By Panneerdoss Subbarayalu, PhD
This article was first published in the September 2026 issue of the Bexar County Medical Society’s San Antonio Medicine magazine.
Osteosarcoma is an aggressive cancer that grows quickly, spreads early to the lungs, and has a remarkable ability to resist treatment. It is the most common primary bone cancer in children and is diagnosed each year in children and adolescents throughout the United States. The disease is relatively rare, but its effects can be devastating.
Chemotherapy and surgery have advanced dramatically over the past several decades, leading to greatly improved outcomes for patients with localized disease. Treatment usually involves a combination of chemotherapy and surgically removing the tumor. These strategies have improved survival, but the prognosis for patients with recurrent or metastatic disease has not changed substantially for more than 30 years.
For these patients and their families, the challenges are more than just the cancer. Long-term complications of intense chemotherapy can include hearing loss, infertility, heart and kidney damage, growth abnormalities and a higher risk of secondary cancers. Osteosarcoma is more common in children, adolescents and young adults so the physical and emotional impact of treatment can be substantial.
Decades of research have failed to make osteosarcoma a tractable scientific problem. Unlike many other cancers, it does not contain one genetic mutation that can be easily targeted with existing precision-medicine approaches. But instead, researchers have found a disease of astonishing genetic complexity and diversity, highlighting the critical need for novel therapeutic approaches.
Our lab at the Greehey Children’s Cancer Research Institute and UT Health San Antonio is committed to better understanding the biological mechanisms that drive osteosarcoma growth, metastasis and treatment resistance. Our work has been concentrated into two promising directions of investigation: RNA epigenetics and Leukemia Inhibitory Factor (LIF)/ its Receptor (LIFR) signaling pathway.
Looking Beyond DNA
For years, scientists concentrated most of their efforts on DNA mutations as the main cause of cancer development. However, more recently, it has been demonstrated that chemical modifications of RNA also have a major role in the regulation of gene expression and cellular behavior.
In our laboratory, we have been especially interested in a process known as m6A RNA modification. Small chemical changes affect how genes are expressed and how cells respond to their environment. In this study, we found that a gene, ALKBH5, critically controls osteosarcoma progression. Our data showed that ALKBH5 was frequently overexpressed/amplified in osteosarcoma cells and promoted tumor growth and survival. We also found a surprising link between RNA regulation and other epigenetic pathways that lead to the aggressiveness of cancer cells.
Finding New Uses for Existing Medicines
One of the most exciting aspects of cancer research is the opportunity to rapidly translate laboratory discoveries into new therapies.
After we had identified ALKBH5 as a promising target, we screened hundreds of compounds to see if any existing drugs could inhibit its activity. This search, based on a drug repurposing approach, led us to a surprising candidate, mefloquine, a drug originally developed for treating malaria. There is an important advantage to this strategy — the drug has already been studied extensively, potentially accelerating the path from laboratory discovery to clinical application. As a result, therapies identified through drug repurposing may reach patients more quickly than entirely new compounds developed from scratch.
Discovering Another Therapeutic Opportunity
In our latest work, we have identified a new promising target in osteosarcoma, the LIF/LIFR signaling pathway.
We have shown that the LIF receptor is highly expressed in pediatric osteosarcoma tumors. Blocking the pathway dramatically slowed tumor growth and greatly reduced the ability of cancer cells to migrate and spread.
Most importantly, we saw a dramatic reduction in the number of cancer stem cells. These specialized cells are thought to be critical in disease recurrence, metastasis and therapy resistance. By targeting this pathway, we hope to disrupt one of the key mechanisms that allows osteosarcoma to survive and progress.
A Collaborative Effort
Scientific discovery rarely happens in isolation. Progress in osteosarcoma research depends upon close collaboration among basic scientists, clinicians, computational biologists and experts in drug development.
In recognition of the potential impact of this work, the American Cancer Society awarded our laboratory a four-year $879,000 Research Scholar Grant to support the development of innovative therapeutic strategies for osteosarcoma.
This effort brings together investigators from multiple institutions across Texas who share a common goal: developing safer, more effective treatments for children and young adults facing this disease.
Collaborators include Peter Houghton, PhD, UT San Antonio professor .emeritus; Gail Tomlinson, MD, PhD, division chief of Pediatrics Hematology/Oncology in the Department of Pediatrics, Greehey Institute and Mays Cancer Center at UT San Antonio; Yidong Chen, PhD, professor in the Department of Population Health Sciences at the Long School of Medicine and the Greehey Institute at UT San Antonio; Suryavathi Viswanadhapalli, PhD, associate professor in the Division of Reproductive Research in the Department of Obstetrics and Gynecology in the Long School of Medicine at UT San Antonio; and Hareesh B. Nair, PhD, associate professor at Texas Tech University Health Science Center.
Nair, the lead inventor of a patented LIFR inhibitor, provides a particularly important translational perspective that strengthens the path from laboratory discovery to clinical application. Together, this collaborative team is working to translate fundamental discoveries in osteosarcoma biology into innovative treatments that may ultimately improve outcomes for children and young adults affected by this disease.
Looking Toward the Future
Recurrent and metastatic osteosarcoma remains one of the greatest unmet challenges in pediatric oncology. Our research has discovered two promising therapeutic opportunities: targeting the m6A RNA demethylase ALKBH5 and disrupting LIF/LIFR signaling. These findings are, taken together, beginning to provide new insight into the molecular mechanisms that contribute to tumor growth, metastasis and treatment resistance.
We will keep investigating the relationship between RNA epigenetics, cellular stress responses and oncogenic signaling pathways for better, less toxic therapies. Ultimately, we want to translate these discoveries to innovative clinical approaches that improve survival and quality of life for children, adolescents and young adults with osteosarcoma.
These advances move us closer to establishing targeted therapies that offer new hope for patients and their families, but much work remains to be done.
Panneerdoss Subbarayalu, PhD, assistant research professor in the Department of Cell Systems and Anatomy in the Joe R. and Teresa Lozano Long School of Medicine and the Greehey Children’s Cancer Research Institute at UT San Antonio, is a cancer biologist specializing in RNA regulation and m6A epigenetics in pediatric cancers. His research integrates mechanistic studies of tumor biology with translational therapeutic development to advance novel treatment strategies for osteosarcoma and other aggressive childhood malignancies. His work has generated foundational preclinical evidence supporting clinical trial development and has facilitated the translation of laboratory discoveries into potential therapies for pediatric cancer patients.
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