The arginine metabolome in acute lymphoblastic leukemia can be targeted by the pegylated-recombinant arginase I BCT-100

Carmela De Santo, Sarah Booth, Ashley Vardon, Antony Cousins, Vanessa Tubb, Tracey Perry, Boris Noyvert, Andrew Beggs, Margaret Ng, Christina Halsey, Pamela Kearns, Paul Cheng, Francis Mussai

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
125 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1490-1502
Number of pages13
JournalInternational Journal of Cancer
Volume142
Issue number7
Early online date23 Nov 2017
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • arginine
  • arginase
  • ALL

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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