Targeting infant tumors: A new hope for cancer treatment
Thursday, January 2, 2025
Media Contact: Taylor Bacon | Public Relations and Marketing Manager | 405-744-6728 | cvmcommunications@okstate.edu
A treatment for one of the deadliest childhood cancers is undergoing testing at Oklahoma State University.
Neuroblastoma is the most common type of extracranial solid tumor in infants and primarily affects those under 5 years old. Despite advances in treatment, more than half of children diagnosed with neuroblastoma don’t survive, and many others face long-term health challenges.
However, groundbreaking research by Dr. Natarajan Aravindan and his team at OSU may hold the key to not only improving treatment for neuroblastoma but also revolutionizing how we approach cancer therapy.
For the past three decades, Aravindan, a College of Veterinary Medicine physiological sciences professor, has focused on understanding the molecular mechanisms behind therapy-induced stress in aggressive cancers, including neuroblastoma, brain, head and neck, thyroid, breast, colon, endometrial, ovarian and bladder cancers.
His work aims to uncover how these stress responses contribute to tumor progression and resistance to treatment, intending to develop more effective therapies to improve patient outcomes.
Aravindan, the Kerr Endowed Chair for Biomedical Laser and BioPhotonics Research and Williams Company Foundation Presidential Professor, first became interested in molecular oncology when studying the role of intercellular, bystander and abscopal signaling events in response to radiation therapy.
“While the primary cancer treatments seemed to be effective, the occurrence of frequent tumor recurrence in rapidly decreasing timelines is a grim reality,” Aravindan said. “It is the tumors that escape or resist the primary treatment modalities that are hard to treat after and often correspond to poor clinical outcomes.”
There is a gap in understanding why some patients respond and others don’t survive. This is true for both children and adults faced with deadly solid tumors, which led Aravindan to focus his research interest on molecular oncology.
Aravindan is a champion for One Health research, as his own work is fueled by the desire to create therapeutics that will eventually improve both animal and human health. Although his lab studies diverse solid cancers, the primary focus is neuroblastomas. His research has identified how tumors evolve through genetic and molecular changes in response to chemotherapy and radiation and has led to new molecular-targeted therapeutic approaches to overcome this reprogramming.
His lab develops unique disease models based on human cancers, as well as novel preclinical models of residual disease and complex transgenic mice. These models help study how cancers evolve after standard treatments and are used to develop new therapeutic strategies that can be quickly translated into clinical practice.
“The study focus is on defining the thus far unrealized existence of cancer cell plasticity, its function in tumor evolution and, in developing molecular targeted maintenance therapy for these children where there is no effective treatment currently available,” Aravindan said.
As the most common extra cranial solid tumor in children, Neuroblastoma comprises one-tenth of all childhood cancer deaths. To date, immunotherapies have been relatively unsuccessful in combatting neuroblastoma. Understanding the drivers and mechanisms behind tumor immune evasion is crucial for developing effective treatments for high-risk and therapy-resistant tumors.
While Aravindan’s lab examined the genetic, epigenetic and molecular differences between clinically favorable primary tumors and high-risk, aggressive metastatic disease, they identified Retinal Degeneration Protein 3 (RD3), a protein typically associated with the eye. These researchers noticed a correlation between RD3 loss and advanced disease stage with poor clinical outcomes.
“These, thus far unrealized, novel findings opened doors to address the crucial and warranted gaps in disease evolution,” Aravindan said. “Investigating RD3 will define its driver role and could identify a novel molecular targeted therapy for children affected with deadly cancers where no therapy is currently available.”
His lab team discovered that RD3 is present in various tissues of both adults and fetuses, not just in the eye. They also found that RD3 expression is lost when tumors are exposed to therapy, which can help predict how neuroblastoma will progress. The protein also plays a crucial role in stabilizing the evolution of neuroblastoma.
“With our understanding of RD3’s significance in neuroblastoma evolution and prognosis, we identified that RD3 determines immune cell type composition in the neuroblastoma tumor microenvironment,” Aravindan said.
The study showed that RD3 plays a crucial role in maintaining the immune environment around neuroblastoma tumors, and its loss allows the tumor to evade the immune system and grow.
“Our studies uniquely identified the availability and abundance of RD3 beyond retina and defined its constitutive expression in all human adult and fetal tissues,” Aravindan said. “As a novel finding, we identified the significant loss of RD3 in extremely plastic, aggressive, undifferentiated tumor cells, correlating its loss to cellular metastatic potential, disease aggravation and clinical outcomes underscoring the role of RD3 loss in tumor progression.”
Aravindan also said their bed-to-bench studies affirmed an ongoing acquisition of RD3 loss with therapy pressure and its significance in tumor evolution. The team discovered RD3 helps control the activity of genes in the tumor, which prevents the cancer from hiding from the immune system. When RD3 is lost, the immune cells that should attack the tumor (specifically CD4+ and CD8+ T cells) have trouble reaching the tumor, allowing it to grow and spread.
It’s important to note that the loss of RD3 can happen during treatment, making the cancer harder to fight and helping it evolve. The researchers also found a set of 27 genes linked to RD3 that could be used to predict how the tumor will behave or respond to therapy.
“Overall, the study provides compelling evidence that RD3 plays a key role in stabilizing the tumor’s environment and shifts a huge archetype in the understanding of the biology of tumor immune evasion,” Aravindan said. “This paves a way to the development of novel and effective molecular targeted therapy for deadly cancers.”
Very few researchers have made progress in understanding the mechanisms and biology of the tumor immune microenvironment. This may be the first study focused on this topic and the first that recognizes the driver and mechanisms involving tumor immune evasion. The outcomes of this study identify RD3 as the genetic driver that dictates tumor immune evasion.
“Therapeutic delivery of RD3 could serve as the new and effective maintenance therapy for infants presented with the progressive disease that defies the current clinical intensive multimodal therapy,” Aravindan said. “This could save the lives of countless children and could change the quality of life of infants who suffered high-risk tumors.”
In the future, Aravindan’s lab plans to explore how tumor cell RD3 rearranges the cancer cell and T cell metabolism. Ultimately, the team wants to understand how RD3 affects cancer and immune cells, particularly how it influences their energy use and behavior, which is key to their ability to fight the tumor.
The goal is to develop a treatment that targets RD3 directly, especially for cancers that don’t respond well to standard treatments. Since RD3 is important in many types of solid tumors, his approach could help improve outcomes for patients with a variety of hard-to-treat cancers, not just neuroblastoma.
“Cancer is not a simple disease, and there are many intricate molecular interactions that coordinate its survival beyond clinical therapy,” Aravindan said. “Countering anything less than the primary genetic determinant of the response will open Pandora’s box of issues that compensate and complement disease progression.”
Photos By: Taylor Bacon
Story By: Taylor Bacon | Vet Cetera Magazine