Tuesday, October 28, 2014

Exploring new frontiers in personalized cancer care

Personalized medicine is turning medical care on its head, and cancer treatment is at the forefront of that revolution. The UAB Comprehensive Cancer Center’s 17th Annual Research Retreat introduced this cutting-edge work to an audience of nearly 400 clinicians and researchers. The topic was timely after this summer’s announcement of major initiatives in genomics and personalized medicine at UAB, including a research consortium between the Cancer Center and Huntsville’s HudsonAlpha Institute for Biotechnology.

“Personalized medicine is the future of cancer care,” noted Eddy Yang, M.D., Ph.D., associate professor in the UAB Department of Radiation Oncology, who organized this year’s symposium. “This is certainly a glimpse of what is to come for the Cancer Center and UAB as a whole.”

The Future: Cancer as a Chronic Disease

“Oncology has been a first mover for personalized medicine,” said invited speaker Mark Boguski, M.D., Ph.D., founder of Genome Health Solutions and a faculty member at Harvard Medical School.

Boguski shared his remarkable vision. With the use of personalized medicine, he said, we can now begin to reimagine cancer as a manageable chronic disease. Subsequent speakers amplified that theme, describing advances, challenges and roadblocks to delivering personalized cancer care to patients across the United States.

Boguski began with three patient case histories.

The first was a patient in 2010 with adenocarcinoma that was EGFR-positive (that is, it contained mutations that activated the EGFR pathway). When treatment with the usual drug failed, genomic and transcriptomic analysis showed why — metastases from the original cancer were no longer EGFR-positive. But biomarkers on those cancer cells successfully identified a target for a different drug that was effective.

The second case was a metastatic squamous cell carcinoma. Genomic analysis showed, surprisingly, that it could be treated with a hematological cancer drug.

“You wouldn’t guess to use that on a solid tumor,” Boguski said.

Similarly, in a case of advanced lymphoblastic leukemia, genomic analysis unexpectedly pointed to using a renal cell carcinoma drug. With this sea change in the way that oncologists can make their treatment decisions, cancer patients are beginning to ask that their genomes be analyzed, Boguski said.

The UAB Cancer Center’s Molecular Tumor Board, initiated last year, identifies patients who could benefit from DNA sequencing of their tumors, said Yang. These tests, usually conducted in patients with rare tumors or tumors that do not respond to typical treatment, can identify off-label uses for cancer drugs. For example, BRAF inhibitors, which are approved for melanoma, have been used to treat patients with other tumor types that nevertheless harbor the BRAF V600E mutation, Yang said. In another important consideration, “treating physicians have been successful in getting third-party payers to pay for these drugs outside the ‘approved’ indications using the profiling results,” he explained.

Cancer Center Honors Research Excellence

In addition to talks by leading investigators, the Cancer Center’s research retreat also features the work of a new generation of cancer researchers. Graduate students, postdoctoral fellows and junior faculty members took part in the annual poster competition; the 131 presentations emphasize the breadth of studies ongoing in the Cancer Center, from cancer prevention to bioinformatics. See the award winners here.
But roadblocks prevent the widespread delivery of such personalized, targeted care, Boguski noted in his talk, because:

80 percent of cancer care is delivered away from the top 50 cancer centers.
Most doctors suffer from a knowledge gap; they need accelerated genome training to understand the top molecular biomarkers and how these markers can guide patient therapy.
Pathologists — who are a key link to alter the delivery of care — need to know not only tissue pathology but also how to test for and report the molecular drivers of cancer.

Genomics Identifies Actionable Targets

Mark Kris, M.D., an attending physician at the Memorial Sloan Kettering Cancer Center and professor at the Weill Cornell Medical College, showed how genomics and personalized care can be harnessed to improve lung cancer survival.

Working with 11 cancer centers, Kris and colleagues tested 1,000 patients who had stage IV lung cancer. While tissue pathology confirmed adenocarcinoma, the cancers also underwent mutational analysis to probe for oncogenic drivers, and these findings were shared with physicians.

Two-thirds of the patients had at least one of 10 known oncogenic drivers. These drivers are “actionable targets” that helped to guide treatment choices, leading to increased median survival for these advanced cancer patients.

The French medical system, Kris noted, has provided genotyping to every lung cancer patient since 2011, at a rate of 20,000 patients a year. This equity of access to innovation does not exist in the United States, Kris said, even though the National Comprehensive Cancer Network clinical practice guidelines for non-small-cell lung cancer already list a set of molecular drivers that should be looked to to classify and guide treatment.

Needed: A New Kind of Trial

Another roadblock is the need for new ways to perform clinical trials of investigational drugs, said Donald Berry, Ph.D., professor of biostatistics at the M.D. Anderson Cancer Center and a co-founder of Berry Consultants.

Berry described how the use of Bayesian biostatistics in an adaptive platform trial can lower the numbers of patients needed for the trial, while simultaneously investigating multiple drugs and targets. He focused on a current study, I-SPY2, which is investigating treatments for breast cancer. (Berry noted that UAB is one of the largest contributors of patients to the trial.)

Data obtained during trials such as I-SPY2 are used to guide changes in the studies midstream, Berry explained. The result is nimble, lean studies that yield a more dependable estimate of the chance that a particular drug will succeed in its subsequent Phase III trial. Such information is crucial, given the cost and the failure rates of conventional Phase III trials.

Predicting Patient Response With Avatars

The final outside speaker, Paul Haluska Jr., M.D., Ph.D., associate professor of oncology at the Mayo Clinic, described an “Ovarian Avatar” model to personalize ovarian cancer treatment. The avatar is created by implanting live cancer tissue from the cancer patient into a mouse within two hours of surgery.

Haluska shared several definitions involved in this model:
“Xenograft” is a tumor taken from one species and implanted in another;
“Orthotopic” means the implant is placed in the natural body location for that type of tumor;
“Patient-derived Xenograft” is a direct implant from the patient into the other species, without any intermediate in vitro growth or manipulation; and
“Avatar” is thus an orthotopic, treatment-naïve, patient-derived xenograft.

Mayo implanted its first model in March 2010. Through this September, 404 models have been injected and 294 of them successfully engrafted. The avatar responses to a drug, Haluska said, appeared to mirror the patient responses to treatment with the same drug, and the avatars are being used for drug development.

The next step will be to actually use a particular patient’s avatar to direct her therapy. “It will be the first ovarian cancer with xenograft-directed therapy,” Haluska said. “The best predictor of response is response.”

Oncogenic Drivers and Racial Disparities

UAB has its own xenografts that are derived from glioblastoma multiforme tumors, said Christopher Willey, M.D., Ph.D., an associate professor in the Department of Radiation Oncology and director of the UAB Kinome Core (pronounced “k-eye-nome”). But these personal avatars have a problem — they take too much time to establish compared to the rapid and fatal course of glioblastomas. So Willey hopes instead to use “kinomic” profiles of established avatars from other patients to guide the treatment for a new patient; glioblastoma tissue removed from the new patient during surgery can quickly be kinomically profiled.

Kinomics uses substrate arrays to identify which kinase enzymes — often found to be key oncogenic drivers — are active in the cancer cells. This can help select among about 30 cancer chemotherapeutic agents that target kinases.

The other UAB speaker, Phillip Buckhaults, Ph.D., associate professor in the UAB Division of Hematology and Oncology, described his search for genetic mechanisms that lead to earlier onset and higher incidence of breast and colon cancers in African-Americans, as compared to Caucasian-Americans. His trail began with the discovery of a point-mutant variant of the TP53 tumor suppressor gene in African-Americans, and it has led to the variant’s effect on the PRDM1 chromatin-silencing gene.

Translating research insights from the laboratory to the clinic is a major focus of the UAB-HudsonAlpha cancer consortium, noted Cancer Center director Edward Partridge, M.D. “We’re not at the point yet where we can routinely apply genomics information from the tumor to treatment; but we’re clearly learning, and learning at a rapid pace,” Partridge said. “The goal of the consortium is to accelerate that, and we’re excited about what it means for the care we can bring to our patients.”

Jeff Hansen

Wednesday, October 22, 2014

Hunting for clues to healthy aging, from the lab to the sea floor

Researchers are "making an incredible amount of progress" in the search for molecular mechanisms underlying successful aging, says Steven Austad. His own studies are uncovering the secrets of long-lived animals, and investigating the anti-aging effects of the immunosuppressive drug rapamycin.

The longest-lived human on record didn’t make it much past 120 years. That’s nothing compared to the ocean quahog, a fist-sized clam found off the coast of Maine. “They can live 500 years or longer,” said Steven Austad, Ph.D., chair of UAB’s Department of Biology and associate director of the UAB Comprehensive Center for Healthy Aging. “They’ve been sitting out there on the sea floor since before Shakespeare was born.”

Austad’s research focuses on understanding the underlying causes of aging at the molecular level. Although his studies take him in many fascinating directions, it’s the ancient clams that everyone remembers. “I’m known in the field as the guy who works with weird animals,” Austad said.

So what do animals like the quahog know about healthy aging that we don’t? That question drives Austad’s studies in comparative gerontology, which look to long-lived animals to identify new molecular targets to help humans.

Protein Power

Clams — technically, bivalve mollusks — live longer than any other animal group; more than a dozen species have lifespans of a century or more. But they are not all masters of aging. Austad’s lab is studying mitochondrial function, protein stability and stress resistance across seven species of clams, with lifespans ranging from one year to the ocean quahog’s 500-plus years.

Studying long-lived animals is “a way to quickly identify new genes that might be targets for new drugs to keep people healthy longer.”
Austad’s research has convinced him that one key to slowing aging is to protect the proteins inside our cells. “Proteins make everything work in the cell, and to do that, they have to be folded precisely like origami,” Austad said. “But as we get older they get battered about, and ultimately lose that precise shape.”

That’s why Austad is so excited by what he’s found in ocean quahogs. “They keep their proteins in shape century after century,” he said. When Austad takes human proteins and adds them to a mix of tissues from the clams, “they become more stable, less likely to unfold.” His lab is now working to identify exactly what is protecting the clams’ proteins. That mechanism could point to a potential treatment for aging, along with new therapies for Alzheimer’s disease and other conditions caused by protein misfolding, Austad notes.

Enter the Hydra

In addition to clams, Austad studies a tiny freshwater creature called a hydra, which is basically immortal. Or so scientists once thought, until they found one particular species of hydra that begins to age rapidly under the right combination of environmental conditions.

“Under certain conditions, this hydra turns on a symphony of genes that prevent aging; under others, it does not,” Austad said. His lab is working to discover the molecular mechanisms that get switched on, or off, as the hydra’s environment changes. “These kinds of studies are a way to quickly identify new genes that might be targets for new drugs to keep people healthy longer,” Austad said.

He adds that the opportunities for collaborative, translational work in the Comprehensive Center for Healthy Aging, which brings together a wide range of basic and applied scientists from schools across campus, helped draw him to UAB.

Living Longer — and Better

This is a very exciting time to study aging, says Austad, who is in a position to survey the field as the scientific director for the American Federation for Aging Research. “We’re making an incredible amount of progress,” he said. “We know a lot of things from animal work that will slow aging by 20 percent, and that’s the difference between being healthy for 60 years and being healthy for over 70 years.”

Old Friends

Austad’s book “Why We Age,” published in 1997 and since translated into eight languages, explained the latest aging research in layman’s terms. Ever since, “publishers have been after me to do an updated version,” he said. “But there are lots of books out there now on that topic.”

Instead, he’s working on a book called “Methuselah’s Zoo,” which he described as “a natural history of successful aging.” It will include profiles of his favorite 500-year-old clams, but also 200-year-old whales and 40-year-old bats.
Living longer wouldn’t be much fun if you got progressively sicker, but “what we’re finding is that, if you treat the underlying causes of aging, you can push back cancer, heart disease, blindness, hearing loss — all of these diseases associated with aging,” said Austad.

One particularly intriguing lead, being followed by Austad and other researchers worldwide, is the drug rapamycin, which is FDA-approved to prevent rejection after organ transplants. A series of studies, from yeast, worms and mice, have shown that rapamycin can extend lifespan as well.

Rapamycin has “almost miraculous” effects against aging in mice, Austad says. “It prevents cancer, heart disease, Alzheimer’s — a whole host of things.” His lab is now working to understand how administering rapamycin at different points in an animal’s life affects the aging process.

Curb Your Enthusiasm?

Despite these exciting findings, caution is required, Austad notes. “Nothing I have learned so far has changed my behavior,” he said. “I don’t take a bunch of pills; I’m not even tempted to take rapamycin at this point.” For one reason, rapamycin has several side effects in mouse studies, including an elevated incidence of cataracts, loss of glucose sensitivity and testicular atrophy. Austad believes that the right dosing and formulation could overcome these issues in humans, but “we still don’t know what the best dose is,” he said.

At the moment, the best advice about healthy aging “is still the boring stuff your mother already told you,” Austad said. “‘Eat the right foods; don’t eat too much; exercise.’ But come back in 10 years and it will be a different answer.”

Biology’s Moment

The development of ever-better tools for investigating genes has brought about a revolution in biology, Austad says. He believes biology is set to dominate the 21st century the way that engineering and physics shaped the 20th — making vital contributions to everything from personalized medicine to climate change. And UAB’s Department of Biology will take a leading role in training, research and discovery in these areas, he adds.

“The human world 50 years from now will be unrecognizable,” Austad said. “People never realized that they could go faster than a horse and suddenly they had airplanes. We haven’t had this fancy DNA technology for more than a decade and a half, and we’ve already come so far.” Learn more at www.uab.edu/cas/biology.

Wednesday, October 8, 2014

Wheel genuises: UAB team is teaching Army's self-driving trucks a new way to move

Amazon got the world talking with its promise of aerial drone deliveries. Google is making progress toward its dream of a driverless car. But the U.S. Army has already surpassed the tech giants with an operational convoy of robot-driven trucks capable of traveling up to 40 miles per hour.

A self-driving convoy could deliver supplies without putting soldiers in harm’s way, or let those soldiers keep their eyes out for bandits instead of keeping them glued to the road. The Autonomous Mobility Appliquè System (AMAS), built for the Army’s Tank Automotive Research, Development and Engineering Center (TARDEC), has demonstrated its prowess in several online videos (see an example below).

Now researchers in the UAB School of Engineering are working with TARDEC on an even more powerful unmanned system — one that will use smart tires, enhanced sensors and some very quick thinking to guide trucks safely over rough terrain.


Vladimir Vantsevich, Sc.D., Ph.D., professor in the Department of Mechanical Engineering, and director of the UAB Vehicle and Robotics Engineering Laboratory, is an expert on the unique design challenges of multiwheeled vehicles. He has teamed up with UAB Ph.D. candidate Jeremy Gray, who is also a member of TARDEC’s Ground Vehicle Robotics group, on the unmanned convoy project.

Teaching a six-wheeled, 18-ton truck to make smart driving decisions is one problem. String several more behind it, and the challenges multiply. “Imagine: no drivers, just five trucks, following the lead vehicle,” said Vantsevich. One issue is that, even though they are in a line, each vehicle is experiencing different terrain.

“They’re following the same track, so each vehicle will compress the soil a little more, changing its physical properties,” Vantsevich said. “How do you redistribute power between the wheels to overcome this? If one gets stuck, how do you teach the others to avoid that obstacle? No one has ever done this before.”

Big Wheels Keep on Turning

In 2013, Vantsevich and Gray, along with TARDEC’s Jim Overholt, presented an algorithm that unmanned vehicles can use to react to changing ground conditions in real time. Putting that method into practice has required them to make several technical leaps.

Compared to Google’s self-driving car, “an off-road vehicle requires much more information about its surroundings,” Vantsevich explained. A car driving on a highway will pretty much experience the same interaction between tire and asphalt throughout its trip, he says. “But a wheel going over off-road deformable terrain is experiencing continuous changes in its dynamics and motion.”

The UAB researchers are dealing with this challenge by developing tires that read and react to their environment at unprecedented speeds — fast enough to respond to an obstacle while they are moving over it. “You have 60 milliseconds to understand what is going on with the tire, make a decision — should you change the torque of the tire, and in which direction? — and send a signal to the motor controlling that tire,” Vantsevich said.

At One With the Road

To accomplish this, the engineers are designing new types of high-speed sensors, and embedding them in the trucks’ tires and wheels. They are also devising ways to transmit this information from truck to truck, giving following trucks early warning about approaching hazards and terrain conditions.

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Vantsevich declines to describe the new sensors and transmission methods in detail while patents are pending. He is no stranger to innovation, with 30 certified inventions related to the dynamics, energy and fuel efficiency of multiwheel-drive vehicles. In a related project, Vantsevich and Mostafa Salama, a Ph.D. candidate at UAB, are developing new control algorithms to boost fuel efficiency in unmanned vehicles by giving each wheel its own electronic brain.

“I want my vehicle to be able to move from point A to point B with minimum power loss, and to do that I need to minimize the power loss that happens between each tire and the terrain,” said Salama. He has already adapted his original mathematical solution to this problem into a working prototype. Now he is refining that prototype in the Vehicle and Robotics Engineering Laboratory.

These techniques could eventually let unmanned vehicles travel farther, and improve the efficiency of even conventional vehicles, Vantsevich notes. A 40-ton truck, for example, could improve efficiency up to 12 percent with this approach, he says. “That represents a huge fuel savings.”

Lessons From the Frontier

This summer, Vantsevich shared details from his unmanned convoy work with researchers from 15 nations at a NATO Advanced Study Institute (ASI) on “Advanced Autonomous Vehicle Design for Severe Environments” in Coventry, England. The ASI, supported by a NATO grant received by Vantsevich, was arranged and conducted with Coventry University and Sweden’s Royal Institute of Technology. Vantsevich is also the editor of two new series of books that explore hot topics in ground vehicle engineering (Taylor & Francis, CRC Press) and robotics engineering (ASME Press).

UAB students can learn the fundamentals of these new fields in several courses that Vantsevich has developed in the School of Engineering. Although they cover everything from robot design to innovative methods of power distribution, the courses have a unifying theme: mechatronics. This emerging discipline takes an interdisciplinary approach to engineering problems, acknowledging that today’s devices are a complex intermingling of mechanical, electrical and computer systems.

Courses such as Systems Modeling and Controls, which Vantsevich taught to undergraduates in the spring 2014 semester, are all part of a mechatronics track that encompasses classes at the undergraduate and graduate levels, Vantsevich says. “We’re sharing our knowledge with a younger generation, and encourage them to work in these directions.”

Wednesday, October 1, 2014

Using magnets to find new drugs: Inside UAB's high-field nuclear magnetic resonance facility

Most high-end lab equipment is inaccessible to the public eye, but one of UAB's most powerful drug-discovery tools is clearly visible from the Campus Green. The Central Alabama High Field Nuclear Magnetic Resonance Facility occupies a gleaming ground-floor space in the Chemistry Building. Its massive magnets give researchers invaluable insight into disease-causing proteins — and the data they need to find new ways to stop them.

UAB Magazine Fall 2014 cover
The cover story of the latest issue of UAB Magazine features the Alabama Drug Discovery Alliance, a partnership between UAB and Southern Research Institute that aims to accelerate high-potential discoveries from the lab to patient-ready treatments. One key tool in that process is the Central Alabama High Field Nuclear Magnetic Resonance Facility, which opened in 2013. The Mix takes a closer look in this new feature.

Spin This Way

Each of the facility's NMR machines specializes in a different type of job, but the basic functioning is the same, explains NMR director N. Rama Krishna, Ph.D., UAB professor in the Department of Biochemistry and Molecular Genetics. The machines generate strong magnetic fields that polarize the tiny magnets in the nuclei of hydrogen atoms. “Then, using radiofrequency pulses, you can count all of the individual hydrogen atoms in a sample, which tells you what amino acids are present and how they are arranged in space,” Krishna says. And that’s precisely the information you need to create a detailed picture of a protein’s structure.

Mapping a protein's structure is crucial to understanding its function — and to finding ways to alter that function to treat disease. For instance, locating suitable "binding pockets" on a protein linked to brain cancer tells medicinal chemists how to design a drug to block (or enhance) that protein. "That's why NMR is one of the most versatile tools for drug-discovery research," Krishna says.

The bigger your magnet, the better images you can get. The centerpiece of the NMR facility is an 850 MHz Bruker BioSpin model, one of the largest in the South, which allows scientists to analyze structural data on even the largest proteins.

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Building a Better Drug

The 850 MHz machine can also accelerate the drug-discovery process "by allowing researchers to rapidly test new compounds they've developed in the lab," Krishna adds. Using a technique called saturation transfer difference NMR (STD-NMR), Krishna and his team can register the minute changes in signals from hydrogen atoms that occur when a compound binds to a protein. It would be nearly impossible to capture this interaction directly, he points out, because "it may last only a few microseconds." With STD-NMR, researchers can screen a number of potential drugs at once, then focus on the ones that show signs of binding to the target protein.
UAB's Rama Krishna and scientists from Southern Research
Institute have collaborated in developing a novel high-field
NMR-based protocol for determining the binding of
allosteric ligands to target proteins. They used the kinesin-5
protein Eg5 (a cancer target) and its inhibitor monastrol
 as an example (see above) for this protocol.

Using other techniques, researchers can analyze the disease-causing interaction between two proteins, and then find the right location to dock an inhibitor that would prevent the proteins from coming together. Or they could do the opposite, in an approach dubbed “fragment-based discovery” — using NMR data to identify two compounds that bind close together on a protein and “cross link” them to significantly improve their binding.

Krishna uses these techniques in his own National Cancer Institute-funded research to find new treatments for pancreatic cancer. Other UAB investigators are using the NMR facility to further their drug-discovery efforts in Parkinson's disease, brain tumors, breast cancer, heart disease, HIV and more. And as word of these capabilities has spread, researchers at institutions across the South have begun sending in samples to the NMR facility for evaluation.

Early Warning Signs

NMR is useful for many applications beyond drug discovery, Krishna adds. The facility's 600 MHz machine specializes in a hot area of medicine known as metabolomics, which studies the way the body processes everything from food to medicines.

"If you are taking a drug that is toxic to the liver, the body will generate some small molecules — known as metabolites — associated with liver damage,” Krishna explains. "We can detect these molecules in the NMR spectra of biofluids such as urine and blood plasma and say, 'Aha, after this patient started taking the drug, we can see an increase in these signals, so something is going wrong." That can warn researchers of side effects from new drug treatments "long before there is any major problem," Krishna says.

"The range of applications in this facility is amazing," adds Krishna. "It is a unique platform for everything from basic science to translational research.”