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Promise and Progress - Personalized Medicine is Here: The Time is Now
The Time is Now: 2010-2011
Personalized Medicine is Here: The Time is Now
Valerie Matthews Mehl
Date: November 11, 2010
Bert Vogelstein (center) discusses a research project with graduate student William Hendricks (left) and postdoctoral fellow Jian Yang (right)
Personalized cancer medicine is here. Within the next few years, all cancer patients at the Kimmel Cancer Center will have their tumors analyzed to reveal a unique “fingerprint.” The fingerprint represents the combination of genetic alterations specific to each person’s cancer. Just as every person is genetically unique, so, we have found, is every cancer. Targeting these alterations, say scientists, will improve treatment outcomes, thwart cancers before they develop, and slash the costs of new drug discovery.
Kimmel Cancer Center investigators pioneered the science that led us here. “When it comes to this piece,” says Kimmel Cancer Center director William Nelson, “we are at the center of the universe.”
The path was paved by Bert Vogelstein, an iconic figure in the world of cancer research, and his long-time colleague Kenneth W. Kinzler. Their work is universally regarded as the most relevant in the field. In the 1980s, without the benefit of today’s automated gene sequencing technology, they revealed cancer as a genetic disease, caused by a building series of inherited and acquired gene alterations. As the genetic errors accumulate, cancers originate, grow, and finally spread.
More recently, Vogelstein, Kinzler, and their colleagues deciphered the genetic landscape of cancer, uncovering an unexpected terrain, one not characterized by previously known genetic errors. There were a few of those, but overall, cancers were quite diverse with a variety of less common alterations that varied from cancer to cancer.
Never before had the need for personalized cancer medicine become so apparent. If each individual’s cancer is unique, then new diagnostic and treatment approaches would have to take this into consideration.
In the Ludwig Center for Cancer Genetics, Vogelstein, Kinzler, Victor Velculescu, Nickolas Papadopoulos, Luis Diaz, and their team of brilliant young scientists have done the lion’s share of work in this new phase of cancer genetics. In all, they have deciphered the genetic sequence of 90 types of cancer, nearly all of the cancers sequenced to date. For his efforts, Vogelstein has become the most often cited scientist in the world, meaning his team’s work is the classic model that others have built upon.
“In the case of cancer genetics, we are on the cutting edge of the cutting edge,” says Nelson. “Everyone wants to do this type of research, and Johns Hopkins is where they want to do it.”
“This is a watershed moment,” says Nelson. The impact of cancer gene research is poised to change cancer medicine.”
The Basics of Cancer Genetics
Think of cancer as a clock. As every tumor cell divides, it begins to mutate at a certain frequency. Over time, these mutations accumulate. Some of them drive the development of cancer, and others just go along for the ride.
Vogelstein is interested in the drivers. For each type of cancer, Vogelstein and team found that it is a small number of gene alterations—approximately ten—that actually drive the cancer. The problem is that these ten genes vary from patient to patient. There are a few alterations common among all cancers, but what has become increasingly clear is that, like a fingerprint is specific to every individual, so is the genetic profile of his or her cancer. It explains why two seemingly similar cancers, can respond quite differently to therapy. The genes driving them are likely not the same.
Vogelstein, who has spent the last three decades deciphering cancer’s genetic code, has issued a call to action. When he spoke at a recent meeting of the American Association of Cancer Research, he said that most of the big discoveries in cancer genetics have been made. “There may be a few more surprises. We may find a few more genes frequently mutated in many types of cancer,” says Vogelstein. “But, these types of common mutations would likely have been found by now,” says Vogelstein. Most new discoveries in this field, he says, will be of less frequently occurring mutations that vary from cancer to cancer and patient to patient.
The bad news is that these alterations are overwhelmingly numerous and diverse. The good news is that Vogelstein has found that the cell pathways they work through are not. Virtually all of the driving cancer genes operate through 12 core cell pathways, and Vogelstein says, all of these pathways are well known and well studied in the research world.
“One of the challenges confronting us is determining how these cancer genes operate in human cells,” says Kinzler. “Human cancer cells do not necessarily behave like the cells of mice or other organisms.”
Think of our highway system. We can block off an exit to prevent cars from entering a road. It may stop traffic flow briefly, but eventually cars will begin to take other exits to gain access to the roadway. The same is true of gene pathways. Clinical investigators are studying drugs that block activity promoting the growth and spread of cancer cells. The therapies work for a time, but over time, cancer genes seem to adapt corrupting other pathways to accomplish their mission. As a result, multiple targeting agents may be needed to fully combat cancer.
While considerable progress has been made in this direction, Kinzler says it will take researchers many years to have it adequately figured out. “But, we already have an immediate application in the form of gene-based tests,” he says.
A Universal Test for Cancer
New technologies allow scientists to look at the whole genome—not just for research, as we’re accustomed to, but in the clinic—patient by patient. It is the reality of personalized diagnosis and therapy.
As tumor cells divide, they develop their own blood supply to get the nutrients they need to nourish and grow, and as a result, pieces of the cancer’s DNA get carried in the bloodstream, leaving telltale evidence of their existence. The DNA contains the alterations specific to the cancer—the accumulation of errors that occur as normal tissue transforms to evasive, deadly cancer. It’s been there all along, floating among a sea of normal cells, but, until now, scientists did not have the technology to see it and pull it out.
Victor Velculescu, a colleague of Vogelstein and Kinzler in the Ludwig Center, was looking for common gene mutations that could be therapeutic targets when he observed gene rearrangements in the cells of all of the patients they studied. “We realized that these rearrangements could be used as the basis for very sensitive tests for cancer,” says Velculescu.
What Velculescu found was not the typical single letter sequence changes to the ATCG alphabetical human gene code, but rather two chunks of DNA from distant locations brought together in error. Like a jumbled up jigsaw puzzle, pieces of DNA of different parts of the genome had come together where they didn’t belong. The error only happens in cancer cells. It never occurs in normal cells, putting in place all of the elements needed for a tailor-made biomarker specific to cancer and cancer alone.
“Functionally, we don’t know what they do,” says Veclulescu, “but we know they are in virtually every cancer.” “We recognized that they weren’t therapeutic targets, but they were so unique we thought they could be used for individualized screening and monitoring.”
The researchers called their technique for finding the jumbled up DNA chunks Personalized Analysis of Rearranged Ends, PARE (pronounced pair) for short.
The test, the first application of the current generation of gene sequencing technology, not only detects cancer but can also tell if a therapy is working by measuring, in real time, the amount of cancer DNA in the bloodstream. If it’s working, cancer DNA should decline. If it’s not, it will increase. Rising levels of cancer DNA can also quickly alert clinicians that a previously- treated cancer has returned.
Universal, precise, and specific, the test is able to pluck one abnormal cell from within a sea of 400,000 normal ones. It sees cancers invisible to CT scans, X-rays, and other existing methods of cancer detection.
Velculescu and team worked with tumorsamples from six patients, analyzing 40 million paired sequence tags (short segments of DNA that serve as landmarks in creating a physical map of the genome) per sample and were able to create a personalized and accurate biomarker test for each patient and every type of cancer.
Right now, the tests cost several thousand dollars. The study test cost $5,000 per patient. By comparison, CT scans cost about $1,500 but do not provide nearly as much detailed and tumor-specific information as the biomarker test. The investigators anticipate the tests being ready to use in the care of patients within five years, as the infrastructure is in place to automate the test and bring down the cost.
The personalized test can tell if a person is cured with surgery or if there are cancer cells left behind that will require additional treatment. “If there is no cancer DNA in the blood, then no additional therapy is necessary,” says Luis Diaz, a clinician-scientist working with the Vogelstein team to help move their laboratory discoveries to patients. By the same token, if the biomarker levels begin to rise after surgery or chemotherapy, then doctors will know there is still cancer remaining, even amounts so small they are undetectable by CT scans.
Currently, there is no definitive way to determine if a patient has any microscopic cancer cells hidden among the much more plentiful normal cells. As a result, Diaz says, everyone receives chemotherapy, but not chemotherapy tailored to their cancer, a generic, one-size-fits-all version. “The people who still have cancer cells need intensive chemotherapy, not the diluted version they get now,” says Diaz. “Just as importantly, the people that don’t have cancer left behind should be spared treatment.”
The new test may solve this dilemma. To date, the test has had 100 percent sensitivity and specificity. Unlike cancer screening tests we have become accustomed to, such as PSA for prostate cancer, this test is specific to the cancer, not simply associated with it. “If this test says there is cancer,” says Vogelstein, “then a cancer is almost definitely there.”
Finally, clinicians may be able to definitively answer that key question, “Am I cured?” says Diaz.
With the ability to monitor each patient’s cancer progression in real time, clinicians hope to attack the spread of disease very early on, holding it at bay and keeping it from impeding on the function of vital tissues and organs. “We hope eventually to be able to develop customized therapies tailored to the genetic environment of each patient’s tumor, and as a result, we will improve outcomes,” says Diaz.
As director of the Center, this is the type of progress Nelson wants to see. “There are other institutions that have lots of equipment and researchers working on sequencing the DNA of everything from moths to elephants,” says Nelson. “We have been very focused in our use of the technology, and, as a result, with less resources and in less time, we have become one of the very few to apply it to human medicine.”
Ultimately, Vogelstein says, these advances could lead to the prevention of cancer. Most common cancers have a long history. The biological timeline of cancer—from initiation to metastatic disease—is 20 to 30 years. The last two to three years of this process, says Vogelstein, are when cancers spread from their original sites to other parts of the body.
“Nearly every patient that dies of a solid tumor, such as colon cancer or pancreatic cancer, is within this two to three year time frame,” says Vogelstein. “That gives us about 27 years to intervene and cure them, maybe with surgery alone.”
“Thirty years ago, we started with a black box,” says Vogelstein. “Now, we know most of the major genes involved and virtually all of the gene pathways through which the genes act. The greatest achievements are still to come as we use this information to help people.”
The Cancer Epigenome
In applying cancer gene discoveries to treatment, investigators are focusing on the pathways through which altered cancer genes work because the genes themselves can often be elusive to therapy. Many of the gene mutations driving cancers are in tumor suppressor genes. The loss of these genes removes important brakes on cell growth, but it’s difficult to attack a target that’s already missing.
Sometimes, however, tumor suppressor genes become ineffective without being mutated. The causes of this are known as epigenetic alterations. Biochemical changes to the environment of the DNA, rather than directly to it, can silence key genes. Investigators have found that using drugs to block this biochemical activity provides an opportunity to reverse the changes and reset the DNA to its pre-cancer environment.
Kimmel Cancer Center researcher Stephen Baylin is to the field of cancer epigenetics what Vogelstein is to cancer genetics. He, and colleague Jim Herman, are the leading experts on the topic, cited more frequently than any other researchers in the field. Their epigenetic work in lung cancer earned Baylin recognition from the National Cancer Institute for the most outstanding research in its SPORE (specialized programs of research excellence) program, an endeavor aimed at rapidly moving laboratory discoveries to patient care.
Baylin began his epigenetics work in the 1980s when he noticed regions of genes with increased methylation, a biochemical process that seemed to occur only in cancer cells. This chemical change, he found, was like an off switch to tumor suppressor genes. With support from the Commonwealth Foundation, Ludwig Fund, Hodson Trust, and the National Institutes of Health, he and his team began to look for ways to apply these observations to cancer patients.
Early laboratory studies in lung cancer and leukemia at the Kimmel Cancer Center and elsewhere led recently to clinical trials of the first demethylating agent, 5-azacytidine. Promising results in a leukemia and a pre-leukemia condition known as myelodysplastic syndrome (MDS) resulted in FDA approval of the drug for MDS. Now, they are working to prove the effectiveness of the drug in other cancers.
Their research has led them to other changes working in concert with methylation, specifically something known as the chromatin structure.
Chromatin is a complex combination of DNA and proteins, mainly histones. Its job is to compress DNA to make it fit inside cells, providing a mechanism for controlling gene expression and DNA replication. Changes in the structure of chromatin are controlled by the histones. A loose chromatin allows for normal gene expression. But, add methylation to the equation and histones hold DNA together tightly interfering with the normal expression of genes, including tumor suppressor genes. It keeps genes in a constant state of non-expression.
Prior to this discovery, most investigators studying cancer genes looked at gene silencing as a linear process across the DNA, as if genes were flat, one dimensional objects. Research did not take into account the way genes are packaged.
For a key set of tumor suppressor genes, this packaging can cause cells to behave in a primitive, embryonic cell-like fashion. Unlike true embryonic cells which receive and respond to signals to stop making cells, cancer cells maintain their ability to replicate, renew, and divide. The cells never receive the command to stop dividing partly because abnormal DNA methylation has silenced the key growth-limiting signals. “Chromatin is held in a tight, compressed form, particularly when associated with DNA methylation,” says Baylin. “These tighter coils and loops touch and interact with many gene sites, folding it into a structure that shuts off tumor suppressor genes,” says Baylin.
When the researchers removed DNA methylation from the genes, using a combination of 5-azacytidine and a drug known as a HDAC inhibitor for its ability to block histones, the coils loosened, and some gene expression was restored.
What prompts the cancer-promoting changes in chromatin structure is unknown. Baylin suspects some of it is due to continued environmental assaults to the cells, such as chronic inflammation. As cells try to renew and repair over and over, something breaks, epigenetic alterations accumulate, and some cells become locked in this primitive state.
As a result, these cells learn to live outside the context of their normal environment and begin to expand autonomously beyond the limits of normal cell control mechanisms.
With funding from Stand Up To Cancer, Baylin and team have now moved their laboratory discoveries to the clinic in studies with lung, breast, and colon cancer patients. Learning from the earlier clinical trials in leukemia, the new patient studies combine the DNA demethylating agent 5-azacytidine with histone-specific HDAC inhibitors to target both abnormal methylation of genes and the alterations to DNA packaging that help give cancer cells their edge.
It is a novel concept. Rather than attacking and destroying replicating cells as standard chemotherapy drugs do, this therapy actually aims to reprogram cells to behave more like normal cells. Clinical responses in lung cancer patients that have lasted long after treatment has ended indicate that it’s working. It’s too early in the breast and colon cancer trials to evaluate, but Baylin and team are optimistic that they will see favorable results in these cancers as well.
Using drugs that specifically target the abnormal mechanisms, allows the investigators to give patients lower doses and still maintain effectiveness. They believe the lower doses allow them to hit the epigenetic target without interfering with the activity of other non-target genes. As a result collateral damage to normal cells has been low, with relatively mild and few side effects, including fatigue, minor decreases in blood counts, and irritation at the injection site.
It is a striking contrast to high-dose studies of the drug in the 70s and 80s when it was all but abandoned because it was too toxic. “We reduced the dose and added an HDAC inhibitor and are working to prove in clinical trials what we already suspect; that the combination of the two drugs is safe and works better than either individually,” says Baylin.
In early clinical trials, clinician-scientists Charles Rudin and Rosalyn Juergens are having remarkable success in lung cancer patients. Patients who had failed at least three attempts with standard chemotherapy are getting results. “We are even seeing responses to metastatic disease. Lesions in the liver, where the lung cancer had spread, are disappearing,” says Baylin. “We are not saying cure, but these are lasting regressions of the worst stage of disease. So, maybe we are at a place where we are beginning to control even the most difficult cancers.”
Baylin and team are now ready to move the therapy to earlier-stage patients, just after surgery to prevent cancer recurrence.
Sixty-six year-old Myra Thompson is among the patients who has benefitted from the new therapy.
After being diagnosed with non small cell lung cancer, she began chemotherapy. Despite six months of treatment, the cancer continued to grow. Out of options, the local oncologist she was seeing near her home in Harrisburg, Pa. told her he would need to refer her to a larger cancer center. “I told him to get me to Johns Hopkins,” says Thompson.
Under the supervision of Juergens, she began treatment with the demethylating drug 5-azacytidine in combination with an HDAC inhibitor. Her cancer hasn’t grown since. Thompson comes to the Kimmel Cancer Center once a month for ten days of outpatient therapy, which includes a pill and an injection in her abdomen. Other than feeling a bit tired and losing a little weight, Thompson has experienced no other side effects. “I feel wonderful,” she says. “I see people with lung cancer who aren’t doing as well as I am. I tell them go to Johns Hopkins and get on this research trial.”
Despite the success of the trials, Baylin says there are still challenges to overcome. “We’re going back to the laboratory to learn how to personalize it. We need to develop a molecular fingerprint that will tell us which patients it will help and who it will not.”
The revival of 5-azacytidine may be indicative of a change in the cancer culture. “Clinical trials have been set up to find the highest tolerable dose, but this won’t work for this particular drug and other therapies designed for personalized medicine,” says Baylin.
Unlike the cancer therapies the world has become accustomed to that indiscriminately kill cells—cancer and normal ones—this new generation of targeted therapies doesn’t directly kill cells. Instead, we hope they will reprogram cancer cells to kill themselves.
Preparing the Next Generation of Cancer Clinicians and Scientists
Each year Johns Hopkins School of Medicine receives thousands of applications to fill just a few hundred spots. Many more come to study as graduate students. The very best of them are kept on as Johns Hopkins faculty. They are the reason the tradition of excellence continues here. As we educate the next generation of researchers and clinicians, we recognize that novel approaches in the laboratory and clinic begin with novel approaches in medical education.
Leisha Emens is a clinician and a scientist with both an MD and a Ph.D. When she is working in the laboratory, she is always thinking about how she can take her discoveries to patients. When she sees patients, she wonders what she could learn in her laboratory to improve their care.
When Kimmel Cancer Center director William Nelson asked his education committee, of which Emens is a member, to come up with ideas for a cancer course that would prepare and motivate aspiring young cancer clinicians and investigators, she proposed that the scientists and clinicians trade places.
Laboratory scientists would learn how cancer clinicians take care of patients, and clinicians would learn laboratory science.
Working with colleagues Fred Bunz, Jim Herman, Stuart Grossman, Sara Sukumar, and Kala Visvanathan, they came up with Fundamentals of Cancer: Cause to a Cure.
“We wanted to lay the groundwork for establishing collaboration between the laboratory and clinic right away,” says Emens. “This type of cooperation is particularly relevant in the Cancer Center. There is so much more science involved in what we do, and we want to instill this philosophy early on with our young physicians and scientists-in-training.”
The Kimmel Cancer Center is known as a leader in translational research—discovery that extends beyond the confines of the laboratory to rapidly improve patient care. “We do this better than anyone else,” says Nelson. “It seemed to make sense that we also teach it.”
The course takes students out of their comfort zones and challenges them to think in a different way.
Will Hendricks is a graduate student who came to the Kimmel Cancer Center from Arizona State to work in the laboratory of world famous cancer genetics researcher Bert Vogelstein. He spends his virtually all of his time in the laboratory, developing a novel mechanism to get genes into cancer cells. The course provided him a rare opportunity to explore the clinical aspects of his work. “It was helpful to learn how a clinician approaches things. While my work is ultimately aimed at helping patients, I don’t work directly with patients like they do,” says Hendricks. I’ve never taken a course where I interacted with a clinician on real patient cases. I’ve learned more in this course than most of the others I have taken.”
“Working with clinicians helped me visualize what my research might look like as a therapy and brought out things I might not have considered,” says Hendricks.
Hendricks and others taking the course, work with the Center’s clinical faculty to learn the basic clinical features of cancer and then manage actual cases. Conversely, clinically-oriented students learn from laboratory investigators, including the likes of leading cancer genetics expert Bert Vogelstein and epigenetics pioneer Stephen Baylin.
“Clinicians need to learn how to apply science to clinical care,” says Emens. “We want to them to think about the molecular basis of the disease so they can explore therapeutic targets, determine what drug they would use and how it would best be tested in patients.”
Laboratory scientists, Emens says, need to think about clinical problems that present true unmet needs and how they will apply their work beyond the bench to the bedside.
Beyond Our Walls
Connie Trimble is a dynamic clinician, by all accounts dedicated to her patients. In her cervical dysplasia practice, she saw woman after woman come in with precancerous lesions. Some of them regressed on their own. Most did not. With the human papillomavirus as the cause of the most cervical cancers, she knew that, in the women whose precancerous lesions were going away, the immune system was playing a role.
She wanted to understand exactly what role it was playing in order to help the women whose lesions didn’t regress. She felt she owed it to her patients. “I couldn’t just continue to treat their diseases, without trying to figure what was causing it and what was making some more resistant than others,” says Trimble.
Five years ago she took a chance when she learned about a meeting at Cold Spring Harbor laboratories that Hy Levitsky, a cancer immunology expert and Kimmel Cancer Center colleague was helping to organize. It was by invitation only, and currently she was not on the invitation list. Those attending were a virtual who’s who of basic immunology.
In addition, to Levitsky, this think tank of basic scientists included Carl June from University of Pennsylvania, Jim Allison, from Memorial Sloan Kettering, and Phil Greenberg from the Fred Hutchinson Cancer Center. “I walked into Hy’s office, and said, ‘May I come to your meeting?’” Levitsky, a bit surprised at first, said yes.
Recognizing the importance of the clinical and basic science worlds coming together to solve the cancer problem, he later invited her to give a talk on her clinical experiences.
From there she began attending other key immunology meetings and interacting with leaders in the field, including Ian Frazier from Australia who was a key player in the development of the HPV Gardasil vaccine. With their guidance as well as support from Levitsky and Diane Hayward, director of the Kimmel Cancer Center’s Viral Oncology Program, she now has laboratory space and has earned four translational research grants from the National Cancer Institute.
She is focused on cervical lesions that are precursors to cervical cancer. Nearly one quarter go away without any medical treatment. While immune T cells circulating in the blood have been the focus of much research, Trimble decided to look instead at the immune reaction within the cervical tissue. “When you have the flu, T cells reacting to it hang out in the lung. When you get diarrhea, T cells become activated in the gut. It seemed to make sense that in cervical lesions, we should look at the cervical tissue to understand the immune response,” explains Trimble.
She began an interSpore collaboration with Rachael Clark from Harvard University. SPORES are specialized projects funded by the National Cancer Institute to speed the transfer of research discoveries to patient care.
Clark was using tiny skin samples about the size of a pinhead left over from plastic surgery procedures to see if she could isolate T cells. It turns out there were more immune cells in the skin cells than in the blood. Based on this work, Trimble began working with Clark, sending her cervical tissue samples. Together they are studying cervical T cells to figure out what cellular signals are telling T cells to go to the cervical tissue, what tells them to stay there, and what could activate the immune system.
In fact, they learned, cervical precancers do elicit a cervical immune response. T cells travel to the cervix, but are unable to get into the tissue because a biochemical signal prevents T cells to go out of blood vessels into cervical tissue. As a result, the immune soldiers can’t go to work against the precancerous lesions. The lesions continue to make their own blood vessels, nourishing them, and all the while keeping the T cells out.
In clinical trials, Trimble is using findings from her work with Clark to develop ways to get the T cells in. One approach uses a substance applied directly to the cervix that changes the “stickiness” of the vessels, allowing T cells to go to work. Another approach looks at vaccine delivery. Trimble is exploring if where the vaccine is given makes a difference in how well it works. She is comparing standard injection of the vaccine to a non-needle delivery that literally blows the vaccine onto the skin as well as injection directly into the cervix. Trimble believes delivering the vaccine directly to its target may enhance its activity.
She recognizes that her collaborations with leaders in the field of immunology have been instrumental in advancing the understanding and treatment of cervical cancer. She wants to return the favor. She recently gave Grand Rounds at the MD Anderson Cancer Center and is now mentoring one of its faculty members. “It is important for
Articles in this Issue
Cover Story: Personalized Medicine is Here, The Time is Now
- Personalized Medicine is Here: The Time is Now
- Cover Story Sidebar: Our Cancer Research is Curing Other Diseases Too
- Cover Story Sidebar: A New Paradigm for Cancer Drug Discovery
- Cover Story Sidebar: Personalized Approaches in Pediatric Cancer
- Cover Story Sidebar: The Frankenstein Project
- Cover Story Sidebar: The Serendipitous Discovery of a Cancer Starter
- Cover Story Sidebar: The Mathematics of Curing Cancer
- Immune Cell Commander
- A Personalized Genetic Profile for Brain Cancer
- A New "Twist" in Breast Cancer
- JHU Engineering Student Invents Melanoma Screening Device
- Special Delivery: Biodegradable Particles Transport Drugs to Diseased Tissues and Organs
- Targeting Brain Cancer Stem Cells
- Vaccine Clears Out Leukemia Cells
- Does Low Cholesterol Equal Lower Risk of High-Grade Prostate Cancer?
- A Common Good - The Commonwealth Foundation
- Helping Us Solve The Cancer Puzzle
- The Skip Viragh Center
- Making Waves to Fight Cancer
- Gift Brings Complementary Care to Cancer Patients
- A Major Gift for Kidney Cancer Research
- Giant Food Supports Childhood Cancer Research
- Wawa Cares About Cancer Patients
- Young Lacrosse Players Faced Off Against Childhood Cancer