Grants and Contracts Details
Each year ~250-300 children, adolescents, and young adults in the United States are affected by Ewing’s sarcoma (ES), an understudied form of bone sarcoma1. Approximately half of all ES patients develop either recurrent or metastatic disease, with less than 20% of such patients surviving long-term. The standard of care for ES patients includes multi-agent chemotherapy to treat documented or potential metastatic disease, coupled with surgery and irradiation to treat the primary tumor. Although some incremental advances have been made in the last three decades through intensification of conventional chemotherapy agents, more significant improvements will likely depend on the identification of novel treatment strategies. Two clinical hallmarks of ES are: 1) the accumulation of intracellular glycogen deposits that are Periodic acid-Schiff positive (PAS+) during histopathology analysis (Fig. 1A) and 2) the EWS-FLI1 fusion oncogene 2. Contribution of EWS-FLI1 to tumorigenesis and epigenetics is well studied 2-5, but little is known about the metabolic and tumorigenic aspects of glycogen in ES nor has glycogen metabolism been explored as an anti-ES target. ES tumors are Positron emission tomography (PET) positive using 18F-fluorodeoxyglucose, an indicator of increased glucose uptake (Fig.1B). The PET data, together with increased glycogen accumulation, strongly suggest that glucose metabolism is uniquely dysregulated in ES tumors. Aberrant glycogen accumulation leads to defects in autophagy6,7, protein unfold response/ER stress8, and mitochondrial dysregulation 9 , all of which have been implicated in cancer signaling and metabolism. Enzyme replacement therapy is the current standard of treatment for glycogen accumulation; Genzyme and Valerion, LLC are world leaders in the field. Lumizyme is an FDA approved enzyme therapy from Genzyme, while VAL-1221 from Valerion is currently in a phase 2 clinical trial with promising early results10. We analyzed 24 ES patient samples resected from surgery and their matching distal noncancerous controls. Glycogen levels were dramatically higher in the cancer tissue. The ESglycogen displayed structural/architectural abnormalities compared to muscle and liver glycogen, implying dysregulation of glycogen metabolism. Further, we present strong evidence connecting ES-glycogen accumulation with cancer metabolism. Eliminating ES-glycogen by CRISPRknockout or small molecule inhibition of the enzyme required for glycogen synthesis, glycogen synthase, drastically reduced ES tumor growth in vivo. Our data support the notion that ESglycogen is a driver of ES proliferation and a viable therapeutic target. Finally, we have developed an antibody-enzyme fusion (AEF) therapeutic, VAL-0417 with Valerion Therapeutics specifically targeting intracellular glycogen accumulation. We have demonstrated its efficacy in clearing aberrant glycogen in vivo and ES glycogen ex vivo. We will expand on testing VAL-0417 in ES preclinical models. Based on these results, we hypothesize that ES-glycogen is a driver of tumor proliferation by remodeling cellular metabolism, which presents glycogen as a promising target for the newly developed AEF therapeutic VAL-0417. The overall objective of this study is to define the metabolic flux between glycogen and central carbon metabolism in ES models using highresolution mass spectrometry-based metabolomic techniques. Finally, we will assess the preclinical efficacy of the genetic-engineered antibody-enzyme fusion therapeutics as a novel treatment of xenografted ES tumor models.
|Effective start/end date||12/1/20 → 10/31/22|
- V Foundation: $200,000.00
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.