oncology

Curators Versus Cancer

By Kim Krieger | Illustrations by Kailey Whitman

illustration of scientist look over hundreds of books

A special team of medical literature experts are on the hunt for cancer’s kryptonite, one mutation at a time.


If the genetic code is like a book, then a mutation is like a typo. Some typos are meaningless. Others have such dramatic consequences for a book, or a life, that the error alone could have an entire novel written about it.

Cancer mutations are like that. As oncology moves toward precision medicine — the idea that if we knew exactly which genetic mutations make a particular cancer tick, we could pick exactly the right treatments — oncologists have to keep up with an ever-expanding library of mutations and the drugs that might foil them. The number of cancer research papers published increases every year; there were about 35,000 published in 2015 just in the U.S. It’s far more than any one person can keep up with.

In the same way that a university has research librarians who keep up with the literature in specific fields, JAX has experts who keep up with cancer gene and drug research, even studies that are ongoing and not yet published.

A new collaboration between UConn Health and The Jackson Laboratory (JAX) hopes to help oncologists find the right treatments by keeping up with research for them — and using the institutions’ combined expertise in cancer treatment, molecular biology, and genetics to improve patient outcomes for cancers that currently don’t have good treatments. In the same way that a university has research librarians who keep up with the literature in specific fields, JAX has experts who keep up with cancer gene and drug research, even studies that are ongoing and not yet published. JAX already successfully connects these experts with doctors in the Maine Cancer Genomics Initiative, a philanthropy-funded statewide precision medicine program. UConn Health and JAX hope to expand the concept and demonstrate its feasibility more widely.

A UConn Health researcher holds a tumor sample.

A UConn Health researcher holds a tumor sample. Kristin Wallace

Bull’s Eye Treatment

Imagine that a patient has surgery or a needle biopsy to diagnose a tumor. It’s a particularly ugly tumor, the surgeon, oncologist, and pathologist all agree. Invasive, spreading, and perhaps this isn’t the first time this patient has had to come in for cancer surgery. The tumor is sampled and sent for genetic testing. In about two weeks, the results come back: there are three genetic variants in the tumor that might be drug targets.

At UConn Health, oncologists can send portions of particularly malignant tumors to a team at the JAX Clinical Laboratory. JAX sends back a report with information the oncologist can use to pick a drug regimen with the best chance to shrink that ugly tumor. “The goal is to define the optimal treatment regimen for each individual patient” who may not have good options otherwise, says Dr. Ketan R. Bulsara, chief of neurosurgery at UConn Health and one of the principal investigators on the project.

At UConn Health, oncologists can send portions of particularly malignant tumors to a team at the JAX Clinical Laboratory. JAX sends back a report with information the oncologist can use to pick a drug regimen with the best chance to shrink that ugly tumor.

The report is intended to be a standalone reference an oncologist can use to inform a treatment plan. But if the oncologist is unfamiliar with one of the mutations identified in the report or just wants more information, they can request that a genomic tumor board be convened. The board is composed of surgeons, pathologists, and molecular oncologists who act as external advisors, sharing their opinions with the oncologist. In just 15 minutes, the oncologist can get a wealth of expert opinion to combine with their own expertise and judgment. In the end, the oncologist and patient decide on the best treatment, based on all the available information.

“In a multidisciplinary fashion, doctors and scientists work hand in hand in this with one common goal: identify the best treatment regimen for that particular patient’s pathology,” Bulsara says.
The focus is always on the patient. But behind the scenes, there’s an entire team of researchers whose work goes into the genetic tumor report. Scientists at JAX Clinical Laboratory sequence the tumor’s genetic code and report information on more than 200 cancer-related genes. The genes were picked because they are associated with both malignancy and potential drug treatments. Any mutations or variants in these genes might be a clue to the cancer’s weakness. Or a red herring.

“A typical tumor might have 2,000 mutations. Not all of them really matter,” says Andrey Antov, the program director for the Maine Cancer Genome Initiative at JAX. Finding the key mutations that matter, the two or ten or twenty that could possibly inform treatment and a better outcome for the patient, is the job of the clinical genomic curators.

Personal Librarians

The clinical genomic curators are specialists in fields such as molecular oncology and oncological pharmacology. They’re dedicated to keeping up with the literature on cancer genes and the drugs that target them. More and more of these drug-gene connections are being discovered every day. It’s exciting, but the sheer volume of papers can be overwhelming. Navigating that ocean of scientific papers is the medical curators’ full-time job. They’re like librarians curating a Boston Public Library–size collection of genes and drugs with no cross references in the card catalog and only an imperfect search function. The hope is that just as a good librarian’s knowledge of the subject matter can unearth texts a researcher would never otherwise find, a medical curator’s grasp of oncological genetics and pharmacology can identify potential treatments that would otherwise remain obscure.

Each mutation identified by the genetic panel might require 10 to 20 scientific publications to understand. Once the curators have a handle on the variants’ significance, the clinical laboratory decides which two or three should be described in the report to the oncologist.

illustration of books in a library cart

Sifting the information down to something relevant and digestible is the ultimate goal.

“Today, all this information is disorganized and may not all be in the oncologist’s head. We’re trying to bring it together,” says Jens Rueter, medical director for the Maine Cancer Genome Initiative.

The ideal outcome of a tumor genetic analysis would be to identify a mutation such as the HER2 gene that is turned on in the most aggressive breast cancers. HER2 is responsible for the cancer’s malignancy. But it’s also the cancer’s Achilles’ heel. Once drugs were developed to block the HER2 protein, survival rates climbed sharply.

The goal of the Maine Cancer Genomics Initiative is to enable oncologists to identify other drug-gene connections as potent as the ones found for HER2. Although more and more of these drug-gene connections are being discovered, it remains difficult to provide a patient with access to these drugs. Many of them are only available if a patient participates in a clinical trial. And often, there are barriers to accessing clinical trials, and getting drugs off-label is the only way to get patients to treatments. That’s another benefit that Antov, Bulsara, and Rueter hope UConn Health’s collaboration with JAX will bring.

Positive Outcomes

Ultimately, the researchers hope to demonstrate that this approach leads to better outcomes for patients. During the past year more than 350 patients and 70 oncology practitioners (more than 80 percent of the Maine oncology community) enrolled in the Maine Cancer Genomics Initiative study protocol. A few patients have already been offered a targeted treatment through a trial or a compassionate drug access program as a result of enrollment in the program. And Maine health care professionals have logged more than 1,200 certified education hours through 35 genomic tumor boards, online modules, and annual forums held by JAX.

So far, five patients have done this at UConn Health within the last two months. Generous donors have given enough to fund 20 more.

The hope is that just as a good librarian’s knowledge of the subject matter can unearth texts a researcher would never otherwise find, a medical curator’s grasp of oncological genetics and pharmacology can identify potential treatments that would otherwise remain obscure.

“We hope to get funding for at least 100 patients to show the feasibility of this approach,” Bulsara says. “We want to show we can do this reliably, and that it reliably improves patient care.”

UConn Health already has the infrastructure to do this, in particular a biorepository for tumors set up by Neag Cancer Center Director Dr. Pramod Srivastava and pathologist Dr. Melinda Sanders. With that foundation and support from UConn medical school Dean Dr. Bruce Liang and UConn Health CEO Dr. Andrew Agwunobi, the program was piloted in the Department of Surgery by Bulsara, its chief of neurosurgery, with support from Department of Surgery Chairman Dr. David McFadden, hematology and oncology chief Dr. Susan Tannenbaum, anatomical pathology chief Dr. Qian Wu, and JAX Clinical Laboratory Director Honey Reddi.

If the UConn Health–JAX initiative does prove its feasibility, the approach will continue to spread and become a standard of care.

More oncologists could have access to the library of knowledge and advice of a genetic tumor board, and more cancer patients could benefit from longer, healthier lives.

Tumor samples are housed in UConn Health's research biorepository.

Tumor samples are housed in UConn Health’s research biorepository. Kristin Wallace

A Team Approach Improves Lung Cancer Care

illustration; team of people overlook blue lineart in the shape of a human lung


As director of thoracic oncology and interventional pulmonology at UConn Health, Dr. Omar Ibrahim has been working hard to personalize and improve the experience of lung cancer patients.

“As a result of enhancing individualized care, the number of lung cancer patients UConn Health cares for has been rapidly increasing,” says Ibrahim. “We have immensely improved a patient’s time to diagnosis and treatment, as well as the overall quality of care they receive. Plus, our program’s advanced diagnostic imaging and rapid-sequence genetic testing has allowed us to get patients proper therapy in the most effective way possible.”

According to Ibrahim, UConn Health is one of a few institutions in the Northeast to consolidate how they care for lung cancer patients.

“Rather than having patients visit multiple physicians in different locations on our campus, we focus all our care for lung cancer patients in one multidisciplinary clinic,” says Ibrahim, who led the specialized clinic’s development. “This allows for ease of care and greater patient satisfaction and increases the patient’s knowledge.”

We have immensely improved a patient’s time to diagnosis and treatment, as well as the overall quality of care they receive.

The biggest risk factor for lung cancer, which kills more Americans than breast, colon, and prostate cancers combined, is smoking. Ibrahim passionately urges current and former heavy smokers to get screened for the disease with a low-dose computed tomography (CT) scan at UConn Health’s Lung Cancer Screening Program at the Carole and Ray Neag Comprehensive Cancer Center.

“Our goal is to find lung cancer at its earliest stage so we can have options to treat it and cure it,” Ibrahim says.

If a low-dose CT scan catches a suspicious lung nodule or growth, Ibrahim leverages minimally invasive techniques to rule out lung cancer, or diagnose and identify what stage the disease is at. He uses video-guided 3-D navigational bronchoscopy technology and ultrasound in the exam room to closely examine a patient’s lung tissue using a thin, flexible tube via the nose or mouth. The technology also allows for small lung tissue biopsy samples to be taken.

But Ibrahim is not only proud of improving his patient’s experience and outcomes.

“What I am truly proud of is the team effort of everyone involved with a lung cancer patient’s care, from the staffer greeting them at the door to the nurse infusing their chemotherapy. They all are doing an immense job.”

Protecting Cancer Patients’ Heart Health

Kim Agnes looks at heart

Dr. Agnes Kim, director of the Cardio-Oncology Program at UConn Health, uses new echocardiography strain imaging to detect signs of potential heart problems in cancer patients, before clinical symptoms are evident.


There are currently more than 15 million cancer survivors in the U.S., and that number is expected to grow to 20 million within 10 years. But as more patients survive cancer, the risk of developing cardiovascular health issues from lifesaving chemotherapy and radiation treatments also is increasing.

In an effort to detect cardiac health risks or conditions early, UConn Health has begun tracking cancer patients with an advanced heart imaging test before, during, and after chemotherapy and radiation therapy.

New echocardiography strain imaging allows cardiologists to hunt for early warning signs of heart muscle function changes or damage within the heart tissue. The in-depth strain analysis is powered by traditional ultrasound technology, which uses high-frequency soundwaves to create a sonogram of the pumping heart.

Dr. Agnes Kim, director of the Cardio-Oncology Program at the Pat and Jim Calhoun Cardiology Center at UConn Health, says it’s very important to monitor cancer patients for any signs of cardiac toxicity.

“Echo strain imaging has been compared to a canary in a coal mine,” she says. “We are so grateful that our cancer patients have access to this latest technology so that we can monitor and intervene early if any warning signs are present.”

Studies have shown that confirming any changes in heart muscle strain can help doctors predict whether a patient is at risk for cardiotoxicity and its side effect of future heart failure. A decline in heart strain of 15 percent or more suggests cardiotoxicity, and doctors may prescribe cardio-protective drugs, such as beta-blockers or ACE inhibitors, or modify the patient’s chemotherapy dosage.

Possible cardiotoxicity side effects from chemotherapy medications include a lowering of overall heart muscle function, which can lead to heart failure, formation of blood clots, or an increase in blood pressure. The side effects of radiation therapy also can lead to damaged heart muscle, heart valves, and arteries, or impact the lining of the heart.

Kim launched the Cardio-Oncology Program in 2014 to ensure UConn Health had an integrated program of oncologists and cardiologists, allowing for coordinated care to address the potential risks to heart health that can arise from cancer treatment.

The program also is studying the presence of serum biomarkers in the blood for predicting whether a cancer patient is at high risk for cardiotoxicity, as well as tracking cancer patients’ long-term heart health to analyze the impact of additional clinical care protections.

Size Matters for Particles in Bloodstream

UConn Engineering Professor’s Findings Could Mean More Effective Cancer Drugs

UConn researchers used a fluorescence microscope to illuminate a microfluidic device that simulates a blood vessel to observe and measure how particles of different sizes behave in the bloodstream.

UConn researchers used a fluorescence microscope to illuminate a microfluidic device that simulates a blood vessel to observe and measure how particles of different sizes behave in the bloodstream. Their findings could aid the development of more effective cancer drugs. Photo: Anson Ma


A UConn engineering professor has uncovered new information about how particles behave in our bloodstream, an important advancement that could help pharmaceutical scientists develop more effective cancer drugs.

Making sure cancer medications reach the leaky blood vessels surrounding most tumor sites is a critical aspect of treatment and drug delivery. While surface chemistry, molecular interactions, and other factors come into play once drug-carrying particles arrive at a tumor, therapeutic medication doesn’t do much good if it never reaches its intended target.

Anson Ma, assistant professor of chemical and biomolecular engineering, used a microfluidic channel device to observe, track, and measure how individual particles behaved in a simulated blood vessel.

Ma says he wanted to learn more about the physics influencing a particle’s behavior as it travels in human blood, and to determine which particle size might be the most effective for delivering drugs to their targets. His experimental findings mark the first time such quantitative data has been gathered. The study appeared in the Oct. 4, 2016 issue of the Biophysical Journal.

Using a fluorescence microscope, Ma was able to see particles moving in the simulated blood vessel in what could be described as a vascular “Running of the Bulls.” Red blood cells race through the middle of the channel as the particles — highlighted under the fluorescent light — get carried along in the rush, bumping and bouncing off the blood cells until they are pushed to open spaces, called the cell-free layer, along the vessel’s walls.

What Ma found was that larger particles — the optimum size appeared to be about 2 microns — were most likely to get pushed closer to the blood vessel wall, where their chances of carrying medication into a tumor site are greatest. The research team also determined that 2 microns was the largest size that should be used if particles are going to have any chance of going through the leaky blood vessel walls into the tumor site.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, reducing the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

“When it comes to using particles for the delivery of cancer drugs, size matters,” Ma says. “When you have a bigger particle, the chance of it bumping into blood cells is much higher, there are a lot more collisions, and they tend to get pushed to the blood vessel walls.”

The results were somewhat surprising. In preparing their hypothesis, the research team estimated that smaller particles were probably the most effective since they would move the most in collisions with blood cells, much like what happens when a small ball bounces off a larger one. But just the opposite proved true. The smaller particles appeared to skirt through the mass of moving blood cells and were less likely to experience the “trampoline” effect and get bounced to the cell-free layer, says Ma.

Ma proposed the study after talking to a UConn pharmaceutical scientist about drug development at a campus event five years ago.

“We had a great conversation about how drugs are made and then I asked, ‘But how can you be sure where the particles go?’” Ma recalls, laughing. “I’m an engineer. That’s how we think. I was curious. This was an engineering question. So I said, ‘Let’s write a proposal!’”

The proposal was funded by the National Science Foundation’s Early-concept Grants for Exploratory Research, or EAGER, program, which supports exploratory work in its early stages on untested, but potentially transformative, research ideas or approaches.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, Ma says, which in turn will further reduce the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

The findings were particularly meaningful for Ma, who lost two of his grandparents to cancer and who has long wanted to contribute to cancer research in a meaningful way as an engineer.

The results may also be beneficial in bioimaging, where scientists and doctors want to keep particles circulating in the bloodstream long enough for imaging to occur. In that case, smaller particles would be better, says Ma.

Moving forward, Ma would like to explore other aspects of particle flow in the circulatory system, including how particles behave when they pass through a constricted area, such as from a blood vessel to a capillary. Capillaries are only about 7 microns in diameter. The average human hair is 100 microns.

“We have all of this complex geometry in our bodies,” says Ma. “Most people just assume there is no impact when a particle moves from a bigger channel to a smaller channel because they haven’t quantified it. Our plan is to do some experiments to look at this more carefully, building on the work that we just published.”

Melanoma Patients Benefit from New Immunotherapy Drug

Microscopic view of a histology specimen of melanoma on human skin tissue

Microscopic view of a histology specimen of melanoma on human skin tissue.


Patients with advanced melanoma are benefiting from the same drug credited recently with the disappearance of the disease in former President Jimmy Carter.

Physicians with UConn Health’s Carole and Ray Neag Comprehensive Cancer Center are successfully boosting the immune system of some of their advanced melanoma patients with a new, promising immunotherapy tool called Keytruda (pembrolizumab).

The drug was granted accelerated FDA approval in September 2014 for the treatment of melanoma patients who no longer respond to other drug treatments and are not candidates for surgery.

Melanoma is one of the deadliest types of skin cancer. If not detected early and removed from the skin, it can spread deep into the skin and to the body’s other organs, such as the lungs, liver, and brain. It is often fatal.

“Melanoma affects the young and the old, and its incidence is on the rise,” says Dr. Upendra P. Hegde, associate professor in the Department of Medicine, and chief medical oncologist for melanoma and cutaneous oncology and head and neck cancer/oral oncology at UConn Health. More than 75,000 people are diagnosed with melanoma annually, and nearly 10,000 Americans die from it each year.

Hegde says melanoma spreads quickly because tumors evade the immune system’s attack by expressing proteins called PD-L1 and PD-L2 (program death ligand 1 and 2), compromising the ability of a person’s T-cells to fight cancer.

However, Keytruda boosts a patient’s immune system, helping it fight back and preventing the cancer-fighting cells from becoming exhausted.

“Keytruda is the first PD-1 inhibitor drug that is allowing us to shrink the melanoma tumors in up to 35 percent of our UConn Health patients,” says Hegde.

Since not all advanced melanoma patients respond to current available drug therapies including Keytruda, UConn Health researchers are participating in two clinical trials that combine Keytruda with other therapy options. One, called INCYTE and led by principal investigator Dr. Jeffrey Wasser, is testing the efficacy of combining Keytruda with another immunotherapy drug known as an IDO1 inhibitor (INCB024360) to see if together they can enhance the immune system’s response to advanced melanoma and other solid-tumor cancers. A second trial is testing the possible benefits of Keytruda with standard chemotherapy for relapsed head and neck cancer.

UConn Health’s multidisciplinary melanoma team includes Dr. Jane Grant-Kels and Dr. Philip Kerr of dermatology, Hegde of medical oncology, and Dr. Bruce Brenner, a surgeon who specializes in melanoma, among others.

Close at Heart

By Kim Kreiger
Illustration by Yesenia Carrero

Radiation treatment for breast cancer can inadvertently graze the heart, leading to damage and disease years later. UConn doctors are working to change that.

closeatheart


Getting radiation treatment for breast cancer can make you feel vulnerable. Sitting in a machine with radiation pointed directly at your chest, you have to trust that the doctor knows what she’s doing, that the X-rays are aimed right, that the machine is properly calibrated … and then you just sit perfectly still.

But what if you could have some control over the process?

Dr. Robert Dowsett, chief of UConn’s Division of Radiation Oncology, and
colleagues in the Carole and Ray Neag Comprehensive Cancer Center are using a new technique to give breast cancer patients agency in their radiation treatments. And they’re taking better care of the patients’ hearts in the process.

A patient can intentionally increase the heart-chest wall distance by more than a centimeter by controlling her breathing using the Deep Inspiration Breath Hold.

Using the technique, called Deep Inspiration Breath Hold, patients can help control the accuracy and timing of their own radiation dose. The patient takes a breath of specific depth before the radiation machine turns on. Doing this correctly can increase the distance between the heart and the breast by a centimeter or two, lowering the amount of radiation hitting the heart by as much as 50 percent.

Jeryl Dickson, 62, of Manchester, Conn., was one of the first patients at UConn Health to use the technique, from late 2015 through Feb. 2. Her doctors, including Dowsett, prescribed a course of radiation therapy to make sure there were no lingering cancer cells remaining after a lumpectomy removed her breast cancer.

“I practiced deep breathing and breath holds prior to radiation treatment with the radiation oncology staff so I could feel what it would be like,” says Dickson.

Radiation treatment of breast cancer can be very effective, eradicating tumor cells hiding in the chest wall. But breast cancer survivors have a heightened risk of heart disease that shows itself years later. Ironically, the heart disease stems from the radiation that originally saved their lives. Radiation is a type of light, and like visible light, it has a tendency to reflect and scatter. Just as even the sharpest spotlight has blurred edges where it blends into shadow, even the best-aimed medical radiation beam occasionally scatters into tissue outside of the tumor it targets. Sometimes it hits the heart.

Dr. Agnes Kim, director of the Cardio-Oncology Program at UConn Health, analyzes echocardiography images as one way to monitor cancer patients’ risk of heart disease.

Dr. Agnes Kim, director of the Cardio-Oncology Program at UConn Health, analyzes echocardiography images as one way to monitor cancer patients’ risk of heart disease.
Tina Encarnacion/UConn Health Photo

“We worry about heart attacks down the road, 10 to 15 years after radiation treatment of cancer in the chest. We also worry about inflammation on the outside of the heart in the short term. We don’t exactly know how the radiation damages the tissue, but it definitely seems to accelerate damage to blood vessels. It can also cause scarring and fibrosis damage,” says Dowsett.

But the distance between the heart and the chest wall varies from person to person. And a patient can intentionally increase the heart-chest wall distance by controlling her breathing using the Deep Inspiration Breath Hold.

To make the best use of the Deep Inspiration Breath Hold technique, Dowsett and his colleagues at UConn Health combine it with an optical scanning system supplied by C-RAD. The scanning system is essentially a computer with a camera that models the surface of the skin on the patient’s chest. It tracks the patient’s breathing, and coaches her to inhale just the right amount. As the patient, you wear virtual-reality goggles in which you see a bar graph showing your inhalation, with a box at the top. Your goal is to hit the box and then hold your breath for the 20 to 30 seconds it takes to complete the radiation treatment. Some patients can hold their breath that long; others can’t. It doesn’t matter, because if you exhale, or giggle, or cough, the system sees your chest move out of the perfect range and stops the radiation. It won’t restart until you get yourself back in position and inhale to just the right spot again.

“The deep breathing technique was not difficult at all,” says Dickson, “Honestly, I was more focused on my cancer, and heart health never entered my mind. But I am glad I put my trust in my doctors, and I never had any doubts.”

UConn Health is the only hospital using this technology in Central Connecticut. It’s a powerful, precise way to make sure the radiation beam gets the cancer, and to minimize the risk to other organs.

Previously, “the area we treated inevitably ended up being bigger than the target (tumor) itself,” Dowsett says. “Now we’ve expanded this to abdominal targets such as the pancreas and adrenal lesions,” while sparing healthy surrounding organs.