cancer

A Path With Less Pain

Genetic Clues Show Which Breast Cancer Patients Are Prone to Post-Treatment Agony

By Kim Krieger

woman chooses between two marked paths


Sickness and pain go together. We think of them as a matched pair, a married couple. Pain signals sickness, sickness causes pain. But this is not always the case. Especially in early stage cancer, often there is no pain — until the patient is treated.

UConn Health researchers have discovered genetic clues that could eventually reveal which people might be vulnerable to post-treatment pain, they reported in the June issue of Biological Research for Nursing.

“We’ll hear women say ‘If I knew the pain would be this bad, I’d have rather died of breast cancer,’” says Erin Young, a UConn Health pain geneticist. Young and her research partners wondered: Can we really call such treatment a “cure”? It would be better if we could know in advance which patients might suffer from which treatments.

Young worked with data collected as part of a broader study involving nurse-scientist and director of UConn’s Center for Advancement in Managing Pain Angela Starkweather, neuroscientist Kyle Baumbauer, and colleagues at the University of Florida and Kyung Hee University in Seoul, South Korea. Young’s analysis found that common variants in two genes contribute to certain symptoms during and after chemotherapy treatment for breast cancer. The results could one day help patients, and their nurses and doctors, make informed treatment decisions and prepare for — or avoid — damage to patients’ quality of life.

The researchers looked at the genetics of 51 women with early-stage breast cancer who had no previous chemotherapy and no history of depression. The women rated their well-being both before and after treatment for cancer, reporting on their pain, anxiety, depression, fatigue, and sleep quality. Young and her colleagues then looked for connections between genes and symptoms.

Can we really call treatment a “cure”? It would be better if we could know in advance with patients might suffer from which treatments.

They looked at three genes in particular: NTRK1, NTRK2, and COMT. These genes are already associated with pain from other research. NTRK1 is connected to rapid-eye-movement sleep (dream sleep), and a specific variant is linked to pain insensitivity. NTRK2 is associated with the nervous system’s role in pain, fatigue, anxiety, and depression. And some common versions of COMT are linked to risks of developing certain painful conditions. The researchers also chose these genes because the variants associated with pain, fatigue, and other symptoms are fairly common, making it possible to get meaningful results from a sample size of just 51 people.

After the analysis, a couple results jumped out at them. Two of the genes, COMT and NTRK2, had significant correlations with pain, anxiety, fatigue, and sleep disturbance. The other gene didn’t.

“I always like having a yes/no answer — if we get some nos, then we know the analysis wasn’t just confirming what we wanted to see,” says Young.

Such a quick look at a small sample of cancer patients can’t give all the answers as to who is going to develop postoperative and post-chemotherapy pain. But what they did find is very suggestive. Some of the gene variants were associated with symptoms before surgery. For example, women with two copies of the A variant of COMT reported more anxiety than other women did. COMT was also linked with pain, both during and after cancer treatment: women with one variant of COMT reported more pain, while women with a different variant reported less.

Fatigue also seems to have a genetic component. Women with one copy of the T variant of NTRK2 reported more posttreatment fatigue than others, and women with two copies reported much more.

Surprisingly, the genes linked to various symptoms worked independently, and didn’t work together to increase overall pain and discomfort. In other words, they weren’t synergistic; they didn’t make each other worse.

The gene variants predicted pain and fatigue above and beyond any differences explained by treatment effects.

The genes’ effects were also independent of the type of treatment the women received; the 51 women followed a number of different types of treatments: different surgeries, different chemotherapies. The gene variants predicted pain and fatigue above and beyond any differences explained by treatment effects. Other experiments by other researchers have shown the COMT variants are connected to the development of skeletal muscle pain.

“So it’s not just our study but the entire literature that suggests COMT could be playing a role in how sensitive you are to many different types of pain,” says Young.

“We are focusing on how we can identify women who are at risk of experiencing persistent pain and fatigue, as these symptoms have the highest impact on reducing quality of life after treatment,” says Starkweather. “It’s a great example of how we can make progress toward the goal of personalized health care. The next piece of the puzzle is to identify the most effective symptom-management interventions based on the patient’s preferences and genetic information.”

Young, Starkweather, and their colleagues say further research, ideally looking at a person’s whole genome, is needed to refine the connections between genetic profiles and the risk of pain. With that knowledge, patients could work together with their care team to develop individualized symptom-management plans. Properly prepared patients would feel more control and less suffering. And perhaps the cure would no longer hurt worse than the disease.

Scientists Pave Path for Tackling Rare Cancers

An earlier study by Dr. Andrew Arnold (center) provided the basis for the new research on parathyroid carcinoma genes.

An earlier study by Dr. Andrew Arnold (center) provided the basis for the new research on parathyroid carcinoma genes.


An international team of scientists led by the UConn School of Medicine and Icahn School of Medicine at Mount Sinai sequenced a genome for an extremely rare form of cancer, demonstrating the utility of this approach in opening the door for therapy options for rare diseases that are neglected due to scarcity of patients or lack of resources.

The team’s findings were published by JCI Insight, a journal of the American Society for Clinical Investigation.

Leading genomic scientists from UConn, Mount Sinai, and other collaborating institutions performed exome sequencing on tumors and matched normal samples from 17 patients with parathyroid carcinoma, an ultra-rare form of cancer for which there is no effective treatment.

Researchers found several mutations in known cancer-related genes and pathways. This in-depth characterization provides a clear view of genetic mechanisms involved in parathyroid carcinoma and could lead to the first therapy options for patients.

The genetic variants identified in this study have been detected in other cancers and are the subject of ongoing “basket” trials, or clinical trials focused on specific mutations rather than the tissue where the cancer formed.

“This is the largest genomic sequencing study to date for this rare and deadly cancer, and we believe it serves as important validation for using this approach to uncover clinically relevant information in any number of neglected diseases,” said Rong Chen, senior author of the paper and assistant professor in the Department of Genetics and Genomic Sciences at Mount Sinai. “Genomic analysis is opening the doors to diseases that could never have been understood through traditional biomedical research because there simply aren’t enough patients to observe.”

Mount Sinai’s work built upon research by Dr. Andrew Arnold of UConn, published in the New England Journal of Medicine in 2003. In the earlier study, Arnold reported on the first gene discovered in non-familial parathyroid cancer.

“Some of the tumor-specific genomic vulnerabilities we found turn out to be shared with much more common cancers, so drugs already being developed for other cancers may prove valuable in parathyroid cancer,” said Arnold, the study’s co-leader, who serves as the Murray-Heilig Chair in Molecular Medicine, director of the Center for Molecular Medicine, and chief of endocrinology at UConn School of Medicine. “This offers new hope for our patients and serves as a model for approaching other rare and neglected diseases.”

The study was funded by the Icahn Institute of Genomics and Multiscale Biology at Mount Sinai and the Murray-Heilig Fund in Molecular Medicine at UConn School of Medicine through the UConn Foundation.

UConn Health research image of a parathyroid gland (darker) located on the thyroid gland (pink background) during a research experiment where scientists genetically engineered mouse models, knocking out the CDC73 gene to test if cancer would then develop.

UConn Health research image of a parathyroid gland (darker) located on the thyroid gland (pink background) during a research experiment where scientists genetically engineered mouse models, knocking out the CDC73 gene to test if cancer would then develop.

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.”

Lab Notes – Summer 2016

Researchers Reveal a Secret of Sepsis

human cell rendering

Severe bacterial infections can push the human body into sepsis, a life-threatening cascade of inflammation and cell death that can be difficult to cure. In the May 19 issue of Cell, immunologist Vijay Rathinam and colleagues at UConn Health proposed an explanation for how bacteria trigger such a dangerous reaction: The human cells aren’t really being invaded. They just think they are, at least when sepsis is caused by gram-negative bacteria. Gram-negative bacteria secrete vesicles of lipopolysaccharides (LPS) that can get inside human cells and set off alarms. When the cell detects the LPS, it thinks a bacterium has slipped past its defenses and self-destructs, spilling inflammatory cytokines that prompt the bacteria to emit more LPS, setting off a vicious cycle.


Nanoparticles: guided missiles for drug delivery

Powerful drugs such as chemotherapy and steroids can be devastatingly effective against their intended targets — but they have a tendency to devastate other, healthy body systems as well. UConn chemist Jessica Rouge is working to make these medications more discriminating in their action by bundling them into guided nanoparticles. Her lab is developing aptamers, molecules that bind to a specific target proteins or cell receptors, that can be attached to the nanoparticles to guide them straight to damaged or diseased cells. This approach could help cancer patients avoid the worst side effects of chemotherapy. It could also be useful for asthmatics who need steroidal anti-inflammatory drugs. With this strategy, the drugs could be sent straight to the lungs, side-stepping side effects completely.


Walnuts May Improve Your Colon Health

a walnut in its shell

Eating walnuts may change gut bacteria in a way that suppresses colon cancer. A team of researchers from UConn Health and The Jackson Laboratory for Genomic Medicine found that mice that ate 7-10.5 percent of their total calories as walnuts (about an ounce per day for humans) developed fewer colon cancers. Walnuts are packed with compounds known to be important nutritionally, but it may be as a whole food that they pack the most significant anti-cancer punch against colon cancer, the third most common cancer in the world. The research, supported in part by the California Walnut Commission and the American Institute for Cancer Research, was published May 23 in the journal Cancer Prevention Research. UConn Health Center for Molecular Medicine cancer researcher Dan Rosenberg and colleagues are now working on a long-term study in humans.


Congestive Heart Failure plus Type 2 Diabetes Worse Than We Knew

Diabetes blood Sugar monitor and test strip

Data from more than 5,300 patients with Type 2 diabetes has shown that these patients face a one-in-four chance of dying within 18 months of being hospitalized for congestive heart failure, according to the global EXAMINE study, led by UConn Health professor of medicine Dr. William B. White. Patients with Type 2 diabetes have two to three times the heart disease risk of the general population. White hopes the results inspire patients and doctors to focus more on preventing cardiovascular disease. The findings were presented June 11 at the American Diabetes Association’s (ADA) annual meeting in New Orleans and published online in the ADA journal Diabetes Care.

Individualized

By Lauren Woods
Illustration by Yesenia Carrero

UConn Health’s Personalized Ovarian Cancer Vaccine Enters Clinical Trials

illustration of fingerprints overlayed on top of a woman's ovaries


Ovarian cancer relapses are deadly. UConn Health is testing its pioneering vaccine that could prevent them.

The experimental vaccine, named OncoImmunome, is administered as a simple injection in an outpatient setting. It works by boosting the patient’s immune response to enable it to destroy ovarian cancer cells, so that they do not resurface.

The genetic differences between the surface proteins on a patient’s healthy and cancerous cells constitute the fingerprint of that particular patient’s cancer, which is unlike the fingerprint of any other person’s cancer. Based on these variations, scientists create the personalized vaccine.

“This is the first vaccine of its kind developed for women diagnosed with advanced ovarian cancer,” says Dr. Pramod K. Srivastava, the vaccine’s developer, who is a leading cancer immunotherapy expert and director of the Carole and Ray Neag Comprehensive Cancer Center at UConn Health. “The personalized vaccine is specifically created using a patient’s own genomics information to prevent an often life-threatening recurrence of the disease and extend survival.”

There is no early-screening test for ovarian cancer. When a woman with the disease starts to actually experience non-specific abdominal symptoms such as bloating, the disease has often already advanced to stage III or stage IV cancer. Further, there is no effective long-term treatment for ovarian cancer. Even after a woman is successfully treated with traditional surgery and chemotherapy, the disease has a very high recurrence rate within just two years. Tragically, most women die within five years of their diagnosis.

But Srivastava believes that appropriate immunotherapy may stop an ovarian cancer diagnosis from becoming a death sentence.

“There is a huge need for a therapy to actually prevent recurrence in these women and I believe our approach to a vaccine may be just the tool to do it,” says Srivastava.

In October 2014, Srivastava published a study showing that his promising approach to cancer vaccines is effective in reducing tumor growth and in preventing cancer progression in mouse models. Based primarily on that work, the FDA approved testing of the experimental therapy in a human clinical trial.

The individualized vaccine is created using samples of a patient’s own DNA from both her unhealthy cancer cells and her healthy blood cells. Over a period of about two weeks, scientists sequence and cross-reference the entire DNA from both sources to pinpoint the most important genetic differences. These genetic differences constitute the ID card, or fingerprint, of that particular patient’s cancer, which is unlike the ID card or fingerprint of any other person’s cancer. Based on the cancer’s fingerprint, bioinformatic scientists, led by Ion Mandoiu of UConn’s School of Engineering, design the personalized vaccine that is meant to target the cancerous cells’ specific genetic mutations.

UConn Health’s new clinical trial will initially enroll 15 women with stage III/IV ovarian cancer and track them closely for two years, the window of time when recurrence most often occurs. Candidates for the clinical trial are women recently diagnosed with advanced ovarian cancer who will have traditional surgery and receive chemotherapy. If cancer-free three months after traditional treatment, the women will receive their personalized vaccine injections once a month for six months. Also, each month their blood will be drawn and evaluated for immune response.

“Our clinical trial will be testing the vaccine for safety and feasibility, but also will be testing whether the vaccine is making a real difference in patients’ blood; the timing of recurrence of cancers in these patients will also be monitored,” says Srivastava. “If, after receiving the vaccine, their cancer hasn’t recurred for a long time in a substantial proportion of women, we will know that the vaccine is promising.”


lab image of Ovarian Cancer cells

This UConn lab image shows how the new ovarian cancer vaccine works. Tiny immune cells known as lymphocytes (small purple dots) target and attack the cancerous ovarian cancer growths (outlined in blue) and prevent them from spreading to benign tissue (pink). Lab image courtesy of Dr. Pramod K. Srivastava


In October 2014, Srivastava published a study showing that his approach to cancer vaccines is effective in reducing tumor growth and in preventing cancer progression in mouse models. Based primarily on that work, the FDA approved testing of the experimental therapy in a human clinical trial.

Dr. Angela Kueck, assistant professor of gynecological oncology, and Dr. Jeffrey Wasser, assistant professor of medicine at the Carole and Ray Neag Comprehensive Cancer Center, are the principal and co-investigators of this study.

“We have received over a hundred messages from women in Connecticut and from around the world, in the hope of participating in our study,” says Srivastava.

He adds, “The most meaningful part of my life, at this time, is to serve. I hope that our results a few years from now will show that our unique ovarian cancer vaccine can prevent recurrence of the disease and even extend survival.”

If the clinical trials are successful against ovarian cancer, Srivastava plans to expand testing of his vaccine to bladder cancer and other solid-tumor cancers.

“This first-ever genomics-driven personalized vaccine has the potential to dramatically change how we treat cancer,” says Srivastava.

Lab Notes – Winter 2015

Cancer Cells Unreceptive to Vitamin D

Many human colon cancers may not express receptors for vitamin D, limiting vitamin D’s protective role against colon cancer to the early stages of the disease, report Charles Giardina and colleagues at UConn’s Department of Molecular and Cell Biology and Center for Molecular Medicine in the April 14 issue of Cancer Prevention Research. The researchers observed that adenomas in the colons of mice tended to repress vitamin D receptors, while having elevated Class I histone deacetylases (HDAC). However, HDAC inhibitors may reactivate the vitamin D receptors. They propose that vitamin D could still be protective against colon cancer, but how its receptors are expressed and inhibited in cancer cells needs more examination. Read the article at Cancer Prevention Research.

a group of vitamin D suppliments


Rogue X Chromosomes Uncovered in Farmington

Humans only need the genes from one X chromosome to be healthy. The extra one gets trussed up and shut down in the earliest stages of development. But female human embryonic stem cells growing in the lab sometimes reactivate their second X. They express extra genes, fouling up experiments and scuttling potential therapies. Now, researchers including UConn’s Marc Lalande and a team from Paris Diderot University have found a marker, and potentially a mechanism, for how the extra X reactivates – and they have an idea on how to prevent it. They describe their findings in the May 7 issue of Cell Stem Cell.


Friends are Unreliable Sources for Drinking Studies

In recent years, researchers have turned to friends of people in alcohol studies to verify what the subjects report about their drinking habits. People in the same social situations are sought out, in part, because of the inherent impairment caused by alcohol. But according to a UConn study published in Addictive Behaviors, friends don’t seem to provide any new information. In fact, they typically underreport what their acquaintances consume. The finding supports the so-called “protective effect” of friends described in other research. A growing availability of other evidence – hair and fingernail samples, for example – may provide better strategy for corroborating the amount of alcohol study subjects consume, says author Michael Fendrich, associate dean of the School of Social Work.


She Smells Him, She Smells Him Not

Mice rely on their noses to help them navigate the world. But high levels of progesterone “blind” receptors in the noses of female mice to male pheromones, UConn Health’s John Peluso and other colleagues, led by Dr. Lisa Stowers of The Scripps Research Institute, report in the June 4 issue of Cell. Female mice have high levels of progesterone during the infertile phase of their reproductive cycles, and tend to be indifferent or even aggressive toward males. But during the fertile phase, progesterone levels drop and estrogen rises, and their nasal receptors again respond to male pheromones, the researchers found. Female mice in their fertile phase are friendly and sexually receptive towards males – perhaps because they can smell them.

mouse