Heart Failure Drugs May Also Fight Cancer
Researchers recently found that cardiac glycosides, which primarily are used to treat heart failure and irregular heartbeats, can also act like cancer vaccines when combined with chemotherapy drugs.
The study, published July 18, 2012, in the journal Science Translational Medicine, was led by Laurie Menger, a graduate student in the Kroemer Laboratory at Institut National de la Santé et de la Recherche Médicale (INSERM U848) in Villejuif, France.1 She and colleagues used previous clinical trial data to show that cancer patients taking a cardiac glycoside called digoxin (Lanoxin) for other purposes had improved survival compared with cancer patients who were not taking the drug. When taken with chemotherapy drugs, the drugs convert dead cancer cells into a vaccine that prompts the host's immune system to attack the tumor.
“This is a highly original and necessarily controversial breakthrough since it challenges the previous belief that anticancer chemotherapies act solely on the tumor cells, without any significant involvement of the host immune system,” says coauthor Guido Kroemer, MD, PhD, of Université Paris Descartes.
[ Cardiac glycosides, such as digoxin, have been shown to improve survival rates for cancer patients when combined with chemotherapy drugs. ]
Cell death is usually nonimmunogenic, and only a small number of chemotherapeutic agents can induce immunogenic cell death (ICD), Dr. Kroemer notes. In mouse studies, the researchers found that chemotherapy plus digoxin can stimulate anticancer immune response. Encouraged by the results, they performed an extensive retrospective clinical study based on identification of all cancer patients who received digoxin at Institut Gustave Roussy in Paris. Results showed that the overall survival for cancer patients taking digoxin was better than that of the controls, despite the presence of an underlying cardiac problem.
In addition, a subgroup analysis showed improved overall survival for digoxin-treated cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma, but not for nonsmall-cell lung cancer or prostate cancer.
Because the strongest positive effect of cardiac glycosides in the study was observed in patients with head and neck cancer, researchers are now planning a phase I/II trial with head and neck cancer.
Dr. Kroemer says the trial will enroll patients with locally advanced head and neck cancers that are negative for human papillomavirus (HPV). The primary endpoints will be safety and local infiltration of the tumor by immune effectors. Researchers also will assess tumor mass, time to progression, and overall survival.
They are currently screening additional drug collections, hoping to discover more ICD inducers.
National Institutes of Health Funds 3-D Chip Initiative
The Bethesda, Maryland–based National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) has awarded 17 grants supporting the creation of 3-D chips with living cells and tissues that accurately model the structure and function of such human organs as the lung, liver, and heart. The goal of the initiative is to improve the process for determining whether drugs will be safe in humans.
The Tissue Chip for Drug Screening Initiative is a collaboration between NCATS, the Defense Advanced Research Projects Agency (DARPA) of Arlington, Virginia, and the U.S. Food and Drug Administration (FDA).
Once the chips are developed, researchers can use the models to determine if drugs and vaccines are safe or toxic in humans. The tissue chips will provide a faster and more cost-effective method of making this determination by speeding the process through which drugs make it to clinical trials. They can also teach scientists about disease progression and help them to better prevent, diagnose, and treat specific conditions.
According to the NIH, more than 30% of medications have failed in clinical trials because they were found to be toxic, despite preclinical animal studies that appeared promising.
Tissue chips are engineered microsystems that represent units of human organs and model both the structure and function of these organs. These miniature models of living organ tissues exist on a transparent microchip, and are designed by using a combination of techniques from the computer industry and modern tissue engineering. In size, they range from a quarter to a house key, and are lined by living cells that replicate the complex biological functions of different organs.
NIH has committed up to $70 million over 5 years to the tissue chip program. Ten of the awards will support studies to develop the 3-D cellular microsystems. The remaining 7 awards will fund research exploring the potential of stem and progenitor cells to differentiate into multiple cell types that represent the cellular architecture within organ systems. These efforts could provide a source of cells to populate tissue chips.
[ Researchers plan to use 3-D tissue chips—which model the human lungs, liver and heart organs—to determine if various drugs and vaccines are safe for people. ]
At the same time, DARPA has entered into cooperative agreements with two NIH tissue- chip-award recipients—the Wyss Institute at Harvard University and the Massachusetts Institute of Technology, both of Cambridge, Massachusetts—to develop engineering platforms that integrate 10 or more organ systems.
Pharmaceutical Technology and Education Group Partners With NIH to Improve Drug Development for Rare Diseases
Bridging the gap between discovery and bringing a drug to market is the goal of a new partnership between the National Institutes of Health (NIH) and the National Institute for Pharmaceutical Technology and Education (NIPTE).
“Our goal is to create opportunities for research in pharmaceutical technology,” says Prabir Basu, PhD, NIPTE executive director. “People often forget that the critical path from discovery to market is pharmaceutical development.”
NIPTE is an academic, not-for-profit organization dedicated to research and education in pharmaceutical product development and manufacturing. Its membership includes 13 universities and 50 to 60 faculty members who are leaders in pharmaceutical development and engineering. In July 2012, the organization announced a partnership with the National Center for Advancing Translational Sciences (NCATS) and their Therapeutics for Rare and Neglected Diseases (TRND) program, which focuses on encouraging and speeding the development of new drugs for such diseases.
With limited funding for pharmaceutical research available, NIPTE leaders believe it is important for pharmaceutical scientists and engineers to work together in preclinical development, clinical trials, and product development, says Dr. Basu. The latter—NIPTE's primary focus—involves developing a manufacturing process that ensures a safe and effective formulation of the drug.
“We will develop the technology for making large quantities of the active ingredient,” Dr. Basu adds. “Technologies are getting much more complicated and products are getting more sophisticated, but the science behind it is not keeping up.”
[ NIPTE leaders hope their partnership with NIH will help speed research into developing safe and effective formulations of drugs to treat rare and neglected diseases. ]
According to NIPTE, advances in chemistry, chemical engineering, computer modeling, instrumentation, analytical science, and product formulations can be applied to pharmaceutical product development and manufacturing to make those processes faster, less labor-intensive, and better able to predict performance early on. “Scientific advances in formulation, analytical, and manufacturing techniques can make drugs more bioavailable to patients,” which is one of the current challenges in pharmaceutical manufacturing, Dr. Basu says.
Meanwhile, TRND was created to discover, optimize, and test therapies for rare diseases, with the goal of providing sufficient data to support successful Investigational New Drug (IND) applications to the U.S. Food and Drug Administration (FDA) and early clinical studies.
“If TRND identifies a compound they think could be effective against certain diseases, they will look for outside partners who can help them in the development process,” Dr. Basu says. “Because of our diversity, we believe we can help them in a lot of different ways.”
He also hopes that working jointly with TRND will enable his organization to communicate the importance of investing in pharmaceutical technology to NIH.
ResearchMatch Links Researchers, Volunteers through Online System
Tt's not always easy for patients to find a clinical trial that applies to them and researchers cannot always find the right patients for their studies. ResearchMatch.org is helping to make the process easier for both.
Using an online system, ResearchMatch connects volunteers with researchers, even if they are geographically far apart. Based at Vanderbilt University in Nashville, Tennessee, the service was established in 2009 as part of the Clinical & Translational Science Awards (CTSA) Consortium.
To date, nearly 4,300 volunteers have enrolled in studies through ResearchMatch, which is a conservative estimate because not all researchers take the time to report everyone who has enrolled, says Laurie Lebo, PhD, ResearchMatch national program director. Dr. Lebo notes that nearly 26,000 potential volunteers have responded with interest, while more than 500 studies have been listed. At press time, ResearchMatch also had 1,255 researchers registered from 73 institutions.
[ Nearly 4,300 volunteers have enrolled in studies through the online system, which creates an easier way for patients to join clinical trials and for doctors to find study participants. ]
“That's great, but we need 26 million volunteers,” Dr. Lebo says. “We need much larger numbers when you break it down into all the different studies.”
The program recently received a $786,000, 18-month grant from the National Institutes of Health (NIH) to increase connectivity among researchers, volunteers, and stakeholders such as disease-specific organizations and advocacy groups. The award will help to create subregistries with more detailed information about volunteers in an effort to more closely match them to specific research trials.
For example, potential volunteers currently are asked only basic information about their medical conditions, medications, and demographics. The new effort will enable ResearchMatch to develop and pose more detailed questions when a patient reports a specific medical condition.
Specifically, the Interstitial Cystitis Association—with which ResearchMatch has exchanged links in the past—will create an advisory board to design questions asked of volunteers who report that condition when they register.
“At the end of 18 months, the goal is to have a model for this type of registry or engagement with other organizations,” Dr. Lebo says. “We want to have something that's sustainable and that will help us do some target marketing.”
Other ResearchMatch plans include:
- • Asking researchers about the types of organizations they need to reach.
- • Helping researchers who are conducting solely online research to do so through ResearchMatch.org. That way, volunteers who would like to participate in a study can immediately go through the consent process and answer the research survey without waiting for a researcher to contact them.
- • Providing volunteers who express interest in a study with immediate pre-screening questions provided by researchers. Similar to an online dating service, ResearchMatch would select volunteers to receive information about studies they might match. Rather than having to search for studies, volunteers would wait to be contacted and could update their profiles at any time.
Dr. Lebo says coordinators also have plans to expand the program's reach by quickly connecting volunteers to disease-specific sites listing additional studies, as well as including researchers from other non-CTSA institutions. There are some 156 institutions on their waiting list.