Novel Tumor-Targeted Therapeutic Strategy for Progressive Metastatic Disease
Abstract
Metastases, the development of secondary tumors far from the original primary tumor, is the hallmark of cancer and is the primary cause of cancer related death. Unfortunately, metastatic disease is common in almost all cancers and is generally associated with death. Despite 100 years of metastasis research, common therapeutic strategies are still ineffective, primarily due to the lack of information on the biological underpinnings that govern the metastasis development process. In addition, the genetic and biological differences between the primary and metastatic cells themselves need to be well-defined in order to develop a targeted therapy for metastatic cancer. Another crucial gap is the lack of information on the de novo acquisition of genetic and molecular rearrangements in resistant cancer cells, which facilitates the extreme adaptability (referred to as plasticity) in these cells that endorse metastatic disease. We’ve established mouse models for metastatic disease and have showed that Metastatic Site Derived Aggressive Cells (MSDACs) exhibit reversible plasticity that could be used to determine clinical behavior. Our exhaustive genetic and molecular characterization of the metastatic tumors (vs. primary tumors) has identified definitive genetic rearrangements. Hence, it is central to identify the crucial molecular drivers that engineer disease progression in order to appropriately develop improved therapeutic strategies for the cure of metastatic cancers. As a novel finding, we recognized that MSDACs lack a protein called retinal degeneration 3 (RD3) and that this loss of protein is enabling metastasis and disease aggravation and leads poor clinical outcomes. We were the first to show that RD3 is expressed in all human adult and fetal tissues beyond the original claim that it existed solely as an eye protein. Further, our studies confirmed an ongoing acquisition that there would be RD3-loss in cells that survive a prior therapy. Our preliminary findings indicated that RD3 is regulated at the genetic level in MSDACs. In addition, we found that RD3 binds and stabilizes a tumor-suppressing protein called PML. Remarkably, our preliminary findings indicated that therapeutic delivery of RD3 protein alters tumor cell growth and their metabolic and metastatic state. Based on these findings, we hypothesize that the loss of RD3 could play a thus far unrecognized role in metastatic disease evolution. The acquired loss of RD3 in cancer cells could orchestrate modification of PML, promoting metastatic disease progression. Restoring RD3 could provide a therapeutic advantage for the treatment of metastatic cancer and will have a profound clinical impact. Our studies in test cohorts of cancer patients revealed a significant correlation between RD3 loss to poor patient survival in neuroblastoma (infant cancer), ovarian, colon, and pancreatic cancer. Since mechanisms of disease aggravation and appropriate therapeutic measures remains unresolved in many cancers, the outcomes of this study will identify a novel therapeutic strategy that directly translates to the clinic and will impact the cure of such diverse metastatic cancers. Three specific aims are proposed to prove the hypothesis. In Aim 1, we will identify the association between RD3 loss and metastatic disease progression/clinical outcomes for diverse cancers, while pinning its function in cancer initiation and disease evolution. We will investigate the prognostic relevance of RD3 loss to cancer progression with metastasis, patient survival, and the de novo loss of RD3 in cancer cells after clinical therapy. This will be a study in diverse cancers, including neuroblastoma, glioblastoma, endometrial, bladder, colon, thyroid, and head and neck cancer patients (200-250 patients for each tumor type). Using neuroblastoma as working model, we will investigate the function of RD3 in driving metastatic disease. We are exclusively equipped to perform these t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210853
Entities
People
- Natarajan Aravindan
Organizations
- United States Army
- University of Oklahoma Health Sciences Center