What we do
Targeting the Achilles Heel of Ewing Sarcoma
Our lab focuses on Ewing sarcoma, since the tumors contain a unique target that is not found in non-tumor cells. This unique target offers an opportunity to create new medicines that will more specifically eliminate tumor growth while sparing normal cells. In 2009, Dr. Toretsky and his team revealed the molecule called YK-4-279 that targets Ewing sarcoma with an article in Nature Medicine. YK-4-279 has the potential to be a potent new strategy in the fight against not only Ewing sarcoma, but also other cancers and diseases with similar characteristics.Direct screening for small molecules that bind to EWS-FLI1 required recombinant protein along with surface plasmon resonance technology. Once a lead compound was identified, a network of collaborators in medicinal chemistry, biochemistry, structural biology, and pharmacology helped advance the molecule YK-4-279, as an inhibitor of EWS-FLI1, towards a clinical trial. Significant efforts failed to obtain a commercial partner to license YK-4-279 due to the extraordinarily rare incidence of Ewings sarcoma. Therefore, in 2014 Dr. Toretsky cofounded Tokalas, Inc. to advance an analog of YK-4-279 to a clinical trial that is commencing in the spring of 2016.
Current Collaborators:
Aykut Üren, Georgetown University Julie Forman-Kay, The Hospital for Sick Children, Toronto
Stefan Zollner, Muenster, Germany Heinrich Kovar, St. Anna's Kinderspital, Vienna, Austria
Adolescent and Young Adult Cancer Survivors Benefit From Area’s Only Program to Support Their Unique Needs
MedStar Georgetown’s Pediatric and Young Adult (PAYA) Survivorship Program focuses on physical, psychological, and social support with personalized care plans
WASHINGTON – Eileen Fauteux was a 20-year-old junior at Virginia Tech when she was diagnosed with Ewing sarcoma, a rare type of cancer that is often found in bones or the soft tissue around the bones. Her symptoms started with severe back pain and progressed to numbness and tingling up and down her legs. After tests showed the diagnosis, Eileen and her family met Jeffrey A. Toretsky, MD, chief of the Division of Pediatric, Adolescent, and Young Adult (PAYA) Hematology/Oncology at the Georgetown Lombardi Comprehensive Cancer Center at MedStar Georgetown University Hospital, a leading expert in pediatric and young adult survivorship programs.
“Adolescents and young adults with cancer need to be treated by oncologists familiar with the types of therapy required to manage their disease and ensure the best outcomes and quality of life. They also require psycho-social services to help them cope and move forward after a cancer diagnosis. Yet, they are often cared for in a pediatric setting,” said Dr. Toretsky. “By providing services that directly address the unique psycho-social and physical needs and concerns of these young people, we provide an extra layer of hope and confidence in the future beyond just what the medical care provides.”
For adolescent and young adult patients ages 15 to 39 with cancer, the MedStar Georgetown University Hospital Pediatric, Adolescent, and Young Adult Hematology/Oncology team creates a personalized treatment care plan that includes the offering of the PAYA Survivorship program, a team approach to care that empowers patients to feel as supported as possible as they navigate life during and after cancer treatment. The PAYA program includes a comprehensive evaluation of the patient’s physical health, academic and social development, coping skills, and even addresses financial and insurance concerns. The team also provides patient education about diagnosis, treatment, and potential risks for late effects from treatment, and provides access to psychologists, social workers, integrative medicine specialists, nutritionists, and physical and occupational therapists.
“Once a patient is diagnosed with cancer, they become a cancer survivor,” says Tara K. Suntum, MD, a Pediatric Hematologist and Oncologist at MedStar Georgetown University Hospital who specializes in cancer survivorship, as well as treating a variety of forms of cancer including Ewing’s Sarcoma, Lymphoma, and Leukemia. “Because many cancer survivors have unique health needs that often require follow-up care, a comprehensive, personalized survivorship care plan helps cancer survivors prepare for a healthy post-cancer life.”
The cancer survivorship team discusses each individual concern with a patient, their parents (for adolescents), and their school if necessary, to fully understand how they can best help patients reintegrate back into a school or work environment after their cancer treatments. This support system can also help patients cope with the potential stress or anxiety that returning to a school or work environment post-treatment can cause.
“After young adults finish their cancer treatment, there certainly can be some effects on their functioning in their school or work environment, and this can be from a lot of different factors, including chemotherapy,” explains Dr. Suntum. “The PAYA programs aims to assist these young patients cope with these changes, and other possible challenges, that can result from treatment as they navigate re-entry to work, school and social life.”
Now at age 26 and several years removed from successful treatment of her sarcoma, Eileen is a college graduate and Physician Assistant. But she still visits the PAYA clinic for treatment of a different kind -- Eileen now benefits from participation in the PAYA Survivorship program.
“I remember receiving an email from Dr. Toretsky asking about the survivorship program, and just being like, wow, I love the word survivorship,” Eileen said. “He has emphasized how important it is to have a structured treatment plan and a group that targets young adults because it is something that I never realized existed. They have organized all of my treatment for me, so it just gives me a sigh of relief.”
Chris Copeland explains the challenges of creating a drug to target EWS-FLI1
https://j0iningupthed0ts.blogspot.com/2017/11/three-sides-of-triangle.html
The emerging role of the spliceosome in Ewing Sarcoma
Alternative splicing has been implicated as an oncogenic process and provides both a categorization of cancer as well as an opportunity for more effective targeted treatments. Spliceosomal network interactions, including proteins that recognize splice enhancer and silencer regions, are critical for the regulation of alternative splicing leading to oncogenic protein isoforms. Interrogation of complete protein networks remains challenging because it is difficult to modify single interactions while preserving overall network architecture. We hypothesized that EWS-FLI1, Ewing sarcoma (ES) oncoprotein, modulates post-transcriptional gene regulation through novel protein interactions. EWS-FLI1 has multiple connections to the spliceosome and reduction of EWS-FLI1 alters significant numbers of exon skipping and intron inclusion events identified from RNA-seq. Assessment of aberrant splicing driven by EWS-FLI1 may inform oncogenesis and reciprocally, EWS-FLI1 activities may inform splicing mechanisms.
Current Collaborators:
Liquid-liquid phase separation
A deeper investigation into the mechanism of YK-4-279 has led Dr. Toretsky into the world of phase separation and soft matter. He is particularly interested in understanding how phase-separated protein complexes occur and how they function in RNA processing. Small molecules may be useful in disrupting local biochemistry to prevent or induce phase separation
Current Collaborators:
Daniel Blair, Georgetown University
Julie Forman-Kay, Toronto Sick Children's Hospital
Clifford Brangwynne, Princeton University