Key Takeaways
- Ewing sarcoma is a rare and aggressive cancer primarily affecting children and young adults, with a challenging 5-year survival rate of 55%-65% for localized cases and a significant decrease in survival if the cancer metastasizes.
- LINGO1 protein, found in over 90% of Ewing sarcoma tumors, presents a promising target for novel treatments, including monoclonal antibodies and CAR T-cell therapies, offering potential hope for more effective and precise therapies against this challenging disease.
- Ongoing preclinical research at UCLA focuses on leveraging LINGO1 as a gateway protein to develop innovative treatments for Ewing sarcoma, aiming for improved safety and efficacy, while envisioning a future with accessible cancer prevention through a universal vaccine.
Fewer than 1000 cases of Ewing sarcoma are identified worldwide each year, making it one of the rarest, and perhaps most frustrating cancers. The tumors—nearly 90% of which are found in the lower extremities, such as the pelvis, thigh bone, and femur, or in soft tissue—are most frequently diagnosed in children and young adults between the ages of 10 and 20 years and are both difficult to diagnose and to treat.
While the 5-year survival rate for Ewing sarcoma is presently between 55% to 65% if the disease is found while localized, little progress has been made in developing treatments that can help to stop these sarcomas from spreading or coming back.1
That’s an untenable problem for a disease that is not only difficult to treat but is also extremely aggressive. Ewing sarcoma is characterized by tumors that grow and spread rapidly to other parts of the body, including to soft tissues and organs.
Problematically, while metastatic Ewing sarcoma may be very common, imaging only reveals the spread of these tumors in 20% of patients. For those patients whose cancer does become metastatic, the survival rate decreases to between 20% to 35%.
Further, since up to 30% of patients can be expected to face tumor recurrence, the need for approaches that target chemotherapy-resistant tumors and microscopic residual disease is crucial in eradicating this serious pediatric disease.2 To address this need, investigators at University of California, Los Angeles collaborated with investigators at CancerVax to learn more.
Treatment Challenges
Part of what makes Ewing sarcoma so difficult to treat is its ability to rapidly spread and its resistance to chemotherapy treatments. Over the past several decades, breakthroughs in drug discovery and development for novel treatments for Ewing sarcoma were effectively stalled as scientists worked to better understand it, how it differs from other types of cancer, and what causes it.
While scientists have already linked the development of Ewing sarcoma to EWS-FLI1, a fusion protein that is now known to influence oncogenic processes, and to IGF-1R, a protein found on the surface of all human cells that helps to regulate growth hormones but can be hijacked to facilitate the growth of malignant tumors, research is still ongoing to find methods to block or stop these oncogenic processes before they start and to stop them from reoccurring.3,4 The number of different proteins and pathways associated with the development and spread of Ewing sarcoma have also made it difficult for scientists to pinpoint the single best answer for treating and eradicating this cancer.
The LINGO1 Protein
In 2016, researchers discovered that the LINGO1 protein may be the perfect drug target for treating and ultimately putting an end to Ewing sarcoma. LINGO1 is an immunoglobin-like protein rich in leucine that is most often linked to neurological health and the onset of neurodegeneration. However, the protein is also a biomarker for Ewing sarcoma that is present on the surface of more than 90% of related tumors and could be the perfect gateway protein to deliver therapeutics past tumor barriers and to kill them from the inside.5
To better understand the relationship between LINGO1 and Ewing sarcoma, our UCLA research team has been studying both tumor cells and immune cells collected from patients with Ewing sarcoma. This research has directly influenced the ongoing development of chimeric antigen receptor (CAR) T cells and bispecific antibodies to both target LINGO1 and leverage it against Ewing sarcoma tumors.
So far, our team has developed 7 monoclonal antibody candidates for the treatment of Ewing sarcoma. Six of these candidates have been fully humanized. What’s more is that we’ve confirmed that these 6 antibody candidates have a targeting affinity for our LINGO1 protein biomarker for Ewing sarcoma. Two of these antibody candidates are being used to develop CAR T-cell treatments, while 3 others have been selected to become bispecific antibodies.
Importantly, this new research and the confirmation of LINGO1 as a gateway protein for the treatment of Ewing sarcoma will help us to continue to create and evaluate additional tools for activating patients’ immune systems to not only track, infiltrate, and destroy Ewing sarcoma tumors, but also prevent them from spreading or returning.
What’s Next?
Our work with UCLA on Ewing sarcoma treatments is currently in preclinical studies, and we hope to make further positive preclinical progress in 2024, with a primary focus on safety and efficacy. In the meantime, we hope the progress we have made can support and inform research being done by others in search of a cure for Ewing sarcoma.
Importantly, we’re also looking towards a potential universal cancer vaccine that we hope someday will be as easy to get as a flu shot. The goal is ultimately to stop cancer before it ever has the chance to start. In the meantime, we’re continuing to work towards treatments for Ewing sarcoma and other cancers because everyone deserves a chance to live life free from cancer, and we can help with that now while we work towards a hopefully entirely cancer-free future.
About the Author
Ryan Davies is the CEO of CancerVAX.
References
- Daw N, et al. Local control modality and outcome for Ewing sarcoma of the femur: A report from the Children’s Oncology Group. Ann Surg Oncol. 2016 Oct;23(11):3541-3547. doi: 10.1245/s10434-016-5269-1.
- Stahl M, et al. Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Ped Blood and Cancer. 2011 Mar;57(4). doi: 10.1002/pbc.23040.
- Cidre-Aranaz F, Alonso J. EWS-FLI1 target genes and therapeutic opportunities in Ewing sarcoma. Front Oncol. 2015 Jul;5. doi: 10.3389/fonc.2015.00162.
- Clinical trial: Combination chemotherapy with or without ganitumab in treating patients with newly diagnosed metastatic Ewing sarcoma. https://clinicaltrials.ucbraid.org/trial/NCT02306161.
- Town et al. Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target. Proc Natl Acad Sci USA. 2016;113(13):3603-8. doi: 10.1073/pnas.1521251113.
