.”

In 2009, Dr. Patel began searching for microRNAs that might underlie progression of ADPKD. MicroRNAs – or MiRs for short – are tiny RNA fragments that interfere with normal gene expression.

Proof that such RNA fragments even existed came in the early 1990s; their presence in humans was first reported in 2000. Those discoveries led to a groundswell of interest in developing drugs to treat diseases caused by microRNAs, Dr. Patel said – in part because the process can be straightforward once the problem-causing fragment is identified.

“Because miRs are so small, drugs can easily be designed against them. And since we know the nucleotide sequence of every known microRNA, all that is required is to prepare an anti-miR with a sequence that is exactly the opposite of the miR’s,” he said.

In this study, researchers in Dr. Patel’s lab focused on microRNA cluster 17~92 following identification of potential miR targets. A National Institutes of Health grant funded the UTSW research. In 2013, Dr. Patel and fellow researchers reported in Proceedings of the National Academy of Sciences that this microRNA cluster indeed appeared to promote kidney cyst growth.

Using four mouse models, the researchers next studied whether inhibiting this microRNA could slow cyst growth and thus delay ADPKD progression. They found that genetically deleting microRNA-17~92 slowed cyst growth and more than doubled the life spans of some mice tested.

Based on that finding, Dr. Patel’s lab collaborated with Regulus Therapeutics to test an anti-microRNA-17 drug. The test drug slowed the growth of kidney cysts in two mouse models and in cell cultures of human kidney cysts, the study showed.

In the Nature Communications study, UTSW researchers also reported how miR-17 causes cyst proliferation: the molecule essentially reprograms the metabolism of kidney cells so that cellular structures called mitochondria use less nutrients, freeing up resources to instead make cell parts that become cysts. MiR-17 accomplishes this by repressing a protein involved in making RNA called peroxisome proliferator-activated receptor alpha (PPARα), the researchers found.

Other UT Southwestern researchers included lead author Dr. Sachin Hajarnis, a research scientist; Dr. Ronak Lakhia, Instructor in Internal Medicine; Matanel Yheskel and Andrea Flaten, research technicians; Darren Williams, former research associate; Dr. Shanrong Zhang, research engineer; Joshua Johnson, an M.D./Ph.D. student; Dr. William Holland and Dr. Christine Kusminski, Assistant Professors of Internal Medicine; and Dr. Philipp Scherer, Professor of Internal Medicine and Cell Biology, who holds the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research.
Also contributing to the study were researchers from the University of Minnesota Medical School, the Mayo Clinic School of Medicine, the University of Montreal, the University of Kansas, and Regulus Therapeutics.

Funding was provided by the National Institutes of Health (NIH) and the PKD Foundation. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH under Award Number R01DK102572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

UT Southwestern and Regulus Therapeutics have applied for a patent for treatment of polycystic kidney disease with miR-17 inhibitors. In addition, Dr. Patel’s laboratory has a sponsored research agreement with Regulus, and Dr. Patel serves as a consultant for Regulus.

Cancer Drug Could Double as a Weapon Against Heart Disease, Promoting Regeneration of Damaged Heart Tissue

An anticancer agent in development promotes regeneration of damaged heart muscle – an unexpected research finding that may help prevent congestive heart failure in the future.

Many parts of the body, such as blood cells and the lining of the gut, continuously renew throughout life. Others, such as the heart, do not. Because of the heart’s inability to repair itself, damage caused by a heart attack causes permanent scarring that frequently results in serious weakening of the heart, known as heart failure.
For years, Dr. Lawrence Lum, Associate Professor of Cell Biology at UT Southwestern Medical Center, has worked to develop a cancer drug targeting Wnt signaling molecules. These molecules are crucial for tissue regeneration, but also frequently contribute to cancer. Essential to the production of Wnt proteins in humans is the porcupine (Porcn) enzyme, so-named because fruit fly embryos lacking this gene resemble a porcupine. In testing the porcupine inhibitor researchers developed, they noted a curiosity.

“We saw many predictable adverse effects – in bone and hair, for example – but one surprise was that the number of dividing cardiomyocytes (heart muscle cells) was slightly increased,” said Dr. Lum, senior author of the paper, and a member of UTSW’s Hamon Center for Regenerative Science and Medicine. “In addition to the intense interest in porcupine inhibitors as anticancer agents, this research shows that such agents could be useful in regenerative medicine.”

Based on their initial results, the researchers induced heart attacks in mice and then treated them with a porcupine inhibitor. Their hearts’ ability to pump blood improved by nearly twofold compared to untreated animals.

The study findings were published online this week in Proceedings of the National Academy of Sciences.

“Our lab has been studying heart repair for several years, and it was striking to see that administration of a Wnt inhibitor significantly improved heart function following a heart attack in mice,” said Dr. Rhonda Bassel-Duby, Professor of Molecular Biology and Associate Director of the Hamon Center for Regenerative Science and Medicine.
Importantly, in addition to the improved pumping ability of hearts in the mice, the researchers noticed a reduction in fibrosis, or scarring in the hearts. Collagen-laden scarring that occurs following a heart attack can cause the heart to inappropriately increase in size, and lead to heart failure.

“While fibrotic responses may be immediately beneficial, they can overwhelm the ability of the heart to regenerate in the long run. We think we have an agent that can temper this fibrotic response, thus improving wound healing of the heart,” said Dr. Lum, a Virginia Murchison Linthicum Scholar in Medical Research and Associate Director of Basic Research at the Harold C. Simmons Comprehensive Cancer Center.
Additionally, Dr. Lum said, preliminary experiments indicate that the porcupine inhibitor would only need to be used for a short time following a heart attack, suggesting that the unpleasant side effects typically caused by cancer drugs might be avoided.

“We hope to advance a Porcn inhibitor into clinical testing as a regenerative agent for heart disease within the next year,” Dr. Lum said.