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Updated: Apr 22, 2026
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts
Vaidehi Agrawal1, Jung Hee Woo, Jeremy P Mauldin
1aScott & White Cancer Research Institute, Baylor-Scott & White Health bDepartment of Medical Physiology, Texas A&M Health Science Center, Temple cDepartment of Chemical Engineering, University of Texas, Austin dDepartment of Internal Medicine University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract:
Metastatic melanoma is a deadly form of cancer with few therapeutic options and the cause of more than 9480 deaths annually in the USA alone. Novel treatment options for this disease are urgently needed. Here we test the efficacy of a novel melanoma drug, the human recombinant Co-arginase (CoArgIPEG), against an aggressive A375 melanoma mouse model. CoArgIPEG is a modification of the naturally occurring human enzyme with improved stability, catalytic activity, and potentially lower immunogenicity compared with current amino acid-depleting drugs. Marked tumor growth reductions (mean P=0.0057) with apoptosis induction and proliferation inhibition are noted with CoArgIPEG treatment, both in the presence and in the absence of supplemental citrulline. Further, improved therapeutic efficacy has been noted against A375 xenografts relative to the naturally occurring human recombinant arginase enzyme at lower doses of CoArgIPEG. Unfortunately, after 1 month, half of the relapsing tumors showed argininosuccinate synthase induction, which correlated with Ser62-phosphorylated cMyc. Although argininosuccinate synthase induction could not be induced in vitro, a drug targeting pathway previously demonstrated to be associated with Ser62 cMyc phosphorylation - U0126 - in combination with CoArgIPEG demonstrated an in-vitro synergistic response (combination indices 0.13±0.10 and 0.14±0.10 with or without citrulline, respectively). Overall, favorable efficacy and potential synergy with other antimelanoma drugs support CoArgIPEG as a potent, novel cancer therapeutic.
Insights
A novel drug, human recombinant Co-arginase (CoArgIPEG), significantly reduced melanoma tumor growth in mice. This promising cancer therapeutic also showed synergy with other drugs, offering new hope for metastatic melanoma treatment.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Metastatic melanoma is an aggressive cancer with limited treatment options, causing significant mortality.
- There is an urgent need for novel therapeutic strategies to combat this deadly disease.
- Amino acid-depleting drugs are a potential treatment avenue, but improvements are needed.
Purpose of the Study:
- To evaluate the efficacy of a novel modified human recombinant Co-arginase (CoArgIPEG) against a metastatic melanoma mouse model.
- To compare CoArgIPEG with the naturally occurring human recombinant arginase enzyme.
- To investigate potential synergistic effects of CoArgIPEG with other therapeutic agents.
Main Methods:
- Testing CoArgIPEG efficacy in an aggressive A375 melanoma mouse model.
- Assessing tumor growth, apoptosis, and proliferation.
- Investigating drug resistance mechanisms, including argininosuccinate synthase induction.
- Evaluating in-vitro synergistic responses with U0126, a drug targeting c-Myc phosphorylation.
Main Results:
- CoArgIPEG treatment led to significant tumor growth reduction (P=0.0057) via apoptosis induction and proliferation inhibition.
- CoArgIPEG demonstrated improved efficacy over natural arginase at lower doses.
- Tumor relapse was associated with argininosuccinate synthase induction and c-Myc phosphorylation.
- CoArgIPEG showed synergistic effects with U0126 in vitro, both with and without citrulline supplementation.
Conclusions:
- CoArgIPEG is a potent novel therapeutic agent for metastatic melanoma.
- The drug exhibits favorable efficacy and potential for combination therapy.
- Further research into overcoming resistance mechanisms is warranted.
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