# USING ARGININE METABOLIC THERAPIES FOR SARCOMA

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $360,531

## Abstract

Program Director/Principal Investigator: (Van Tine, Brian)
Project Summary
We recently demonstrated that argininosuccinate synthetase 1 (ASS1) expression is silenced in 88% of all
sarcomas (n=708), and this loss is associated with reduced overall survival. In the absence of ASS1, arginine
becomes an essential amino acid that tumor cells must obtain from blood. We demonstrated that PEGylated
arginine deiminase (ADI-PEG20, an extracellular arginine-depleting enzyme) induces prosurvival metabolic
reprogramming in ASS1-deficient sarcomas that redirects glucose into the serine/folate pathway, thereby
funneling carbons from glucose into pyrimidine biosynthesis. Metabolomics analyses suggested that this should
sensitize cells to death by the pyrimidine antimetabolite gemcitabine. In addition, ADI-PEG20 and docetaxel
dramatically increase the expression of SLC29A1, the nucleotide/gemcitabine transporter. The combination of
gemcitabine and docetaxel has been demonstrated to be superior to gemcitabine alone in sarcoma. Therefore,
we will perform a Phase II clinical trial combining ADI-PEG20 with gemcitabine and docetaxel, which are standard
second-line therapeutic agents for soft tissue sarcoma, to model the metabolic consequences of ASS1 deficiency
in the presence and absence of arginine starvation. Progression-free survival and overall survival are the primary
and secondary endpoints, respectively. Paired biopsies before treatment and 21 days after ADI-PEG20 will be
obtained for correlative studies. For preclinical testing, we generated the first conditional murine knockout model
of ASS1 that develops sarcomas in the context of p53 loss, a common alteration in sarcomas. We also developed
sarcoma patientderived xenografts (PDXs) to model arginine deprivation by ADI-PEG20. We will determine the
effect of ASS1 silencing on tumorigenesis in transgenic mice, and model the adaptive metabolic reprograming
response to gemcitabine and docetaxel to determine patterns of sensitivity and resistance to therapy. We
anticipate that the proposed studies will lead to the development biomarker-driven therapy for arginine
deprivation in ASS1-deficient sarcomas.

## Key facts

- **NIH application ID:** 10471182
- **Project number:** 5R01CA227115-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brian Andrew Van Tine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $360,531
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471182

## Citation

> US National Institutes of Health, RePORTER application 10471182, USING ARGININE METABOLIC THERAPIES FOR SARCOMA (5R01CA227115-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10471182. Licensed CC0.

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