The arginine metabolome in acute lymphoblastic leukemia can be targeted by the pegylated‐recombinant arginase I BCT‐100. Issue 7 (26th December 2017)

• Record Type: Journal Article
• Authors: De Santo, Carmela; Booth, Sarah; Vardon, Ashley; Cousins, Antony; Tubb, Vanessa; Perry, Tracey; Noyvert, Boris; Beggs, Andrew; Ng, Margaret; Halsey, Christina; Kearns, Pamela; Cheng, Paul; Mussai, Francis
• Is Part Of: International journal of cancer. Volume 142:Issue 7(2018)
• Page Start: 1490
• Page End: 1502
• Publication Date: 2017-12-26
• Subjects: arginine -- ALL -- arginase; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31170
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Arginine is a semi‐essential amino acid that plays a key role in cell survival and proliferation in normal and malignant cells. BCT‐100, a pegylated (PEG) recombinant human arginase, can deplete arginine and starve malignant cells of the amino acid. Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood, yet for patients with high risk or relapsed disease prognosis remains poor. We show that BCT‐100 is cytotoxic to ALL blasts from patients in vitro by necrosis, and is synergistic in combination with dexamethasone. Against ALL xenografts, BCT‐100 leads to a reduction in ALL engraftment and a prolongation of survival. ALL blasts express the arginine transporter CAT‐1, yet the majority of blasts are arginine auxotrophic due to deficiency in either argininosuccinate synthase (ASS) or ornithine transcarbamylase (OTC). Although endogenous upregulation or retroviral transduced increases in ASS or OTC may promote ALL survival under moderately low arginine conditions, expression of these enzymes cannot prevent BCT‐100 cytotoxicity at arginine depleting doses. RNA‐sequencing of ALL blasts and supporting stromal cells treated with BCT‐100 identifies a number of candidate pathways which are altered in the presence of arginine depletion. Therefore, BCT‐100 provides a new clinically relevant therapeutic approach to target arginine metabolism in ALL. Abstract : What's new? While most children with acute lymphoblastic leukemia (ALL) are cured, only half of adults experience this outcome, and many patients suffer life‐long effects from the toxicities of chemotherapy. To overcome these challenges, therapies targeting novel mechanisms in ALL blast cells are needed. In our study, PEGylated recombinant human arginase (BCT‐100), which depletes the semi‐essential amino acid arginine, is shown to induce ALL cell death in vitro . In a xenograft model, BCT‐100 reduced disease burden and improved survival. Expression of the enzymes argininosuccinate synthetase and ornithine transcarbamylase, which synthesize recycle arginine intracellularly, are reduced in B‐cell ALL blasts, suggesting arginine auxotrophism.