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.

Predicting Colon Cancer:

UConn Health Researchers Redefine ‘Early Detection’

By Chris DeFrancesco

Illustration of colon with areas highlighted and given warning signs


Find cancer early enough and you can treat it. Predict it before it develops and you can prevent it altogether.

Thanks to volumes of epidemiological data they have amassed, UConn Health researchers believe they are closing in on ways to identify who’s most at risk for colorectal cancer by analyzing cells from lesions that, if they are to become cancerous, are years away from doing so.

Once this can be figured out, doctors and patients would have a larger window of time to take steps to stop the cancer before it starts.

In the laboratory of Daniel W. Rosenberg in UConn Health’s Center for Molecular Medicine, concurrent studies — epidemiological, genomic, and molecular — are ongoing and are expected to yield a series of published papers this year and next. One, which describes how the Rosenberg lab uncovered evidence of the origins of colorectal cancer that historically have been poorly understood, was published in the June edition of Molecular Cancer Research, a major scientific journal of the American Association for Cancer Research.

We believe identifying early molecular changes may uncover new targets that could be used for preventing early neoplasia from progressing.

Cancer evolves from what is known as neoplasia — or new, abnormal growth of tissue. Not all neoplasias become malignant tumors, but they are considered an early warning sign of possible cancer.

“Understanding early neoplasia has become such a major focus at the National Cancer Institute — how do we characterize these early changes so we can prevent cancer,” says Rosenberg, HealthNet Inc. Endowed Chair in Cancer Biology and professor of medicine, “and I believe we’re at the forefront of answering this question.”

MD/Ph.D. candidate Allen Mo, first author on the Molecular Cancer Research paper, says colon cancer is thought to be an epithelial disease, meaning that it starts with a mutation in the tissue that lines the surface of the colon (the epithelium), and grows and then invades the underlying support tissue.

“People historically believed these are separate compartments, that there is no interaction between the epithelium and the support tissue until the cells become cancerous and break through the membrane,” Mo says. “We’ve been able to demonstrate that, even at the very early stage, prior to the polyp stage, the supportive tissue is actually influencing how these epithelial initiate cells are evolving.”

That’s important because it provides another potential early intervention point — if scientists can figure out a reliable way to make alterations to the signaling pathways between the two tissue types, perhaps they could influence how the mutated cells progress.

The Devers Data

The work includes collaborators from both within and outside the institution, but central to all of it is Dr. Thomas Devers, a UConn Health gastroenterologist whose volume of consecutive colonoscopies over the past five-and-a-half years has yielded data from 5,000 patients. The resulting demographic database has been powering the engine driving the research that has helped substantiate epidemiological findings, such as how smoking completely cancels the protective properties of aspirin, how consumption of diets rich in Omega-3 fatty acids appear to reduce risk of early neoplasia in the colon, and how walnuts may have protective properties, as described in a study recently published in Cancer Prevention Research.

“Dr. Devers routinely screens patients at a resolution that only a handful of clinicians are doing,” Rosenberg says.

Devers uses a high-definition endoscope with contrast dye-spray that enables him to detect tiny — less than 5 mm — lesions that are scattered throughout the colon.

“Many of the subjects have already returned for follow-up [surveillance] colonoscopy, so we actually have genomic data from three and five years ago that we can use to predict the possibility they may develop advanced adenomas or even cancer,” Rosenberg says. “We’re actually at the point now where we can follow the impact of these early changes over time.”

The work involves the intensive application of bioinformatics, the collection and analysis of complex biochemical and biological information.

What the Earliest Changes Can Reveal

Among the tiny lesions of particular interest are those known as aberrant crypt foci (ACF), which represent the earliest detectable precancerous change in the human colon. ACF tend to be detected less frequently during conventional colonoscopy, occur throughout the colon, and are the source of tissue that the Rosenberg lab uses for many of its analyses.

“We’re one of the only places in the country that actually look for these very early lesions,” says Mo, whose work has been instrumental to a number of ongoing studies in the Rosenberg lab.

“Most people study colon cancer development in the context of polyps as the earliest lesion,” Rosenberg says. “But we’re going one step earlier, with our focus on ACF. ACF present a unique opportunity to study the risk factors that may predispose the development of colon neoplasia, and may help to guide us toward potential interventions that may actually eliminate neoplasia prior to the appearance of polyps.”

Devers says the ACF he’s been finding in one particular area of the colon can be very telling when it comes to predicting future cancer risk.

“Part of our hypothesis is, we’re going to find these tiny lesions on the right side of the colon that have a lot meaning, that are only present in a small percentage of the population compared to the people who have tiny lesions in the rectosigmoid (the lower part of the colon), which everybody has,” Devers says. “And by finding these tiny lesions in the right side of the colon, you may want to screen those people more frequently.”

Biopsies and data from about 300 patient research volunteers have been the basis of several studies, including a collaboration with scientists at the Van Andel Institute in Grand Rapids, Mich., and The City of Hope in Duarte, Calif.

“We’ve done a complete genome-wide analysis of the epigenetic changes present within these tiny lesions, something that has never been done before,” Rosenberg says. “We’re uncovering all these interesting changes that occur to a person’s epigenetic profile years before they may develop a more advanced neoplasia. Much of this transformative epigenetic work was been performed by Matthew Hanley, a fifth-year graduate fellow in my lab. The question is, why we are interested in this ‘predictive’ profile? We believe identifying early molecular changes may uncover new targets that could be used for preventing early neoplasia from progressing.”

Often Hidden, Likely Telling

Another finding: some people seem to have a higher likelihood of forming what are known as sessile serrated adenomas (SSA) in the upper part of their colon. SSA, which also tend to be harder to detect, carry a strong likelihood of progressing, and may contribute to 20 to 30 percent of colorectal cancers.

“We believe that missed right colon cancers, or interval colon cancers, are related to these serrated adenomas,” Devers says.

SSA are larger than ACF but are also very difficult to catch during colonoscopy because of their flat shape and their tendency to be camouflaged in mucus along the colon wall. It takes a high-definition scope and experience — Devers has both — to find them.

“We’re able to actually identify thepeople who form this lesion, then go back to the epidemiological database and develop risk profiles as to which people are more likely to form that type of lesion,” Rosenberg says.

On the molecular level, Rosenberg’s lab routinely uses laser capture microdissection, which enables scientists to select and retrieve small groups of cells from a single biopsy. From there, they can apply genomic technologies to particular cells and screen for cancer-related mutations and genome-wide alterations. This technique was used in the research behind the Molecular Cancer Research paper.

“Early neoplasia has become a very hot area, and because of Dr. Devers, here we probably have accumulated the largest repository of human early neoplastic lesions anywhere in the world,” Rosenberg says. “With this amazing resource, we can now begin to define many of the key changes that are happening at this very early stage. It’s never been done before.”

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.

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.