Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma

Yau, Thomas; Cheng, Paul; Chan, Pierre; Chen, Li; Yuen, Jimmy; Pang, Roberta; Fan, Sheung Tat; Wheatley, Denys N.; Poon, Ronnie Tung‐Ping

doi:10.1007/s10637-014-0200-8

Cited by 74 publications

(80 citation statements)

References 28 publications

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“…7 The addition of a 5000-molecular-weight polyethylene glycol molecule significantly increases the plasma half-life of arginase 1 from 10 to 20 minutes to up to 3.5 days in humans with minimal loss of enzyme activity. 8 We report for the first time that the majority of AML patients' blasts from children and adults, including those at relapse, are sensitive to arginine depletion, leading to necrotic cell death. BCT-100 may be internalized by AML blasts, consistent with other PEG molecules in myeloid cells, which would further contribute to low intracellular arginine concentrations.…”

Section: Discussionmentioning

confidence: 90%

“…Interim analysis of patients enrolled in a phase 2 trial in hepatocellular carcinoma suggests that patients experience significant improvements in overall survival, comparable to the standard of care. 8 For both pediatric and elderly AML patients in particular, concerns over treatment side-effects limit the type of therapies that can be given safely. 59,60 In this study, we show that arginine depletion is not cytotoxic to T cells and monocytes and is well tolerated in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…8 We first demonstrated that BCT-100 catalyzes a dose-dependent reduction in media arginine concentrations in vitro (supplemental Figure 1A, see supplemental Data available on the Blood Web site). Arginine was reduced to ,2 mM within 8 hours at concentrations of 600 ng/mL BCT-100 or higher.…”

Section: Bct-100 Reduces the Number Of Aml Blasts In Vitro And In Vivomentioning

confidence: 97%

“…[7][8][9][10] BCT-100 has shown significant benefit against solid tumors in preclinical studies and early-phase clinical trials. 8 Here, we characterize the mechanisms of dependence of AML blasts on arginine and the potential for arginine depletion with BCT-100 as a therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Mussai

Egan

Higginbotham-Jones

et al. 2015

Blood

135

153

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Key Points• Arginase depletion with BCT-100 pegylated recombinant human arginase is cytotoxic to AML blasts.Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML. (Blood. 2015;125(15):2386-2396

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Bct-100 Reduces the Number Of Aml Blasts In Vitro And In Vivomentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Mussai

Egan

Higginbotham-Jones

et al. 2015

Blood

135

153

View full text Add to dashboard Cite

show abstract

“…These tumors require extracellular Arg in the circulation for survival [1–3]. Arg-starvation therapy using Arg-degrading recombinant proteins, such as pegylated arginine deiminase (ADI-PEG20) which digests Arg into citrulline and ammonia [4] or human arginase 1 which digests Arg into ornithine and urea [5], have been in various stages of clinical evaluations for targeting Arg-auxotrophic tumors [3]. …”

Section: Introductionmentioning

confidence: 99%

Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1α, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation

et al. 2016

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Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza-deoxycytidine (Aza-dC) can induce ASS1 expression. Moreover, it was reported that cisplatin suppresses ASS1 expression through ASS1 promoter methylation, leading to synthetic lethality to ADI-PEG20 treatment. We report here that cisplatin supppresses ASS1 expression is due to upregulation of HIF-1α and downregulation of c-Myc, which function as negative and positive regulators of ASS1 expression, respectively, by reciprocal bindings to the ASS1 promoter. In contrast, we found that Aza-dC induces ASS1 expression by downregulation of HIF-1α but upregulation of c-Myc. We further demonstrated that the clock protein DEC1 is the master regulator of HIF-1α and c-Myc that regulate ASS1. cDDP upregulates DEC1, whereas Aza-dC suppresses its expression. Using two proteasomal inhibitors bortezomib and carfilzomib which induce HIF-1α accumulation, we further demonstrated that HIF-1α is involved in ASS1 silencing for the maintenance of Arg auxotrophy for targeted Arg-starvation therapy.

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

Santo

Booth

Vardon

et al. 2017

Intl Journal of Cancer

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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.

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Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma

Cited by 74 publications

References 28 publications

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1α, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation

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

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