(Press-News.org) BOSTON - Since the discovery that microRNAs play key roles in regulating human disease, the hope has been that these short non-coding RNA molecules could be translated into a therapeutic strategy for the treatment of cancer. But this promising application has been significantly hampered by a number of physiological and cellular barriers that prevent microRNA-based therapies from actually reaching tumor cells.
Now scientists have identified a novel delivery platform by which an antisense molecule - akin to the mirror image of the microRNA - can be used to exploit a unique feature of the tumor microenvironment and thereby gain access to cancer cells. Described online in the journal Nature, the promising findings suggest a new model for the development of microRNA-based anti-cancer drugs and targeted drug delivery.
"We have been building the case that there are certain, critical microRNAs that cause cancer when they are overexpressed in cells," explains senior author Frank Slack, PhD, Director of the Institute for RNA Medicine (iRM) in the Cancer Center at Beth Israel Deaconess Medical Center. "With this publication, we have now shown the applicability and the utility of a new therapeutic target for cancer."
For the past 10 years, Slack has investigated the roles of microRNAs as oncogenes and tumor suppressors, demonstrating how a number of microRNAs regulate processes important for cell growth, division, survival and migration, all of which can go awry in cancer. His work has revealed that microRNAs are both effective targets and therapeutics in cancer.
In this new work, conducted as part of an interdisciplinary team at Yale University, Slack and his coauthors created a mouse model to study miR-155, a microRNA that, when overexpressed, leads to the development of diffuse large B-cell lymphoma (DLBCL), a type of blood cancer that is difficult to treat. "We hypothesized that we could inhibit the function of miR-155 by way of an antisense molecule that would bind to miR-155," says Slack. An antisense molecule can shut down RNA activity when it binds to the original molecule. But first it has to get there.
"There are a number of significant obstacles to reaching the tumor cell target," explains Slack. "Some roadblocks are clearance through the kidneys and accumulation in the liver, which absorbs any systemically injected agent. Furthermore, even if you are able to reach your targeted cells, the molecules must cross cell membranes and escape degradation from a process known as endocytosis. If you can picture our antisense molecule being a warhead, we had to find the right 'rocket' to actually transport it to its target."
The "rocket" turned out to be a peptide with a low-pH induced transmembrane structure (pHLIP), meaning it inserts into cell membranes only in instances when cells are low in pH. And tumor cells provided the ideal environment.
"Unlike normal cells, which produce energy through glycolysis plus oxidative phosphorylation, cancer cells conduct a high rate of glycolysis followed by lactic acid production," says Slack. "This unique feature results in an acidic tumor microenvironment, and that proved to be the trick. When we attached our antisense warhead to the pHLIP peptide, not only did it successfully insert itself into the tumor cell, but it also dragged the antisense molecule itself into the cell. Now the 'warhead' could deploy and actually inhibit microRNA function - and control cancer growth."
The miR-155/DLBCL mouse models showed dramatic differences in tumor size, with slowed tumor growth and extended survival of the animals that were treated with the anti-microRNA therapy. The authors went on to further show that this particular treatment is less toxic than the existing treatment for human disease.
"With this delivery platform, we should also be able to transform other RNAs into druggable targets," says Slack, adding that low pH is also an issue in kidney disease, myocardial infarction, stroke and infection, among other conditions.
"This advance shows tremendous efficacy with no short-term side effects," says Roy Herbst, MD, PhD, Chief of Medical Oncology in the Yale Cancer Center, where the work was conducted. "Under Frank Slack's leadership, this collaboration of biochemists, pathologists, biomedical engineers and basic scientists has demonstrated the enormous value of interdisciplinary translational research in moving biomedical discoveries toward patient care. The hope is that a variant of this therapeutic might soon be able to enter clinical trials."
Adds Pier Paolo Pandolfi, MD, PhD, Director of the BIDMC Cancer Center, "With this new work, Dr. Slack has made a critically important step in demonstrating how relevant it will be to effectively target microRNAs in the treatment of cancer in the years to come. MicroRNAs and other non-coding RNAs are among the most promising avenue in our pursuit of personalized cancer therapies, and with this novel delivery platform, we are poised to begin testing these agents in humans."
INFORMATION:
Coauthors include investigators Christopher J. Cheng (first author), Raman Bahal, Imran, A. Babar, Zachary Pincus, Francisco Barrera, Connie Liu, Alexander Svoronos, Demetrios T. Braddock, Peter M. Glazer, Donald M. Engelman and W. Mark Saltzman.
This work was supported by the following grants from the National Institutes of Health (NIH): R01CA131301, R01HL085416, R01GM073857, R01ES005775, R01CA148996, R01EB000487, 2T32HL007974 and pilot grants from the Yale Comprehensive Cancer Center.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide.
BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance, and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Senior Life and is a research partner of Dana-Farber/Harvard Cancer Center and The Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www.bidmc.org.
Small pieces of synthetic RNA trigger a RNA interference (RNAi) response that holds great therapeutic potential to treat a number of diseases, especially cancer and pandemic viruses. The problem is delivery -- it is extremely difficult to get RNAi drugs inside the cells in which they are needed. To overcome this hurdle, researchers at University of California, San Diego School of Medicine have developed a way to chemically disguise RNAi drugs so that they are able to enter cells. Once inside, cellular machinery converts these disguised drug precursors -- called siRNNs -- ...
Northwestern Medicine scientists have discovered a new potential drug therapy for a rare, incurable pediatric brain tumor by targeting a genetic mutation found in children with the cancer.
By inhibiting the tumor-forming consequences of the mutation using an experimental drug called GSKJ4, they delayed tumor growth and prolonged survival in mice with pediatric brainstem glioma.
Also known as diffuse intrinsic pontine glioma (DIPG), the disease occurs when tumors form in the brainstem, which controls essential body functions such as breathing, heartbeat and motor and ...
BOSTON - A research team led by Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute (DFCI) has uncovered surprising new findings that underscore the role of an important signaling pathway, already known to be critical in cancer, in the development of type 2 diabetes. Their results, published in the November 17, 2014 advance online issue of the journal Nature, shed additional light on how a longstanding class of diabetes drugs, known as thiazolidinediones (TZDs), work to improve glucose metabolism and suggest that inhibitors of the signaling pathway -- known ...
PROVIDENCE, R.I. [Brown University] -- Ample evidence of ancient rivers, streams, and lakes make it clear that Mars was at some point warm enough for liquid water to flow on its surface. While that may conjure up images of a tropical Martian paradise, new research published today in Nature Geoscience throws a bit of cold water on that notion.
The study, by scientists from Brown University and Israel's Weizmann Institute of Science, suggests that warmth and water flow on ancient Mars were probably episodic, related to brief periods of volcanic activity that spewed tons ...
A team of New York University and University of Barcelona physicists has developed a method to control the movements occurring within magnetic materials, which are used to store and carry information. The breakthrough could simultaneously bolster information processing while reducing the energy necessary to do so.
Their method, reported in the most recent issue of the journal Nature Nanotechnology, manipulates "spin waves," which are waves that move in magnetic materials. Physically, these spin waves are much like water waves--like those that propagate on the surface ...
In what is likely to be a major step forward in the study of influenza, cystic fibrosis and other human diseases, an international research effort has a draft sequence of the ferret genome. The sequence was then used to analyze how the flu and cystic fibrosis affect respiratory tissues at the cellular level.
The National Institute of Allergy and infectious Diseases, of the National Institutes of Health, funded the project that was coordinated by Michael Katze and Xinxia Peng at the University of Washington in Seattle and Federica Di Palma and Jessica Alfoldi at the Broad ...
LA JOLLA, CA - November 17, 2014 - For decades, scientists thought drug addiction was the result of two separate systems in the brain--the reward system, which was activated when a person used a drug, and the stress system, which kicked in during withdrawal.
Now scientists at The Scripps Research Institute (TSRI) have found that these two systems are actually linked. Their findings, published November 17 in the journal Nature Neuroscience, show that in the core of the brain's reward system are specific neurons that are active both with use of and withdrawal from nicotine. ...
Joseph B. Muhlestein, M.D., of the Intermountain Medical Center Heart Institute, Murray, Utah, and colleagues examined whether screening patients with diabetes deemed to be at high cardiac risk with coronary computed tomographic angiography (CCTA) would result in a significant longterm reduction in death, heart attack, or hospitalization for unstable angina. The study appears in JAMA and is being released to coincide with its presentation at the American Heart Association's Scientific Sessions 2014.
Diabetes mellitus is the most important coronary artery disease ...
Yasuo Ikeda, M.D., of Waseda University, Tokyo, Japan, and colleagues examined whether once-daily, low-dose aspirin would reduce the total number of cardiovascular (CV) events (death from CV causes, nonfatal heart attack or stroke) compared with no aspirin in Japanese patients 60 years or older with hypertension, diabetes, or poor cholesterol or triglyceride levels. The study appears in JAMA and is being released to coincide with its presentation at the American Heart Association's Scientific Sessions 2014.
The World Health Organization estimates that annual global mortality ...
DALLAS - November 17, 2014 - Using next generation gene sequencing techniques, cancer researchers at UT Southwestern Medical Center have identified more than 3,000 new mutations involved in certain kidney cancers, findings that help explain the diversity of cancer behaviors.
"These studies, which were performed in collaboration with Genentech Inc., identify novel therapeutic targets and suggest that predisposition to kidney cancer across species may be explained, at least in part, by the location of tumor suppressor genes with respect to one another in the genome," said ...
