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Promise and Progress - The Healing Power of Radiation

Promise & Progress - A Spectrum of Achievements

The Healing Power of Radiation

Date: January 15, 2015

How we are harnessing it to fight cancer


Moody Wharm
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Moody Wharam

Undeterred. This may be the best word to describe the tenacity of Kimmel Cancer Center radiation oncology clinicians and scientists in advancing patient care and radiation science. When others were content with the status quo, they resolved to do better than the best. This persistence sparked inventions, innovations and adaptations that have benefited patients and expanded the scope of radiation science. This setting where engineering gadgets, feats of physics, and medical science collide, is the ultimate laboratory. If it can be imagined, they are determined to achieve it.

 

 

The Pioneer

Moody Wharam came to Johns Hopkins in 1975 as was one of the early radiation oncologists. His lengthy and accomplished career makes him the historian of the department, and he recalls a constant theme among many milestones. Beginning with a novel radioactive antibody therapy for liver cancer, developed by then Radiation Oncology director Stanley Order and looking ahead to current Department of Radiation Oncology and Molecular Radiation Sciences’ director Ted DeWeese’s aptamer technology that shuts down cancer cells’ ability to repair the injury caused by radiation, it is clear that patient-centered innovation was the mission in the beginning and remains that way today.

Back then, they were a small team working in the basement of the Halsted Building waiting to move to state-of-the-art facilities in the new comprehensive cancer center.  Wharam’s work began before there was a Department of Radiation Oncology and Molecular Radiation Sciences.  Computer technology was limited at the time, as were the machines that delivered radiation to patients. Like the current generation of radiation oncologists, however, Wharam and colleagues were focused on advancing clinical research and improving the standard of care for patients, albeit at a time when the technology and radiation-delivering machinery had not quite caught up with their forward-thinking ideas.  “We had state-of-the-art knowledge and with the comprehensive cancer center in planning, state-of-the-art facilities were coming,” says Wharam.

Wharam began his career at the same time that deaths from cancer were rising, and then-President Richard Nixon announced a national war against cancer.  Sites for National Cancer Institute-funded comprehensive cancer centers were being determined, and Johns Hopkins was selected to be home to one of the first.  It was then that radiation oncology broke off from the Department of Radiology and Radiological Sciences and joined forces with the Department of Oncology to tackle a cancer epidemic.

When the comprehensive cancer center opened in 1977, it had all of the technical aspects needed for cutting-edge radiation therapy.  “We are the only specialty that makes its own medicine,” says Wharam.  “We retired the old cobalt machines and replaced them with linear accelerators, and we hired physicists to make sure the machines were doing what they were supposed to.”  Johns Hopkins was one of just a handful of strong academic programs in radiation oncology in the U.S. at the time, and Wharam recalls that when the center opened, they were immediately inundated with cancer patients. The radiation oncology clinic had to expand to twice its original size to accommodate the growing patient load. Years later, Wharam oversaw two additional expansions, one with the opening of the Kimmel Cancer Center’s Harry and Jeanette Weinberg Building and another with a satellite facility at Green Spring Station.

Wharam treated all types of cancer, but as the clinic expanded and more radiation oncologists were recruited, he made pediatric cancers his primary focus. The photographs around his office bear testimony to his pioneering contribution to advancing the care of children with cancer.  Cancer, and particularly pediatric cancer, was a troublesome problem, and Wharam was among a group of cancer clinicians who ushered in a era that offered the first glimmer of hope.

In 1975, just 50 percent of children diagnosed with cancer survived. The National Cancer Institute appointed four study groups to investigate common childhood tumors, and Wharam received the unusual distinction and honor to be named to two of these groups.  From 1980 to 1990, he served as director of the radiation oncology committee of the Pediatric Oncology Group, a U.S. and Canadian collaborative group that studied childhood cancers. His roles in these premier groups made him an active participant in all of the pivotal pediatric cancer research of the time. It was research which led to dramatic increases in pediatric cancer survival rates. The four separate groups have since merged into one, known as the Children’s Oncology Group. 

The merger, Wharam says, was a marker of the success that had been made against these cancers.  It was not good enough for him. He talks of a young girl he treated for Hodgkin’s lymphoma. She died of a second cancer when she was 48.  “That cancer was probably caused by the treatment I gave her as a child,” he says.  It is a cruel irony that is particularly problematic for pediatric cancer patients.  The same treatment that saves their young lives can also set into motion genetic alterations that manifest decades later as new cancers.

This was not something Wharam took lightly. “Knowing that the therapies we give children for their cancers could cause other problems for them was one of the most difficult aspects of our job,” says Wharam. He was a leader in the early research that led to scaled back treatment for many diseases.  “I had two missions,” he says.  “We were having great success in certain cancers, so we had to see if we could back off in the amount of radiation we were giving these patients.  At the same time, kids were still dying, so we also had to figure out how we could do a better job of treating them.”

In addition to the risk of second cancers decades later, radiation to growing bones and organs could impede normal development, and radiation to the brain, a common site of pediatric cancers, often resulted in impairments to learning and other cognitive brain functions.

Still, scaling back therapies was a risky endeavor.  The primary indicator that therapy could be reined in was increased survival. Go too far in reducing treatment and children would likely suffer deadly cancer recurrences.  Few were willing to take on the challenge, but Wharam became one of the first when he collaborated with Johns Hopkins pediatric medical oncologist Brigid Leventhal in a groundbreaking study of treatment reduction in Hodgkin’s lymphoma.  Their research led to refinements in therapy that allowed certain patients, based on specific characteristics, to receive less radiation or forgo it altogether without increased risk of recurrence.

DeWeese says Wharam’s pioneering influence earned the department the distinction as one of just a select few in the nation with a long history of expertise in treating pediatric patients. This reputation of excellence was instrumental in helping the department earn approval for a proton beam facility, he says.  Proton beam therapy is state-of-the-art technology that very precisely zeroes in on tumors and increases the damage to cancer cells without harming normal tissue.  Its precision and safety makes it desirable for treatment of pediatric tumors and particularly tumors of the brain, spine, eye, lung, head and neck, and bone. The facility, which will be located on the Kimmel Cancer Center’s Washington, D.C., campus and is scheduled for completion in 2018, will include space and staff for treating pediatric patients.

“Proton beam is another major advance in managing late effects of radiation therapy,” says Wharam.  “It allows us to control the depth of the beam and stops it from passing through and harming critical structures like the pituitary gland and brain stem.”  The department’s history of strength in treating pediatric cancers also led to a collaboration with Children’s National Medical Center. Under the direction of pediatric radiation oncologist Stephanie Terezakis, the Kimmel Cancer Center will become the exclusive provider of radiation therapy to its pediatric cancer patients. The collaboration creates one of the largest pediatric radiation oncology programs in the country, and the increase in patient volume promises to speed clinical discovery.

He points to photographs in his office and smiles.  “This little girl just graduated from college.  This one is married now and has a baby.  See this one—I treated her for brain metastases, and she survived,” says Wharam.  His face lights up when he speaks of his patients.  It is clear that they are his fondest memories from a long and impressive career.

He has retired from seeing patients now and has turned the reins over to Terezakis. He quips that today’s patients are in even better hands. “Knowing and working with some of the founders of the oncology center has brought me great joy. Those of us who were there in the beginning were right for the time, but Ted DeWeese’s leadership and people like  Stephanie Terezakis are moving the field forward in ways we couldn’t even imagine then,” says Wharam.  “Our program has grown into the best one in the country.  We have first class scientists and clinicians and the finest physicists, residents, nurses, radiation therapists, and dosimetrists in the business.  Our future is looking good.

 

 

The Inventor

John Wong sees problems and he fixes them.  A physicist rather than a physician, he does not treat patients. Instead, his mind is always working on ways to help patients by putting better tools in the hands of physicians. He is focused on logical ways to make equipment work better, which allows researchers to dig deeper and move faster so they can get improved treatments to patients.

“We recognize that in radiation oncology, we need the right balance of technology development, laboratory research, and dissemination of knowledge for clinical decisions,” says Wong. 

He is the quintessential scientist, the one with endless ideas and a multitude of projects. Many are able to identify the problems, but few can envision and create the remedies as Wong does.  He smiles, and his voice is filled with excitement as he talks about his inventions. It is not an overstatement to say they have revolutionized the field of radiation oncology.

Some inventions, like the active breathing coordinator (ABC) provide somewhat simple fixes to significant problems. The ABC is a non-invasive, interactive device that coordinates breathing with radiation treatment. As patients breathe, tumors move, and ABC locks the breath in place for short, comfortable periods to ensure the tumor is not a moving target, making sure the radiation hits the cancer.

Another, cone-beam computed tomography (CBCT), has become an integral part of radiation oncology treatment and research.  CT imaging delivers clear images of bone, soft tissue, and tumor, making it a desirable guidance system for radiation treatment. The cone beam, which uses a cone of divergent X-rays, captures images of the patient on the treatment machine to allow quick and more accurate irradiation of the tumor.

The invention referred to as SARRP, for small animal radiation research platform, is a favorite and staple among radiation oncology scientists, because it transforms radiation research done with animal models.  “Before SARRP, there was no laboratory counterpart for what we do in the clinic,” says Wong. That was unacceptable, so he invented a downsized version of a human machine for mice. With unprecedented precision, investigators can use  Wong’s machine to perform human-quality radiation delivery on mice. It provides a realistic model to study what they do in treatment. “In radiation oncology, we don’t have the means to study mechanisms in a living animal subject, and this machine helps us do that,” says Wong.

In radiation oncology there is nearly equal interest in how to destroy tumors as there is in how to prevent damage to normal tissue.  Being able to study human therapies in animal models is paramount to developing more effective and safer ways to treat patients.  A recent improvement he made to SARRP addresses another critical need.  “One of the biggest problems we have in radiation oncology is not the treatment technology but rather the ability to characterize the tumor,” says Wong.  “If I don’t know where the disease is, it doesn’t matter how great the equipment is:  I can’t treat it.”  In animal studies it can be particularly difficult to see the target, especially at the molecular level, so Wong added  molecular  imaging on the SARRP to enhance visualization of the tumor for irradiation.  The imaging component involves a complex mirror system that allows both light and radiation to be visualized. It sparked the idea behind his latest contrivance, which moves laboratory research back to the clinic in the form of a small black box with huge functionality for radiation measurements.

The device is named Raven, in honor of Baltimore’s beloved football team. Wong competed for the Alliance BioMaryland LIFE Prize to develop his product the week after the Ravens won the 2013 Super Bowl. The alliance competition is judged by pharmaceutical and biotech executives, medical device designers and manufacturers, entrepreneurs, venture capitalists, and angel investors with the goal of helping Johns Hopkins faculty commercialize their research and technological innovations.  It is science and medicine’s version of Shark Tank, the reality TV show in which inventors try to get backing for their products. Wong won the Life Prize competition.

He competed against scientists who were pitching exciting new drugs, but they had at least 10 years of validation work ahead of them before their products could be commercialized.  Wong’s invention was a quality assurance device that connects to linear accelerators—the high-tech machines that produce the beams of radiation during treatment—and performs a series of measurements to verify that the machine is functioning correctly. It could be ready for market in less than a year, and it would be appealing to any clinic providing radiation therapy. 

The Raven device performs measurements in a fraction of the six to eight hours each month per machine it would typically take a physicist. The measurements are essential to patient safety and quality delivery of care, because they ensure the machines are generating and delivering radiation accurately. Currently, the device operates as a stand-alone system for a clinic, but companies that manufacture linear accelerators envision incorporating it as part of the quality assurance accessories that accompany new machines. It is expected to be particularly useful in developing nations with less skilled manpower to perform the timely measurements manually.

Raven has been licensed to an outside company and is currently in testing.  Wong has already moved on to his next project—Raven II, which will incorporate quality  assurance measurements for personalized treatment of individual patients.

 

 

The Scientist

When radiation oncology received departmental status in 2003, the establishment of a research arm, molecular radiation sciences, was a priority for Ted DeWeese.  He selected basic scientist Marikki Laiho to head the research program.

“When we think about radiation therapy, it is high technology, but the complexity of cancer requires that we have a better understanding of the biology,” says Laiho, the Willard and Lillian Hackerman Professor of Radiation Oncology. “Now, we combine technology with biology, and that ultimately means improved treatments for patients.”

The work of Laiho and team is focused on understanding the mechanisms cancer cells use to sense and repair DNA damage and to maintain their own survival. “This has tremendous relevance in radiation oncology, because we don’t want cancer cells to be able to make repairs after treatment,” says Laiho. She and her team are looking for kinks in cancer cells’ armor that they can exploit to prevent them from making these fixes. “If we can give a drug that blocks DNA repair and follow it up with radiation treatment, maybe we can kill more cancer cells,” explains Laiho. They have made significant progress toward this goal.

She credits the young investigators she has recruited with the success.  “DNA damage biology research is not unique, but our focus is,” says Laiho.  “There is not a radiation and molecular sciences research program anywhere with the depth we have here.”

In her own research, Laiho has made an exciting discovery that appears to stop cancer cells in their tracks.  The studies are in an early stage, but they have demonstrated the ability in laboratory and animal studies to completely shut down the cellular machinery cancers need to survive.

The research focuses on the RNA polymerase pathway, called POL I, which is necessary for mutant cancer genes to communicate with cells.  In studies using human cancer cell lines, a new, never-described compound known as BMH-21 destroyed this critical communication pathway.  “Without this transcription machinery, cancer cells cannot recover,” says Dr. Laiho.  “The cancer cells cannot function.”

POL I is known as a transcription pathway. It is how proteins, which direct cell division, are translated and put into action by cells.  Uncontrolled cell division is a hallmark of cancer, and BMH-21 has demonstrated an ability to bind to the DNA of cancer cells and completely shut down this transcription pathway, stopping cancer cells’ ability to replicate. 

Preliminary studies were completed using human tumor cells obtained through the NCI-60 platform, a collection of 60 human tumor cell lines of nine different cancer types. Laiho and team collaborated with experts from the National Cancer Institute’s Developmental Therapeutics Program who tested their molecule for potential anticancer activity.  BMH-21 showed exceptional activity against cancer cells from many tumor types.  In fact, in these studies, the drug functioned better against the cancer cells than many FDA-approved cancer drugs.

With these promising results, Laiho has been busy working to move her findings to clinical trials. She turned to drug discovery expert James Barrow from the Lieber Institute for Brain Development, located at the Science + Technology Park at Johns Hopkins. Barrow analyzed 30 new synthesized molecules based on BMH-21. Analysis of these results confirmed the predicted mechanism of action. “This tells us that our thoughts that BMH-21 works by binding to DNA was spot on,” says Laiho.  “The fact that the activity of the original molecule is very confined suggests that we’re near the optimal stage.”

Laiho says this is a somewhat unusual occurrence in drug discovery.  Typically, many revisions to the lead molecule are required before it is ready for clinical studies.  “We are very excited, because it means we are closer to the clinic than we could have ever imagined would be possible,” says Laiho. 

With most of the science in place, the research could be translated into a new treatment in a little over a year. Still, Laiho and team face some hurdles.  She needs funding and a pharmaceutical partner to make the leap from laboratory to clinic. The Prostate Cancer Foundation is helping Laiho get there, awarding her a $1 million Global Treatment Sciences Challenge Award. The funding will allow her to test BMH-21 or one of its derivatives in animal models of advanced prostate cancer.  Collaborating with Kimmel Cancer Center prostate cancer experts Angelo De Marzo, Vasan Yegnasubramanian, bioinformatics specialist Sarah Wheelan, and University of Maryland, Baltimore County animal tumor model scientist Charles Bieberich, Laiho hopes to interest pharmaceutical companies by demonstrating the drug’s effectiveness against cancers where treatment options are scarce, such as prostate cancer that has spread beyond the prostate.

That said, the exquisite beauty of Laiho’s discovery lies in its application across many cancer types. “It appears to work in any solid tumor with high dependency on the pathway,” says Laiho.  “The transcription machinery the compound shuts down is common among all cancer cell types, so even though we are looking at prostate cancer, we believe it has broad therapeutic potential.”

In a personalized cancer medicine approach, De Marzo has developed biomarker tests that would identify prostate cancers that highly express the pathway and would be likely to respond to the drug.  Similar approaches could be used in other cancers.  “The more a tumor depends on this pathway, the better this treatment should work,” says Laiho.

 

 

 

Discoveries in Molecular Radiation Sciences

DNA Damage Report

PARP Inhibitors:  Young investigator and pediatric oncologist Sonia Franco is exploring cell repair molecules known as PARP (Poly ADP ribose polymerase) proteins.  She has found that using drugs called PARP inhibitors to shut down this repair function in cancer cells increases the killing power of radiation treatment. Franco, who is fascinated by the complexity of the PARP-deficient mouse model, has uncovered a previously unrecognized complexity to PARP-like proteins—a family of 17 different proteins. She is working to decipher their functions and their potential role in cancer therapeutics. She has built new mouse models to conduct experiments aimed at solving these mysteries. Her unique insight led the American Association for Cancer Research to designate one of her recent research publications as a “must-read.”

Radiation oncologist and breast cancer expert Richard Zellars and colleagues are studying PARP inhibitors and pre-operative radiation in patients who have received chemotherapy as their first line of treatment but still have cancer remaining.  In this Breast Cancer Research Foundation-funded study, women with advanced, treatment resistant cancers are given three weeks of radiation and treatment with an oral PARP inhibitor. PARP inhibitors sensitize cancers to radiation. “These women have the worst prognosis and very few treatment options.  Their cancers tend to advance quickly, but we are seeing large tumors shrink to just a few scattered cells,” says Zellars.  “We are the first to do a study like this, so we are proceeding slowly and cautiously, but the early results are looking very promising. We are getting great responses in the worst cases of breast cancer.  If we can get these results in the most advanced cases, we should really be able to get even better responses in patients with earlier stages of cancer.”

DNA Damage Signaling:  Mihoko Kai is focused on understanding cell signaling pathways for DNA damage and, in particular, the role they play in deadly glioblastoma brain cancers. Kai wants to understand the relationship between two natural processes—DNA repair and cell cycle checkpoints—and how it contributes to cancer cell development and survival. While each has been well studied individually, Kai is among the first to explore how they work together in cancer.

DNA Damage Checkpoints in Cancer Therapies: Fred Bunz is researching why some tumors respond well to radiation and cancer chemotherapies and others do not. He is working to learn if they have constitutive differences that dictate their responses to therapies and if they are dependent on the DNA damage responses. Identifying those differences could be extremely important in selecting the optimal treatments for each patient. Bunz is using genetic tools that he has created to selectively introduce cancer-specific mutations into tumor cells so that he can explore and observe how they respond to cancer therapies. His research has revealed a rich and complex landscape of alterations that dramatically changes how the tumors respond to treatments.

RNA Particles:  Department director Ted DeWeese is working to identify new radiosensitizing agents. The goal is to combine radiation with factors that render cancers—but not normal tissues—vulnerable to DNA damage. Working in collaboration with Department of Urology basic scientist Shawn Lupold, they have shown that blocking DNA repair does just that and devised a strategy to deplete the cells of repair factors by using RNA-mediated silencing of the repair genes. Moreover, they used RNA particles, called aptamers, to deliver the silencing RNAs specifically into the cancer cells. This approach has been highly successful in killing prostate cancers and tumors in mouse models and will soon be ready for clinical trials. 

Nanoparticle Platforms for Cancer Theranostics: Robert Ivkov is a physical chemist whose research is focused on magnetic nanoparticles and their uses to improve the effectiveness of radiation therapy and imaging. He has developed particles that generate intense heat when they are exposed to alternating magnetic fields and improve magnetic resonance and x-ray CT imaging. Heat is an excellent agent that increases the sensitivity of cancer cells to radiation. He has developed novel nanoparticles, and also builds the instruments that generate the alternating magnetic fields. Tests have now been conducted in models of several types of cancer—including prostate, breast, liver and pancreas–with impressive improvement of tumor control when the nanoparticle heating is combined with low doses of radiation.  Enhancing the effectiveness of radiation therapy with heat offers potential to treat patients with lower radiation doses and minimize severe side effects

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