Premium
The arginine metabolome in acute lymphoblastic leukemia can be targeted by the pegylated‐recombinant arginase I BCT‐100
Author(s) -
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
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31170
Subject(s) - arginase , argininosuccinate synthase , arginine , ornithine transcarbamylase , argininosuccinate lyase , cancer research , arginine deiminase , medicine , biology , amino acid , biochemistry , urea cycle
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.