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Promise and Progress - More Than X-Ray Beams

Promise & Progress - A Spectrum of Achievements

More Than X-Ray Beams

Date: January 15, 2015

The Expanding Science of Radiation Therapy and its Role in 21st Century Medicine


Andrew Sharabi
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Andrew Sharabi

Before there were prodrugs, radiolabeled nanoparticles or proton beams, sophisticated machines that delivered targeted X-ray beams with complex and precise trajectory calculated by skilled physicists were a mainstay of cancer therapy.  They remain so today, but they are better and safer, just part of a cadre of technologies and biologic therapies that radiation oncologists, physicists, and molecular scientists use to fight cancer.  Radiation oncology and molecular radiation sciences seamlessly unites physics, engineering and medicine to plan and deliver care that is based on the biologic underpinnings of cancer. Advances in our understanding of radiation biology, molecular biology, and imaging are resulting in unique radiation oncology treatment strategies never before imagined, and these innovations are allowing our scientists to see, study, and treat tumors in completely new ways.

Focused Radiation Stimulates Cancer Immunity

The prevailing opinion in cancer research was that chemotherapy and radiation therapy suppressed the immune system, but radiation oncology resident Andrew Sharabi proved that creative thinking and a fresh perspective sometimes opens up new avenues of research and innovation.

“We’re finding that focused radiation, like what is used in stereotactic radiosurgery, may actually stimulate an immune response,” says Sharabi.  He is collaborating with Kimmel Cancer Center cancer immunology expert Charles Drake to decipher how to harness this power to improve cancer treatment.

He recently presented his research at the 2014 annual meeting of the  American Society of Therapeutic Radiation Oncology (ASTRO). His research was selected from thousands of submissions to be one of the featured plenary presentations at the meeting, making him the first resident ever to receive the honor and the first basic science research to be highlighted at the meeting in over a decade.

Drake was the ideal mentor for Sharabi. He was part of a research team that recently reported a two-pronged immune therapy approach coupled with targeted radiation treatment significantly prolonged the life of the mice with glioblastoma brain cancer.  The study found the treatment also protected the mice from new tumors. 

Sharabi, too, was employing a novel mouse model for his studies. He used mice with tumors on each side. One side was shielded from radiation, and the other side was treated with radiosurgery using John Wong’s small animal research platform.  Not surprisingly, tumors that were treated with radiosurgery were destroyed, but when the mice also received an immune therapy drug,  tumors on the side not treated with radiation also responded. “Radiation therapy has always been thought of as a localized treatment,” says Sharabi.  “But in our model, when we combined radiosurgery with immune therapy it gained an added systemic activity.”

Sharabi suspects that cell damage invoked by radiation to the tumor causes cancer cells to present antigens—molecules that induce an immune response—on their surface. But that’s not enough to activate an attack against cancer cells.  Sharabi says tumors also generate regulatory cells that shield cancers from an immune response.  This tug-of-war leaves the immune system in neutral, ready and poised to attack but with the brakes still on.

To remove the brakes, Sharabi employed a novel new type of immune treatment, known as checkpoint blockade therapy.  Pioneered by Kimmel Cancer Center immunology experts, it was the same type of approach Drake took in the brain cancer studies.  Checkpoint blockade prevented cancer cells from recruiting immune dampening regulatory cells.  With regulatory cells taken care of, he could use radiosurgery to enlist an entire complement of immune cells to fight the cancer—killer T cells that, as the name implies, kill cells; memory T cells that remember the tumor cells and have the power to keep the cancer in check; and B cells, which generate antitumor antibodies that  can tag cancer cells for destruction.

When Sharabi removed the tumors from the mice and looked inside,  what he saw provided an even greater insight into cancer’s immune regulatory actions and how they are influenced by radiation.  Most of the time when researchers look inside of tumors, they don’t find immune cells.  “The immune system is shut out,” says Drake.  “It has been a vexing problem in immune therapies.”  Yet, when Sharabi looked inside the mouse tumors that had been radiated, he found an increased number of tumor-infiltrating lymphocytes, a type of white blood cell involved in killing tumor cells and typically associated with better outcomes.  “Tumors are typically hard but interestingly become softer when they are radiated.  So something happens—either cell death, or a breakdown of the vasculature, or the release of inflammatory markers—that allows immune cells to get in,” says Sharabi.  “Radiation opens the door, and blockade therapy allows the immune cells to go to work.”

To move these promising findings closer to clinical studies, Sharabi plans to study head and neck cancer patients receiving radiosurgery.  He will collect blood samples before, during, and after the radiation treatment and will use them to measure and quantify the immune response it activates.  He also plans to study the addition of immune blockade therapy in cancers—such as prostate, head and neck and early lung cancers—that can be cured with radiation.  “Adding immune therapy in these cancers may give us even better control,” says Sharabi.  “It could essentially makes a vaccine out of the tumor.”  The blood-based research will also facilitate identification of biomarkers that can be used to identify new targets for the immune system and patients most likely to benefit from combined treatment.

Sharabi sees great potential for the combined radiosurgery/immune therapy approach.  He wonders if radiation could be used explicitly to incite an immune response.  “We could give radiation to patients specifically to engage the immune system,” says Sharabi. “Using radiation to shift the tide of immune cells in our favor and immune therapy to remove the brakes on the immune response  could deliver better responses against a wide variety of cancers, even cancers that have spread.”

Theranostics, Aptamers, and Nanoparticles

In a new approach dubbed “theranostics” because it combines the diagnostic properties of molecular imaging with cancer therapy, a multidisciplinary team of experts, including Ted DeWeese, Director of Radiation Oncology and Molecular Radiation Sciences, and cancer imaging experts Martin Pomper and Zhaver Bhujwalla, developed an idea that takes advantage of important molecular components of cancer and allows researchers and clinicians to see inside the cancer cell to view them as they are being treated.  The team is developing ultratiny structures called nanoparticles filled with an anticancer drug that also sensitizes cancer cells to radiation and a radiopharmaceutical or cell-imaging agent.  The nanoparticle is targeted to PMSA, a biomarker for prostate cancer, so that it zeroes in on and delivers its anticancer payload specifically to prostate tumors.  The particle is labeled with a radioactive isotope, which can be imaged or used to treat cancer.  It is given intravenously so that it can attack cells growing anywhere in the body.

In other work, DeWeese and  prostate cancer researcher Shawn Lupold became the first to show that small inhibitory RNA (siRNA)—small molecules that have the ability to interfere with the expression of genes—could be used for cancer therapy. DeWeese and team used aptamers, a guidance system of sorts, to get the RNA molecule to its target inside of cancer cells where it shuts down cancer cells’ ability to repair the injury that radiation inflicts, and as a result, they die.  The aptamers, which allow the repair-blocking inhibitory molecules to be targeted specifically to cancer cells, are unique to Johns Hopkins and considered the gold standard.  Moreover, it is a platform technology that can be used not only for prostate cancer, but for any cancer type, simply by changing the aptamer. 

Another nanotech approach DeWeese is exploring for prostate cancer treatment uses alpha particles, a type of radium isotope, that are naturally targeted to the bone, where prostate cancer most often spreads.  It captures the killing power of decaying radium, but in this form it has a short life of about 10 days and only causes damage in the limited path it travels in the body.  Radium has a chemical relationship to calcium, and so acts in the human body like calcium, naturally traveling to the bone.  Investigators are studying a combined nanoparticle/alpha particle/radiation treatment.  The nanoparticle, loaded with its radiation-sensitizing anticancer drug, is given simultaneously with the bone-metastasis-targeting alpha particle to exquisitely and precisely attack prostate cancer and its spread.

Change the Environment, Change the Tumor

About one-third of patients diagnosed with non-small cell lung cancer, the most common type of lung cancer, have cancers that have begun to spread outside the lung to lymph nodes in the chest.  The best opportunity to cure patients is when they are first diagnosed, but using the best radiation and drug therapies available today, one-quarter to one-half of patients have their cancers come back.  At that point there are very few treatment options.  Radiation oncologist and lung cancer expert Russell Hales is determined to change these statistics.

“I tell my patients, if we are going to cure your cancer, we need to win two battles.  First, we have to get rid of the primary tumor in your chest, and then we have to stop the tumor from spreading,” says Hales. It is not an either/or proposition, he says.  If the tumor spreads to the bone, the patient cannot be cured, but if it comes back locally in the chest, it can still claim the patient’s life. To shift the battle in the patient’s favor, Hales is looking to a cancer pathway called Hedgehog. It is a primitive development pathway that cancer cells hijack to maintain survival. “When tumors are breaking the rules to divide, grow, and spread, they use this pathway,” says Hales.  He believes drugs that block Hedgehog may make radiation treatment work better in patients with this locally advanced form of lung cancer.

When Hales and team turned off Hedgehog in test tube laboratory models, tumor cells didn’t grow, indicating the gene was a key player in at least some lung cancers.  When he added radiation to the mix, he expected to see the cell kill go up.  It didn’t.  “With or without Hedgehog inhibitors, the cell kill was essentially identical,” says Hales.  “This was not what we expected to see.”  He could have scrapped the project at this point and deemed it a failure, but his persistence proves that as much knowledge is gained from what doesn’t work as what does.  Looking back, he could not have predicted the direction the seemingly ill-fated project would take.  “We were staunch in our hypothesis that tumor cells control Hedgehog,” says Hales.  “We were surprised to find that isn’t what happens, but that’s the beauty of science.”

Test tubes are not the same as the human environment, so Hales decided to take another look using mouse models designed to more closely match human tumors.  Tumors do not occur in isolation as in the test tube model; they occur in an environment of other normal cells.  Hales wanted to find what affect these other cells had on the tumor, so he used medical physicist John Wong’s small animal research platform invention, a linear accelerator with an onboard CT scanner scaled down in size for animal research to find out.  The imaging capability allowed him to look more closely at the stroma, the supportive cells surrounding and nourishing the tumor.

What he found confirmed his laboratory studies. Blocking the Hedgehog pathway did not directly do anything to the tumor. Instead, it stabilized the blood cells in the stroma around it, allowing more oxygen to get in the tumor—an essential component for radiation therapy to work.  “A tumor that does not have a good supply of oxygen is difficult to radiate.  It is a radiation oncologist’s nightmare,” says Hales.  He is continuing to study the mechanisms to understand precisely how Hedgehog collaborates with stroma cells to promote cancer growth and, if he can secure funding, will advance to patient studies.  “If more studies prove these findings correct, we now have a the first targeted radiosensitizer out there, and one that works differently than every other targeted therapy,” says Hales. “Other targeted therapy goes after alterations in the tumor cells.  Our approach works by targeting the cells around the tumor.  That means it could work against almost any cancer type.”

Seeding a Cure

Brachytherapy is a widely used and promising tool of radiation therapy and commonly used in the treatment of prostate cancer as an alternative to surgical removal of the prostate. Radiation is delivered to the prostate via tiny seeds about the size of a grain of rice.  Accurate placement of these seeds has been the biggest challenge, but brachytherapy expert Danny Song has been a leader in pioneering guidance systems that ensure the seeds are deployed where they should.

To destroy prostate cancer, about 50 to 100 seeds are placed by needle in the prostate while the patient is under general anesthesia.  The greatest limitation to brachytherapy, Song says, was that there was no good, real-time way to see if the seeds were getting to correct place.  “X-rays show the seeds but do not provide an image of the prostate, and ultrasound shows the prostate well, but not always the seeds,” Song says. 

He decided to combine the two technologies into one.  Through a collaboration with Johns Hopkins University and Queens University engineers and Acoustic Medsystems and funding from the Department of Defense, John and Pembroke France Noble Fund for Oncology Research, and the National Cancer Institute, Song developed RadVision. As seeds are placed, multiple X-rays are taken and fed into a computer to generate a three-dimensional arrangement of seeds.  The seed positions are then superimposed over ultrasound images to guide the placement of additional seeds.

Song compares other methods of seed placement to driving with an outdated GPS. The result could be too many seeds in one place and the potential of excessive radiation and damage to other organs such as the rectum or urethra, or as detrimental, not enough seeds to adequately destroy the cancer.  RadVision, on the other hand, provides real time updates and guidance.  “Now we’re getting updated maps, traffic information, and even accident information that tells us to revise our route,” says Song.  A study in 80 patients using a prototype of RadVision confirmed that it provided the most accurate seed placement information.

RadVision received FDA approval and is being used by Song in a clinical study. In the past, patients who have received brachytherapy may have also required external beam radiation or additional procedures to compensate for inadequate seed placement. Song says seed placement with RadVision is so accurate that it may eliminate the need for additional radiation treatments, saving patients the risk of additional side effects, time, and money. Larger studies are being planned.

Funding the Cure

Brachytherapy expert Danny Song received vital support for his RadVision seed placement guidance system through the continued generous support of a grateful patient.  John and Pembroke Noble began supporting Song’s work in 2009, with several gifts. Subsequently, the couple named The Johns Hopkins University the beneficiary of a $1.1 million IRA bequest to establish the John and Pembroke France Noble Fund for Oncology Research.  The fund will support Song’s clinical research and advance other radiation oncology research projects. “We heard about Dr. Song’s work and wanted to help,” says John. 

His ties to Johns Hopkins go beyond his treatment. His wife Pembroke is the great great niece of  its benefactor Johns Hopkins.  Mr. Noble says he shares his wife’s appreciation of the advances being made at the Kimmel Cancer Center and throughout Johns Hopkins Medicine.  “Johns Hopkins is the place to come if you are sick, and it was the place we wanted to support,” he says.

What is a bequest?

A bequest is a type of gift that has no cost to the donor during his or her lifetime.  It can be created by including Johns Hopkins as a beneficiary in a will, retirement plan, or life insurance policy. Designating a retirement plan, such as an IRA, 401(k), or 403(b) is an easy way to make a bequest, but it’s one of which many people are unaware.  Retirement plan bequests can be made by naming Johns Hopkins as a whole or partial successor beneficiary on the retirement plan’s form and sending a copy to the Johns Hopkins Office of Gift Planning.

Such gifts ensure the future strength of Johns Hopkins, while still allowing the donor to continue to take withdrawals from the plan during his or her lifetime. A gift of retirement assets to Johns Hopkins is exempt from federal estate and income tax, but retirement funds left to individual heirs can get levied with heavy income and estate taxes.

Individuals who make a bequest commitment or life-income gift are welcomed into the Johns Hopkins Legacy Society. More information or call the Johns Hopkins Office of Gift Planning at 800.548-1268, or email giftplanning@jhu.edu.