Researchers hope newly discovered gene interaction could lead to novel cancer therapies

Scientists from Virginia Commonwealth University have revealed how two genes interact to kill a wide range of cancer cells. Originally discovered by the study’s lead investigator Paul B. Fisher, M.Ph., Ph.D., the genes known as mda-7/IL-24 and SARI could potentially be harnessed to treat both primary and metastatic forms of brain, breast, colon, lung, ovary, prostate, skin and other cancers.

Fisher-suit-at-deskIn the study, recently published in the online version of the journal Cancer Research, Fisher’s team found that forced expression of MDA-7/IL-24 (melanoma differentiation associated gene-7/interlukin-24) stimulates SARI (suppressor of AP-1, induced by interferon) expression in what is known as an autocrine/paracrine loop, which ultimately causes cancer cells to undergo a form of cell suicide known as apoptosis. Autocrine/paracrine loops occur when the expression of a particular gene or its encoded protein causes cells to secrete molecules that bind to surface receptors and force the expression of more of the same protein in an ongoing cycle.

“Many previous studies show that MDA-7/IL-24 can selectively kill diverse cancer cells through multiple mechanisms, but what was unclear was how exactly MDA-7/IL-24 interacted with other genes to promote cancer toxicity,” says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, and chairman of the Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine (VIMM) at VCU School of Medicine. “Our study uncovered multiple signaling pathways used by MDA-7/IL-24 that facilitate cancer cell death through the induction of SARI.”

Fisher and his team identified an existing combination of receptors, IL-20R1 and IL-20R2, and a discovered new combination of receptors, IL-22R1 and IL-20R1, through which signaling occurs to induce the MDA-7/IL-24 autocrine/paracrine loop. Once activated by the MDA-7/IL-24 protein, these receptors cause both normal and cancer cells to produce and secrete the MDA-7/IL-24 protein, which, in turn, activates SARI. The process was shown to culminate in apoptosis in cancer cells. Normal, healthy cells were not affected in the experiments.

The researchers are now focusing on developing small molecule drugs that induce MDA-7/IL-24 and/or SARI in cancer cells. They have also been experimenting with cancer-selective replicating viruses that seek out cancer cells and infect them with the toxic genes—an approach that has already been successfully employed in a phase 1 clinical trial using engineered viruses that deliver MDA-7/IL-24.

“This study helped us better understand how MDA-7/IL-24 works to kill a broad range of cancer cells through the induction of SARI,” says Fisher. “In addition to giving us another target for the development of new therapies, our research also suggests that we may be able to monitor the expression of SARI in order to determine the effectiveness of future therapies under development that target MDA-7/IL-24.”

Fisher collaborated on this research with Praveen Bhoopathi, Ph.D., postdoctoral research scientist in the Department of Human and Molecular Genetics at the VCU School of Medicine; Swadesh K. Das, Ph.D., instructor in the VCU Department of Human and Molecular Genetics and VIMM member; Devanand Sarkar, M.B.B.S., Ph.D., Harrison Research Scholar and member of the Cancer Molecular Genetics research program at VCU Massey, associate professor in the VCU Department of Human and Molecular Genetics and associate scientific director of cancer therapeutics at VIMM; Luni Emdad, M.B.B.S., Ph.D., member of the Cancer Molecular Genetics research program at VCU Massey, assistant professor in the VCU Department of Human and Molecular Genetics and VIMM member; Santanu Dasgupta, Ph.D., member of the Cancer Molecular Genetics research program at VCU Massey, assistant professor in the VCU Department of Human and Molecular Genetics and VIMM member; and Rupesh Dash, Ph.D., former postdoctoral research scientist in the VCU Department of Human and Molecular Genetics and now assistant professor at the Institute of Life Sciences in Bhubaneshwar, India.

This research was supported by National Institutes of Health grants 5 R01 CA097318, P01 CA104177 and 1 R01CA127641; and, in part, by VCU Massey Cancer Center’s NIH-NCI Cancer Center Support Grant P30 CA016059.

The full manuscript of this study is available online at: http://cancerres.aacrjournals.org/content/early/2013/11/26/0008-5472.CAN-13-1062.full.pdf+html

Massey first in Richmond to offer cutting-edge therapy for metastatic prostate cancer

Video by the New England Journal of Medicine

Video by the New England Journal of Medicine

VCU Massey Cancer Center is the first cancer care provider in the Richmond metropolitan region to offer radium-223, an innovative, new drug that has been shown to increase survival and quality of life in patients with metastatic castration-resistant prostate cancer (CRPC).

“Recently approved by the Food and Drug Administration, radium-223 is the first drug of its kind for the treatment of metastatic CRPC,” says Melvin Fratkin, M.D., professor and chair of Nuclear Medicine in the Department of Radiology at VCU School of Medicine, who administers the radium-223 at Massey. “It is a significant advancement because it can be combined with standard therapies to fight prostate cancer that has spread to patients’ bones.”

Radium-223 is a radioactive isotope that emits alpha particle radiation. It is similar to calcium because it accumulates in the areas of bone that are undergoing increased turnover, such as areas where bone metastases are forming. When the radium reaches the bone, it emits very low levels of radiation, which travel approximately four one-thousandths of an inch, killing the cancer cells and limiting damage to surrounding tissue.

Bone metastases are a frequent and serious complication of prostate cancer. In fact, more than two out of three metastatic prostate cancers spread to the bones, which can cause intense pain, weakness and bone fractures that greatly impair quality of life and, in some cases, cause death. Although there are several FDA-approved drugs to prevent these symptoms, none of them—except radium-223—increased survival.

A recent phase 3 clinical trial known as the Alpharadin in Symptomatic Prostate Cancer Patients (ALYSMPCA) trial evaluated the effectiveness of radium-223 in men with metastatic CRPC. The study enrolled 921 patients who were randomly selected to either receive radium-223 plus the best standard of care or a placebo plus the best standard of care. The trial found that men who were assigned the radium-223 survived more than three months longer than men assigned the placebo. The trial was stopped early to allow men taking the placebo to “cross over” and take the radium. Learn more about the ALYSMPCA clinical trial.

“Radium-223 is a great example of how clinical trials can lead to medical advances that change the lives of patients,” says Massey medical hematologist-oncologist, Craig Swainey, M.D., who led the ALYSMPCA trial at Massey and specializes in the treatment of prostate cancer.

Radium-223 is given intravenously once a month for six months. The treatment is considered to be safe and manageable for both patients and providers and is covered by Medicare.

Prostate cancer screening: the ongoing debate

bloodcellsSince its adoption by the FDA in 1994, the prostate-specific antigen (PSA) test has reduced prostate cancer mortality rates by 39 percent. Despite the lives saved, whether or how the PSA test should be used for screening is at the center of an ongoing debate.

In 2012, the U.S. Preventative Services Task Force (USPSTF) recommended against the use of PSA-based screening after new studies showed that the test led to overdiagnosis and overtreatment. In 2013, the American Urological Association changed its guidelines to recommend against screening for men under the age of 55 who are at average risk of prostate cancer and for men over the age of 70 who have a life expectancy of less than 10 to 15 years. The American Cancer Society recommends that men make an informed decision with their health care provider about prostate cancer screening; it does not take a stance for or against PSA testing. The National Cancer Institute makes no formal recommendation, but presents information on its website helpful for decision making.

Is the PSA test right for you? The answer to this question varies person to person, so I recommend that you talk to your doctor about your individual risk and educate yourself about the pros and cons of testing.

Here are a few important questions to ask your doctor:

What is my risk of developing prostate cancer?
Common risk factors include: age, race/ethnicity, nationality, family history of prostate cancer, genetics, diet and smoking.

Is PSA testing appropriate for me and if so, when should I begin testing?
Your doctor may or may not recommend testing, but if you are at high risk, he/she may advise testing at a younger age.

What is the purpose of a PSA test and how is it done?
A PSA test measures the level of PSA, a protein that is produced by the prostate gland, in a man’s blood. The higher your PSA level, the more likely it is that you have prostate cancer. The test requires a blood sample that is sent to a laboratory for analysis.

What are common side effects or risks of PSA testing?
The PSA test itself doesn’t have side effects, but overdiagnosis and overtreatment are the risks that have caused the screening debate. Some tumors found through PSA testing grow so slowly that they are unlikely to threaten a man’s life. Detecting non-life-threatening tumors is called overdiagnosis, and treating those tumors is called overtreatment. Overdiagnosis and eventual overtreatment, with procedures such as biopsies, radiation and hormone therapy, can lead to unnecessary complications such as urinary incontinence, problems with bowel function, erectile dysfunction and infection. Also, one of the greatest “risks” for patients who have a high PSA test is their tendency to panic after they hear the word “cancer” and to seek aggressive treatment whether or not it’s warranted, so it is important to thoroughly consider all of your options before taking action.

As with any test, there are both benefits and harms of prostate cancer screening. An important benefit of testing includes catching the cancer before it metastasizes (grows) or becomes life-threatening.

By identifying the cancer early, less-aggressive treatment is needed and outcomes are generally better. By discussing the test with your doctor, you will know more about your options and will be less likely to make hasty decisions out of fear. I also recommend receiving a second opinion from another physician before making any decisions about treatment.

About the author
Paul G. Goetowski, M.D. (known as “Dr. G.”), is assistant professor at VCU Massey Cancer Center and the director of radiation oncology at Community Memorial Healthcenter (CMH) Cancer and Specialty Care on behalf of Massey. He has extensive experience in using radiation to treat many cancer types and noncancerous diseases.

VCU Massey introduces new, high-tech radiation technology to improve cancer care

VCU Massey Cancer Center has made a significant investment in improving the region’s cancer care by becoming the only cancer care provider in Richmond to utilize the TrueBeam™ linear accelerator. This advanced machine made by Varian Medical Systems incorporates the latest image-guided radiation therapy technologies and higher dose rates to more accurately target patients’ tumors while sparing healthy tissue, reducing side effects and decreasing treatment times.

IMG_3608 350pxThe advanced capabilities of the TrueBeam™ system allow physicians to better treat complex cancers such as lung, liver, prostate and head and neck tumors that are close to vital organs and delicate tissue. With advanced imaging techniques, physicians can monitor and adapt to changes in a patient’s anatomy caused by the radiation therapy to personalize treatment plans based on each patient’s unique physiology. The optical camera system even allows physicians to see patient motion during treatments so they can monitor and adjust as needed.

“The TrueBeam™ system offers some very exciting and state-of-the-art features, but if you don’t know how to use them you may as well be using a normal linear accelerator. This is where our experts at VCU Massey Cancer Center set us apart from other institutions,” says Jatinder Palta, Ph.D., chief physicist in the Department of Radiation Oncology at VCU Massey Cancer Center. “We have pioneers in image-guided radiation therapy who have developed advanced radiation therapy techniques that are now being used nationwide. It is this experience that allows us to take full advantage of all of the benefits of TrueBeam™.”

Massey’s downtown location started using TrueBeam™ in June 2013, and the radiation oncology team is already pioneering ways to improve radiation therapy using its advanced features. Elizabeth Weiss, M.D., radiation oncologist at Massey, and Geoffrey Hugo, Ph.D., medical physicist at Massey, have received a grant to study image-guided radiation therapy in the treatment of lung cancers. Using advanced imaging techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET) and computed tomography (CT) scans coupled with the advanced targeting abilities of TrueBeam™, they are monitoring changes in patients’ tumors throughout treatments in order to determine whether patients have better outcomes when their treatment protocol is adjusted to match the changes that are happening in their body. If successful, Weiss and Hugo will help develop new treatment protocols that could be adopted worldwide.

IMG_3655-350x233In addition to the incorporation of advanced imaging technologies, TrueBeam™ also offers a unique advanced motion package that allows doctors to more accurately compensate for movement caused by the patient’s breathing. In addition, TrueBeam™ can deliver much higher doses of radiation compared to other linear accelerators. The increased dose delivery combined with advanced imaging techniques can shorten a 10-minute treatment to just two or three minutes while delivering the same amount of radiation.

“Historically, physicians treated patients as if no physiological changes occur throughout the course of the radiation treatments,” says Palta. “We know this is not the case, and now advanced image-guided radiation therapy using equipment such as TrueBeam™ potentially opens a lot of possibilities for improving patient outcomes by personalizing treatment plans.”

In addition to its downtown location, TrueBeam™ is already in use at Massey’s partner clinic at Spotsylvania Regional Medical Center. Massey also plans to install the TrueBeam™ system at its Hanover facility and at Hunter Holmes McGuire VA Medical Center, where Massey provides cancer care to area veterans.

Biodegradable implant may lessen side effects of radiation to treat prostate cancer

Several years ago, Virginia Commonwealth University Massey Cancer Center became the first center in the United States to test an Israeli-invented device designed to increase the space between the prostate and the rectum in prostate cancer patients undergoing radiation therapy. Now, results from the international Phase I clinical trial show that the device has the potential to significantly reduce rectal injury, a side effect caused by unwanted radiation exposure that can leave men with compromised bowel function following treatment.

BioProtect CT BlogResults of the 27-patient prospective trial were recently published in the journal Radiation Oncology. The device known as the BioProtect Balloon Implant was tested on patients with localized prostate cancer. It is designed to reduce radiation exposure to the rectum by expanding to increase the space between the rectum and the prostate. It remains in place throughout the treatment process and is designed to biodegrade completely within six months.

Anscher-Blog“We found that the addition of BioProtect reduced the radiation dose delivered to the rectum by an average of about 30 percent,” says local primary investigator Mitchell Anscher, M.D., Florence and Hyman Meyers Chair of Radiation Oncology at VCU Massey Cancer Center. “Most notable was the device’s ability to reduce exposure at higher radiation levels, which indicates that the cancer could be safely treated with more aggressive protocols.”

The researchers observed a greater reduction in radiation exposure to the rectum at increasing radiation dose levels. At 50 percent of prescribed dose, there was little difference in rectal tissue exposure. However, there was a 55.3 percent reduction at 70 percent of the prescribed dosage, a 64 percent reduction at 80 percent of the prescribed dosage, a 72 percent reduction at 90 percent of the prescribed dosage and an 82.3 percent reduction at 100 percent of the prescribed dosage.

As anticipated, all implanted balloons started to degrade three months after implantation. The researchers concluded that the device could be especially useful in hypofractionated radiation therapy. Hypofractionated radiation therapy uses larger doses of radiation applied over a shorter number of treatments instead of delivering a small percentage of the total dose during daily treatments spread over a longer period of time.

“Massey has many patients that travel from rural areas for care. If this device allows us to deliver the prescribed radiation dose over a shorter period of time, we can reduce the overall burden on the patient and they can spend less time away from work and their family,” says Anscher. “We hope to initiate a Phase II clinical trial in a larger cohort of patients in order to determine the effectiveness of the device in reducing rectal injury in comparison to standard treatment protocols.”

Anscher collaborated with the study’s lead investigator Gyorgy Kovacs, M.D., Ph.D., from the University of Lubeck, Germany; Dieter Jocham, M.D., and Gunther Bohlen, M.D., also from the University of Lubeck; Eliahu Gez, M.D., Rami Ben Yosef, M.D., Benjamin W. Corn, M.D., and Fabrizio Dal Moro, M.D., all from the Department of Radiation Oncology at Tel Aviv Sourasky Medical Center, Israel; Giovanni Scarzello, M.D., from the Department of Radiotherapy at the University of Padova, Italy; and Isaac Koziol, M.D., Mathew Bassignani, M.D., and Taryn Torre, M.D., all from Virginia Urology; and Shmuel Cytron, M.D., from Barzilai Medical Center, Israel.

The full manuscript of the study is available online at: http://www.sciencedirect.com/science/article/pii/S0167814013000236

Award funds Massey and VIMM research on new prostate cancer therapy

Fisher-head-shot-160x240Virginia Commonwealth University (VCU) Massey Cancer Center and VCU Institute of Molecular Medicine (VIMM) researcher Paul B. Fisher, M.Ph., Ph.D., has been awarded the Prostate Cancer Foundation’s 2012 A. David Mazzone PCF Challenge Award. Fisher shares this award with Drs. Martin G. Pomper and George Sgouros, both from Johns Hopkins University Medical Center. The Challenge Awards are highly competitive, two-year awards that provide a total of $1 million per team in support of large-scale innovative research projects in the area of prostate cancer. The award will provide VCU $400,000 in direct costs over two years.

Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and program co-leader of Cancer Molecular Genetics at Massey, chairman of VCU’s Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine, will serve as one of the project directors, working closely with other investigators on the overall project aims. The team will focus on developing systemically deliverable “theranostic” – combined therapeutic and diagnostic – nanoparticle constructs that will enable simultaneous molecular-genetic imaging and therapy of primary and metastatic prostate cancer. Molecular-genetic imaging essentially is imaging at a molecular level, which allows scientists and doctors to see and monitor things like gene expression and protein functions in cancer cells. In basic terms, the team hopes to develop a new therapy that allows them to monitor and simultaneously destroy primary prostate cancer and its metastases at the molecular level.

The scientists plan to use progression elevated gene-3 (PEG-Prom), a cancer selective gene promoter derived from rodents and first isolated in Fisher’s laboratory, to express a protein known as avidin directly on the surface of the primary and metastatic prostate cancer cells. In addition to being active in cells expressing cancer-promoting genes, the presence of PEG-Prom can also be detected using CT imaging techniques. The team will then use a biotin, or a water-soluble B-vitamin attracted to the avidin, to deliver a dose of radiation directly to the primary and metastatic prostate cancer cells. This novel strategy has high potential for the development of an effective and selective systemic therapy for advanced prostate cancer.

Prostate cancer trial aims to reduce radiation treatments

Radiation EquipmentVCU Massey Cancer Center has opened a Phase I clinical trial testing an innovative radiation therapy for patients with early stage prostate cancer that has the potential to drastically reduce treatment time. In comparison to the standard schedule of eight weeks of daily external beam radiation therapy, the new technique requires just four treatments, administered twice in the first week and twice in the fourth week.

“Many patients travel a significant distance to undergo radiation therapy at Massey,” says the creator of the innovative dosing schedule and lead investigator on the clinical trial Mitchell Anscher, M.D., Florence and Hyman Meyers Chair of Radiation Oncology and co-leader of the Radiation Biology and Oncology program at VCU Massey Cancer Center. “If successful, not only does this shortened dosing schedule mean less time out of work and less time in the clinic for patients, but we also estimate that it will cost at least $7,000 less than the standard eight-week treatment plan.”

The clinical trial shortens the treatment schedule by using a form of external beam radiation therapy called stereotactic radiation therapy. Stereotactic radiation therapy relies on precise imaging techniques, such as Massey’s Calypso 4D Localization System, to deliver a concentrated dose of radiation to the tumor with extreme accuracy. This approach allows physicians to deliver the same total amount of radiation over a much shorter period of time.

“Previous clinical trials and biological models suggest this approach could be an effective way to treat prostate cancer,” says Anscher. “We are testing the feasibility of this novel dosing schedule in hopes of developing a model that can be used by other treatment facilities with similar equipment.”

Approximately 250 patients are expected to enroll in the trial, which will be open at Massey and Hunter Holmes McGuire VA Medical Center, where Massey provides oncology care. Those interested in enrolling or learning more about the clinical trial should contact Massey’s Department of Radiation Oncology at (804) 828-7232 and reference clinical trial MCC-14712.

VCU Massey is currently conducting more than a dozen prostate cancer clinical trials and more than 150 total trials on a variety of cancers. View a complete list of all active clinical trials available at VCU Massey.