Title:Pathway to hope

Author: Karen Doss Bowman
Date Published: November 17, 2021

Georgetown Lombardi Comprehensive Cancer Center’s youngest patients receive research-guided, holistic care throughout the cancer journey

Jeffrey Toretsky, MD, hasn’t forgotten one of the first young cancer patients he encountered. As an undergraduate at the University of Wisconsin in the early 1980s, Toretsky volunteered in a pediatric oncology clinic, where he met a young patient—just a freshman in college—with Ewing sarcoma, a rare type of cancer that forms in the bones and surrounding soft tissue. The patient died a few months later, on the day after Christmas.

Years later, as a fellow in pediatric oncology, Toretsky worked with more patients who had Ewing sarcoma. Eventually, many succumbed to the disease, he recalls.

“My experiences witnessing these patients with Ewing sarcoma dying left me with a very strong sense that we needed to do better for this disease,” says Toretsky, division chief of Pediatric, Adolescent, and Young Adult Hematology and Oncology, and professor of Oncology and Pediatrics at Georgetown Lombardi Comprehensive Cancer Center.

“People wonder how I can be a cancer doctor. How can I get up every day and face some of these challenges? One of the reasons is because as a researcher, I’m directly involved in thinking about, and creating, the next generation of drugs that will provide hope for those patients.”

Cura Personalis for the Childhood Cancer Journey

Thanks to promising advances in pediatric cancer treatments in recent years, there is reason for optimism: The overall 5-year survival rate for children with cancer is around 84 percent, according to the American Cancer Society. In comparison, only 58 percent of children survived for five years or more after a cancer diagnosis during the mid-1970s. Of course, outcomes depend on many factors, including the type of malignancy.

Childhood cancers are rare. Even so, cancer is the number one cause of death from disease among children and adolescents in the United States.

At Georgetown Lombardi, the concept of cura personalis, or “care of the whole person,” is central to the patient experience— for both children and adults. While the goal of treatment is physical healing, each child’s need for emotional and spiritual comfort also is paramount throughout the cancer journey.


One of my goals is to figure out who is not responding to the therapy and why—and that’s really the challenge with any drug development.

The National Cancer Institute (NCI) identifies three critical areas of focus for childhood cancer scholarship: basic research, clinical research, and survivorship. In addition, the NCI recognizes that about 89,000 young people (ages 15 to 39) are diagnosed with cancer each year in the United States, and these adolescent and young adult (AYA) patients require improved outcomes as well as psychosocial support. To address this, MedStar Georgetown University Hospital’s Division of Pediatric, Adolescent, and Young Adult Hematology/Oncology, where Toretsky sees patients, is home to a passionate and diverse team of researchers and clinicians dedicated to the discovery of new therapies and approaches to care.

The Search for Answers

For some of Georgetown’s tiniest patients, the cancer journey begins in the womb. For example, neuroblastoma—a type of cancer that forms in developing nerve cells—is sometimes detected during routine fetal ultrasounds. The disease is usually diagnosed before age 5.

Joanna Kitlinska, PhD, has studied the mechanisms of neuroblastoma and Ewing sarcoma over the past two decades. Much of her work is focused on the role of the protein neuropeptide Y (NPY)—a normal sympathetic neurotransmitter involved in numerous physiological processes, including stress—in the growth and progression of these malignancies. Through clinical studies, Kitlinska and her colleagues found that elevated NPY levels in tissue donated from patients with neuroblastoma correlated with metastatic disease, future relapse, and poor survival rates. These results were published in 2016, and similar results in patients with Ewing sarcoma were published a year earlier.


Basic research is focused on understanding how cancer develops, grows, and spreads in the body.

“No NPY-based therapies have been tested in these patients, but we hope that our studies will lead to such clinical studies,” says Kitlinska, associate professor, Department of Biochemistry and Molecular and Cellular Biology, and a Georgetown Lombardi researcher. “Our data indicate that in both neuroblastoma and Ewing sarcoma, NPY facilitates disease progression to the metastatic and therapy-resistant phenotype. We propose that NPY receptor antagonists could prevent these processes. One of [these drugs] is already FDA-approved for non-oncological disorders.”

The discovery of NPY’s involvement in tumor growth sparked Kitlinska’s interest in the connection between parental stress and neuroblastoma development. While the role of maternal lifestyle factors in fetal development is well-established through research, Kitlinska and her Georgetown Lombardi colleague, Sonia de Assis, PhD, assistant professor of oncology, are looking at the paternal factors. Mouse studies have revealed that paternal age, weight, diet, and psychological stress may trigger genetic changes that may be passed down from one generation of mice to the next. Her lab currently is examining the impact of maternal stress during pregnancy and paternal anxiety before conception on cancer development in their offspring.

“If our research on the effect of the parental lifestyle changes on the risk and malignancy of neuroblastoma brings some promising results, working with families with increased risk of this disease—such as carriers of the genetic mutations predisposing to neuroblastoma— may become an important element of our future work,” Kitlinska says.

Quest for a Cure

For more than 20 years, Toretsky and his colleagues have tried to solve a complicated jigsaw puzzle. Their method seems strange: Instead of letting the pieces fit together to build a complete picture (a cancer), they’ve invented a “dummy piece”—one that would interlock with a specific puzzle piece that leads to cancer and blocks it from other pieces.

Clinical research tests new drugs for effectiveness and safety.

That’s how Toretsky describes his lab’s work that led to the development of a molecule to attack a genetic target in Ewing sarcoma cells.

“In order for the cancer to grow, the correct puzzle pieces must find each other,” Toretsky says. “We basically created a puzzle piece that would block the real ones from attaching correctly to one another.”

The genetic mutation EWS-FLI1 gives rise to Ewing sarcoma. In 2006, Toretsky and his team discovered that the abnormal protein binds to another protein (the puzzle piece), RNA helicase A (RHA), facilitating cancer progression.

Toretsky and his Georgetown Lombardi colleague Aykut Üren, PhD, professor in the Oncology and Biochemistry and Molecular & Cellular Biology departments, created YK-4-279, a chemical that blocks EWS-FLI1 (the cancer-driving puzzle piece) in the lab. Their work on YK-4-279 led to the development of TK216, a first-in-class small molecule that is now being tested in phase 2 clinical trials at eight medical centers around the country.*

“We provided the basis on which the first targeted therapy was created and is now being studied for this rare cancer,” Toretsky says. “One of my goals is to figure out who is not responding to the therapy and why—and that’s really the challenge with any drug development.”

From Surviving to Thriving

“Cancer care is a journey—not an event,” says Nina S. Kadan-Lottick, MD, MSPH, director of the Survivorship Research Initiative at Georgetown Lombardi and professor of oncology and pediatrics.

Survivorship research focuses on reducing the long-term adverse effects of cancer and cancer therapies.

Even after a patient finishes cancer treatments, they need long-term support to manage adverse effects of therapies, psychological needs, return to school or work, and financial concerns. Patients are taught that good nutrition and physical activity can improve the effects of cancer therapy. These services may include screening for post-traumatic stress syndrome, anxiety, or depression. Female patients at risk for early menopause are counseled on issues regarding future childbearing. This area of care, known as survivorship, focuses on physical, emotional, and spiritual wellness.

“The whole goal of being treated for cancer is to live the best life possible—that’s why patients go through cancer treatment,” says Kadan-Lottick, a nationally recognized scholar of issues facing cancer survivors. “There’s more to cancer care than being cancer free. It also has to do with recovering one’s body and one’s mental spirit, and then going forward and to have lifestyle behaviors that optimize your health.”

Much of Kadan-Lottick’s work is focused on a subgroup within pediatrics: adolescents and young adults (AYA). This population, which includes patients from age 15 to 39, often has the same types of pediatric tumors that affect younger children. Though they may have the cognitive ability to understand their cancer experiences, these young people have unique needs based on their stage of development.

“These young people may need support to learn self-management of medications, how to self-advocate, and how to communicate their needs to doctors and nurses,” says Kadan-Lottick, adding that AYAs are poorly represented in clinical research. “We need to help them in very practical ways with life skills as they are facing cancer just as they are becoming adults.”

Kadan-Lottick is the principal investigator of a national study to improve physical activity in AYAs. The participants, aged 15 to 21, wear a Fitbit and receive individual coaching texts each week with recommendations for improving their physical activity. They also join a closed social media group with peers who are also on the survivorship journey. The study, which aims to enroll 384 patients, is open at 80 centers across the country.

“We are really inspired by the messages posted by the patients on the private Instagram account,” says Kadan-Lottick, who received a National Cancer Institute Moonshot grant for the research. “They express hope and resiliency and a determination to live their best lives.” Her team is applying for a grant to adapt the study to Spanish-speaking AYA cancer survivors, a group that has not been well-represented in past studies.

There’s more to cancer care than being cancer free. It also has to do with recovering one’s body and one’s mental spirit, and then going forward and to have lifestyle behaviors that optimize your health.

Only 20 percent of young cancer survivors get the recommended monitoring for late effects throughout their lives—far too few, says Kadan-Lottick. She has a project underway to engage primary care doctors in this effort. Her team will present a telehealth education session with patients and families to talk about the importance of screening for late effects. This study involves patients aged 2 to 22 years at four centers around the country that were chosen because of their high proportions of Black, Latinx, and rural patients, Kadan- Lottick explains. These populations are underrepresented in AYA research.

Survivorship is not a destination, but a lifelong journey for patients of all ages. Kadan-Lottick envisions enhanced coordination for long-term survivor support throughout Georgetown Lombardi.

“My goal is to have survivorship issues integrated in all cancer diagnoses and across the age spectrum so that providers understand that with every cancer, [it matters] what we do when the treatment ends. The choices we make on how best to care for patients can optimize quality of health and wellbeing,” Kadan-Lottick says. “We need to help each person where they are on the cancer journey.”

*Note: Georgetown has licensed the technology directed to EWS-FLI blockers to a company. Toretsky and Üren are listed as inventors on several Georgetown-owned patents directed to the technology and both hold equity shares in the company. Toretsky is also a paid scientific advisor to the company.

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