Cancer protein discovery may aid radiation therapy: Blocking cyclin D1 might help sensitize tumors to radiation

ScienceDaily (June 9, 2011) — Scientists at Dana-Farber Cancer Institute have uncovered a new role for a key cancer protein, a finding that could pave the way for more-effective radiation treatment of a variety of tumors.

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Many cancers are driven in part by elevated levels of cyclin D1, which allow the cells to escape growth controls and proliferate abnormally. In the new research, reported in the June 9 issue of Nature, researchers discovered that cyclin D1 also helps cancer cells to quickly repair DNA damage caused by radiation treatments, making the tumors resistant to the therapy.

Based on this finding, the researchers made cancer cells more sensitive to several cancer drugs and to radiation by using a molecular tool to lower the cancer cells' cyclin D1 levels, said Peter Sicinski, MD, PhD, senior author of the report and a professor of genetics at Dana-Farber.

"This is the first time a cell cycle protein has been shown to be directly involved in DNA repair," said Siwanon Jirawatnotai, PhD, the lead author of the paper. "If we could come up with a strategy to inhibit cyclin D1, it might be very useful in treating a variety of cancers."

The gene for cyclin D1 is the second most-overexpressed gene found in human cancers, including breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Cyclin D1's normal function in cellular growth control is to temporarily remove a molecular brake, allowing the cell to manufacture more DNA in preparation for cell division. When cyclin D1 is mutated or is overactivated by external growth signals, the cell may run out of control and proliferate in a malignant fashion.

The findings came in a series of experiments by Jirawatnotai, a post-doctoral fellow in the Sicinski lab. With the goal of uncovering details of cyclin D1's function in human cancer cells, Jirawatnotai broke open four types of cancer cells, isolated the cyclin D1 protein, and searched for other proteins with which it interacted.

The experiment netted more than 132 partner proteins, most of them part of the cell cycle protein mechanism in which cyclin D1 is a major player. But unexpectedly, the scientists also observed that the cyclin D1 protein was binding to a cluster of DNA repair proteins, most importantly RAD51. The RAD51 protein is an enzyme that rushes to broken parts of the cancer cell's DNA instructions and repairs the damage, including damage caused by radiation therapy administered to stop cancer cells' division and growth. In another experiment, it was observed that cyclin D1 was recruited along with RAD51 to the DNA damage site.

"This was a surprise," said Jirawatnotai. "This finding showed that cyclin D1 has an unexpected function in repairing broken DNA." In additional experiments, he used a molecular tool, RNA interference (RNAi) to drastically reduce the level of cyclin D1 in the cancer cells. "When you lower D1 levels, you get poorer repair," he said.

When cancer cells with reduced cyclin D1 protein levels were administered to mice, the resulting tumor proved to be more sensitive to radiation than those grown from cells with overexpressed cyclin D1.

Currently, cyclin D1 is thought to be responsible for driving cancer cell proliferation. Agents that target cyclin D1 are currently in clinical trials, with the goal of reducing cancer cell growth. The new findings strongly suggest that targeting cyclin D1 may increase susceptibility of human cancers to radiation, said the scientists, and this discovery may encourage targeting cyclin D1 even in these cancers whose cells do not depend on cyclin D1 for proliferation.

"Our results potentially change the way we think about cyclin D1 and cancer and may encourage targeting cyclin D1 in a very large pool of human cancers which do not need cyclin D1 for proliferation, but may still depend on cyclin D1 for DNA repair," said Jirawatnotai, who also holds a faculty position at the Mahidol University in Bangkok, Thailand.

In addition to Sicinski and Jirawatnotai, the paper's other authors include Wojciech Michowski, PhD, Yiduo Hu, PhD, Lisa Becks, Yaoyu Wang, PhD, John Quackenbush, PhD, Mick Correll, and David Livingston, MD, Dana-Farber; and Steven Gygi, PhD, Harvard Medical School.

The research was supported by grants from the National Institutes of Health.

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Radiation after prostate removal is cost-effective, but less likely to be recommended by urologists

ScienceDaily (June 9, 2011) — Receiving radiation therapy immediately after a radical prostatectomy is a cost-effective treatment for prostate cancer patients when compared with waiting and acting on elevated prostate-specific antigen (PSA) levels, according to a new study by researchers at Thomas Jefferson University and Hospital.

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What's more, a separate, but related study, found that urologists were less likely than radiation oncologists to recommend adjuvant radiation therapy or to believe it improves overall survival.

There has been question over whether administering adjuvant radiation therapy after removing the prostate is an appropriate course of action because of associated toxicities, risk of overtreatment and costs, even with data supporting its benefits to overall survival, but a new decision analysis published online in the Annals of Oncology on June 9 found that the procedure is a practical option for patients.

"This work demonstrates that adjuvant radiation therapy is a cost-effective strategy for selected patients after prostatectomy," said Laura Pizzi, PharmD, associate professor at the Jefferson School of Pharmacy, and senior author of the study. "It is typical for cancer treatments to provide clinical benefit at a cost; however, the cost per success that we reported for adjuvant radiation therapy is on the low end when one broadly considers the cost per success reported for other cancer treatments."

The objective of the study was to construct a decision analytic model to estimate the real world cost of adjuvant radiation therapy versus observation from the payers' perspective, using peer-reviewed, published data from a Southwest Oncology Group prospective, randomized trial. Side effects, overtreatment and the price tag were taken into account.

Nearly one-third of newly diagnosed men with prostate cancer -- almost 220,000 men were diagnosed in 2010 -- undergo radical prostatectomy. Previous studies have shown that adjuvant radiation therapy improves biochemical progression-free survival and overall survival for these patients; however, most do not receive the treatment.

"Despite being shown to be effective, less than 20 percent of qualifying patients receive it," said Timothy Showalter, M.D., assistant professor of Radiation Oncology at Thomas Jefferson University, associate research member of the Kimmel Cancer Center at Jefferson, and lead author of the study. "Although not all patients will benefit from adjuvant radiation therapy, the level of utilization is lower than expected based on the positive, published results of randomized clinical trials."

"Studies like this one are an important step toward establishing the value of this treatment and suggest that adjuvant radiation therapy should have a role in the treatment of selected patients. Our group has embarked on a large-scale research program to evaluate and improve treatments after prostatectomy for patients with high-risk prostate cancer, and these studies are critical foundational accomplishments," he added.

Side effects, risk of overtreatment (the subset of patients who may not have failed PSA tests after radiation therapy despite adverse pathologic factors) and the high price have cast some doubts for patients and physicians alike. In many cases, physicians choose to observe patients closely with serial PSA tests and offer radiation therapy only as a salvage treatment after a rise in the PSA levels.

But this new analysis, Dr. Showalter says, "substantiates the benefit of adjuvant radiation therapy," taking these factors into consideration, including toxicity and overtreatment.

Another study by Dr. Showalter and colleagues, published online in the International Journal of Radiation Oncology

Intensity modulated radiation therapy cuts GI side effects from prostate cancer in half vs. 3D-CRT, study shows

ScienceDaily (June 1, 2011) — Intensity modulated radiation therapy, a newer, more precise form of radiation therapy, causes fewer gastrointestinal side effects when combined with hormone therapy than using three-dimensional radiation therapy, according to a study published in the June issue of the International Journal of Radiation Oncology•Biology•Physics, the official scientific journal of the American Society for Radiation Oncology (ASTRO).

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Three-dimensional radiation therapy (3D-CRT) combined with hormone therapy has been proven very effective at treating men with intermediate to high-risk prostate cancer. However, these treatments can cause very uncomfortable gastrointestinal side effects due to exposure of the rectum to radiation during treatment.

Researchers at Fox Chase Cancer Center in Philadelphia conducted a study to see if IMRT, which allows doctors to better concentrate radiation in the prostate and limit rectal exposure, reduces the side effects while continuing to deliver the necessary radiation to successfully treat the cancer.

Two hundred ninety-three men were studied -- 170 received 3D-CRT and 123 received IMRT. With a mean follow-up of 86 months, a multivariate analysis shows that patients treated with 3D-CRT were more than twice as likely to develop gastrointestinal toxicity compared to patients treated with IMRT.

"The use of IMRT significantly reduces the risk of late GI toxicity in men undergoing concurrent radiation therapy and hormone therapy for prostate cancer," Mark Buyyounounski, MD, MS, a radiation oncologist at Fox Chase Cancer Center, said. "I encourage men with prostate cancer receiving hormone therapy and radiation therapy to talk their doctors about whether IMRT has advantages over other types of radiation therapy."

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Higher doses of radiation in fewer treatments proved safe, effective for low-risk prostate cancer, study finds

ScienceDaily (June 2, 2011) — In a multicenter clinical trial, UT Southwestern Medical Center researchers have found that higher doses of stereotactic radiation therapy requiring fewer treatments are safe and effective for patients with low-to-intermediate-risk prostate cancer.

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Results of the trial, available in the Journal of Clinical Oncology, showed that stereotactic body radiation therapy (SBRT), which delivers ultra-precise radiation, was effective in treating patients with localized prostate cancer in five 30-minute sessions every other day over two weeks. That compares to the typical radiation protocol for prostate cancer of 42 to 45 daily treatments administered over eight to nine weeks.

"We were trying to develop a fast, convenient, outpatient, non-invasive treatment," said Dr. Robert Timmerman, vice chairman of radiation oncology and professor of neurological surgery and senior author of the study. "In the low-risk population, there are a lot of good options, but none of them are altogether convenient. The most convenient treatment would finish quickly without the need for a prolonged recovery."

SBRT has been used in the last decade to treat patients with lung, liver and brain cancers. The current study tested whether high-potency treatments would work in a moving target like the prostate, which moves considerably due to normal bladder and bowel filling.

"We're trying to kill the prostate cancer, but without injuring the urethra, the bladder or the rectum," Dr. Timmerman said. "Each treatment had to be very potent in order to get the full radiation effect in only five treatments."

To avoid injury to healthy tissue, researchers used beams of radiation that were just millimeters larger than the target itself. That narrow scope helped avoid consequences such as rectal injury, impotence and difficulty urinating.

Prostate cancer is the most common cancer in men, with some 200,000 diagnosed each year in the U.S. About half of those who are treated undergo radiation therapy, typically for eight weeks. Not everyone is cured, however, because some tumors are resistant to radiation.

In the current clinical trial, researchers tested escalating doses for safety levels in 45 patients enrolled from November 2006 to May 2009. In a 90-day follow-up procedure, they looked at how much injury occurred in adjacent areas, including the rectum or urethra, and any changes to the patients' quality of life.

"There were a few more complications associated with higher doses, but they were fairly predictable and rarely severe," said Dr. Yair Lotan, associate professor of urology and a co-author of the study. "By giving these higher doses, we might be able to kill more resistant tumors with shorter treatments."

In the next stage of the clinical trial, a larger group of patients will be treated at one dosage level, and follow-up will be 18 months.

Other UT Southwestern researchers involved in this study were Dr. Paul DeRose, radiation oncology resident; Dr. Xian-Jin Xie, associate professor in the Harold C. Simmons Comprehensive Cancer Center; Jingsheng Yan, statistician; Dr. Ryan Foster, assistant professor of radiation oncology; Dr. David Pistenmaa, professor of radiation oncology; and Susan Cooley, senior research nurse in radiation oncology.

The study was supported by the Department of Defense.

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Emerging trends in radiation therapy for women over 70 with early stage breast cancer

ScienceDaily (June 2, 2011) — Patterns of radiation usage in breast conserving therapy for women 70 years and older with stage I breast cancer are changing: more women are opting for radioactive implants and those with estrogen positive tumors are opting out of radiation therapy, according to an abstract being presented at the American Society of Clinical Oncology annual meeting in Chicago by Thomas Jefferson University Hospital researchers.

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In another abstract, the researchers report that women with estrogen negative tumors were 91 percent more likely to die from breast cancer if they did not receive radiation therapy after a lumpectomy.

Given the relatively recent developments in radiation therapy (i.e., an increased use of brachytherapy and external beams) and data supporting the idea that radiation isn't necessary for women with estrogen positive tumors, researchers wanted to see how actual practice patterns were impacted.

Researchers found that there was a modest increase in the percentage of women with estrogen receptor positive cancers who did not get radiation therapy starting around 2004, and increasing use of radioactive implants, such the MammoSite, Contura, Savi or similar devices, since 2002.

There was also a corresponding drop in women who received external beam radiation, according to Xinglei Shen, M.D., a resident in the Department of Radiation Oncology at Thomas Jefferson University Hospital. "Among women with estrogen receptor negative cancers, there was not the same increase in frequency of women who did not get radiation, but there was an increased use of radioactive implants," he said.

The consequence of those findings was determining what impact omitting radiation has on survival. While there is data that the omission of radiation therapy in women with estrogen receptor positive tumors who receive endocrine therapy, such as Tamoxifen, is not associated with a survival difference, limited data exists for estrogen receptor negative tumors in older women who undergo breast conservation.

"From the randomized trial data, we know that women with estrogen receptor positive stage I breast cancer have no detriment to survival by avoiding radiation, as long as they took Tamoxifen," Dr. Shen said. "However, it is unknown if this would be the case in women with estrogen receptor negative cancer."

Dr. Shen worked with Jefferson Medical College student Andrzej Wojcieszynski to examine survival in these women, and found that they were 91 percent more likely to die from breast cancer if they did not receive radiation therapy after a lumpectomy. (Abstract #1037).

"We have to be cautious when interpreting survival data from the SEER because of potential confounding variables, such as the health of the patients and use of chemotherapy," Dr. Shen said. "However, these data do raise hypotheses for future study."

"Our conclusion is that adjuvant radiation therapy after lumpectomy reduces breast cancer mortality in women over 70 with stage I, estrogen receptor negative breast cancers, and that radiation is currently underutilized in these women," said Wojcieszynski.

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Yoga improves quality of life in women with breast cancer undergoing radiation therapy, study finds

ScienceDaily (May 18, 2011) — For women with breast cancer undergoing radiation therapy, yoga offers unique benefits beyond fighting fatigue, according to new research from The University of Texas MD Anderson Cancer Center.

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While simple stretching exercises improved fatigue, patients who participated in yoga that incorporated yogic breathing, postures, meditation and relaxation techniques into their treatment plan experienced improved physical functioning, better general health and lower cortisol (stress hormone) levels. They also were better able to find meaning in their cancer experience.

The findings, to be presented next month in an oral session at the 47th annual meeting of the American Society of Clinical Oncology by Lorenzo Cohen, Ph.D., professor and director of the Integrative Medicine Program at MD Anderson, are the latest in an ongoing effort to scientifically validate the age-old belief that mind-body interventions have a beneficial impact on the health of cancer patients. The research was conducted in collaboration with India's largest yoga research institution, Swami Vivekananda Yoga Anusandhana Samsthana in Bangalore, India.

The study assessed, for the first time, yoga benefits to cancer patients by comparing their experience with patients in an active control group who integrated simple, generic stretching exercises into their lives. "The combination of mind and body practices that are part of yoga clearly have tremendous potential to help patients manage the psychosocial and physical distress associated with treatment and life after cancer, beyond the benefits of simple stretching," said Cohen.

To conduct the study, 163 women with breast cancer (stage 0-3) averaging 52 years of age were randomized to one of three groups: 1) yoga; 2) simple stretching; or 3) no instruction in yoga or stretching. Participants in the yoga and stretching groups attended sessions specifically tailored to breast cancer patients for one hour three days a week throughout their six weeks of radiation treatment.

Participants were asked to report on their quality of life, including fatigue, daily functioning, benefit finding, depression and spirituality. Saliva samples were collected and electrocardiogram tests were administered at baseline, end of treatment, and at one, three and six months post-treatment.

After completing radiation treatment, only the women in the yoga and stretching groups reported a reduction in fatigue. At one, three and six months after radiation therapy, women who practiced yoga during the treatment period reported greater benefits to physical functioning and general health. They were more likely to perceive positive life changes from their cancer experience than either other group.

Women who practiced yoga also had the steepest decline in their cortisol across the day, indicating that yoga had the ability to regulate this stress hormone. This is particularly important because higher stress hormone levels throughout the day, known as a blunted circadian cortisol rhythm, have been linked to worse outcomes in breast cancer.

According to Cohen, developing a yoga practice also helps patients after completing cancer treatment. "The transition from active therapy back to everyday life can be very stressful as patients no longer receive the same level of medical care and attention. Teaching patients a mind-body technique like yoga as a coping skill can make the transition less difficult."

Through a grant from the National Cancer Institute -- the largest ever awarded for the study of yoga in cancer -- Cohen and his team will next conduct a Phase III clinical trial in women with breast cancer to further determine the mechanisms of yoga that lead to improvement in physical functioning, quality of life, and biological outcomes during and after radiation treatment. A secondary aim of the trial, but one of great importance, stressed Cohen, is assessing cost efficiency analysis for the hospital, health care usage costs in general, and examining work productivity of patients.

MD Anderson recognizes the growing body of research indicating that relaxation-based interventions can contribute to the well-being of people with cancer. Through the Integrative Medicine Program, complementary therapies, such as yoga, are offered at MD Anderson's Integrative Medicine Center, and are used in concert with mainstream care to manage symptoms, relieve stress, enhance quality of life, and improve outcomes for patients and their caregivers. MD Anderson's Integrative Medicine faculty also conduct research in the biological and behavioral effects of mind-body based interventions; the anti-cancer potential of natural compounds; and, acupuncture to treat common cancer treatment-related side effects.

In addition to Cohen, other MD Anderson researchers contributing to this study include: Kavita Chandwani, M.D., former senior research coordinator and yoga teacher; Robin Haddad, M.P.H. , research coordinator, George Perkins, M.D. in the Department of Radiation Oncology; Amy Spelman, Ph.D., Kayla Johnson, B.S. and Adoneca Fortier, B.S., all staff in the Integrative Medicine Program; Banu Arun, M.D., in the Department of Breast Medical Oncology; and Qi Wei, M.S., Sr. Statistical Analyst. Clemens Kirschbaum, Ph.D. contributed from the Technical University of Dresden, Dresden, Germany. Collaborators from SVYASA include NV Raghuram, B.E.; R. Nagarathna, M.D., and HR Nagendra, Ph.D., founder.

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