Abstract CT111: Preclinical justification for the Phase II clinical trial ADI-PEG 20 in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma

Autor: Bethany C. Prudner, Richa Rathore, Abigail Godec, Samuel F. Chang, Angela Hirbe, Brian A. Van Tine
Rok vydání: 2019
Předmět:
Zdroj: Cancer Research. 79:CT111-CT111
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2019-ct111
Popis: The response to acute and long-term arginine starvation results in an adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. In examining modulations within the pyrimidine pathway, we identified that the addition of docetaxel (DTX) to cells treated with arginine deiminase (ADI-PEG20) results in a stabilized and translocation c-Myc to the nucleus. This effect drives increased hENT1 cell surface, allowing for the uptake of gemcitabine (GEM) and related analogues. This can be attenuated via a c-Myc/Max heterodimerization inhibitor. Combination experiments showed that the addition of ADI-PEG20 to the combination of GEM and DTX was synergistic. In addition, this combination can be used to overcome intrinsic hENT related GEM resistance to increase GEM uptake. In vivo studies indicate that the triple combination was optimal for tumor growth inhibition providing the preclinical mechanisms and justification for the ongoing clinical trial NCT03449901 ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma. Citation Format: Bethany C. Prudner, Richa Rathore, Abigail Godec, Samuel F. Chang, Angela Hirbe, Brian A. Van Tine. Preclinical justification for the Phase II clinical trial ADI-PEG 20 in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT111.
Databáze: OpenAIRE
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