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

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

doi:10.1002/ijc.31170

Cited by 52 publications

(48 citation statements)

References 44 publications

(96 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Growth of melanoma cell line xenografts was significantly inhibited [ 11 ]. Among other tumour types, BCT-100 has demonstrated preclinical activity, and clinical responses have been seen in two clinical trials in adults with advanced hepatocellular carcinoma (HCC) [ 9 , 10 , 12 ]. The patient experienced no drug limiting toxicity or immunogenicity even after more than 2 years of weekly treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Classically arginine depleting therapies such as pegylated arginine deiminase or BCT-100 are most effective when one or more of the enzymes have low or absent expression [ 8 , 13 ]. Interestingly, BCT-100 also has activity against tumours which express both ASS and OTC, unlike ADI-PEG, suggesting differences in their modes of action or other intracellular pathways are contributing to determine cell fate [ 7 , 9 , 10 , 12 ].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma

Santo

Cheng²,

Beggs

et al. 2018

J Hematol Oncol

Self Cite

View full text Add to dashboard Cite

BackgroundMetastatic melanoma is an aggressive skin cancer with a poor prognosis. Current treatment strategies for high-stage melanoma are based around the use of immunotherapy with immune checkpoint inhibitors such as anti-PDL1 or anti-CTLA4 antibodies to stimulate anti-cancer T cell responses, yet a number of patients will relapse and die of disease. Here, we report the first sustained complete remission in a patient with metastatic melanoma who failed two immunotherapy strategies, by targeting tumour arginine metabolism.Case presentationA 65-year-old patient with metastatic melanoma who progressed through two immunotherapy strategies with immune checkpoint inhibitor antibodies was enrolled in a phase I study (NCT02285101) and treated with 2 mg/kg intravenously, weekly pegylated recombinant arginase (BCT-100). The patient experienced no toxicities > grade 2 and entered a complete remission which is sustained for over 30 months. RNA-sequencing identified a number of transcriptomic pathway alterations compared to control samples. The tumour had absent expression of the recycling enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC) indicating a state of arginine auxotrophy, which was reconfirmed by immunohistochemistry, and validation in a larger cohort of melanoma tumour samples.ConclusionsTargeting arginine metabolism with therapeutic arginase in arginine auxotrophic melanoma can be an effective salvage for the treatment of patients who fail immunotherapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma

Santo

Cheng²,

Beggs

et al. 2018

J Hematol Oncol

Self Cite

View full text Add to dashboard Cite

show abstract

“…), it is important to note the age‐associated increase in bone marrow adipocytes, which can influence oncogenesis through chemokine signaling, as well providing fatty acid substrates for FAO, a key metabolic adaptation observed in some leukemic cells and discussed earlier in this review. Additional niche metabolites can also contribute to HSC and cancer cell behavior, with studies looking at the levels of arginine and asparagine on leukemic cell response. Valine has also been recently revealed as an important effector of the bone marrow microenvironment, although more work will be required to elucidate implications for oncogenesis.…”

Section: Conclusion—tumor Microenvironmentmentioning

confidence: 99%

Metabolic underpinnings of leukemia pathology and treatment

2018

View full text Add to dashboard Cite

Background Carcinogenic transformation of white blood cells during hematopoiesis leads to the development of leukemia, a cancer characterized by incompetent immune cells and a disruption of normal bone marrow function. Leukemias are diverse in type, affected population, prognosis, and treatment regimen, yet a common theme in leukemia is the dysregulated metabolism of leukemic cells and leukemic stem cells with respect to their noncancerous counterparts. Recent findings In this review, we highlight current findings that elucidate metabolic traits unique to the four major types of leukemia, which confer carcinogenic survival but can be potentially exploited for therapeutic intervention. These metabolic features can work in conjunction with or be independent of unique aspects of the bone marrow microenvironment that can also influence cell survival and proliferation, thus sustaining carcinogenesis. Conclusion Deepening our understanding of the interactions of leukemias with their niche environments in vivo will inform future treatments for leukemia, particularly for those that are refractive to tyrosine kinase inhibitors and other therapeutic mainstays.

show abstract

“…In-depth research into various aspects on tumor metabolism reveals metabolic therapy might be a promising option for cancer treatment (11). It has been demonstrated that certain cancer cells (arginine auxotrophy) cannot synthesize arginine independently and are reliant on extracellular arginine for growth (12,13). Therefore, arginine deprivation might be an Achilles' Heel for arginine auxotrophic cancers, including hepatic cell carcinoma, prostate cancer, melanoma, small cell lung cancer and leukemia (12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

“…Consistent with endogenous arginase, BCT-100 catalyzes arginine to ornithine and urea, leading to arginine depletion (19). It has been demonstrated that BCT-100 showed signi cant anticancer effects against several arginine auxotrophic cancers and completed clinical trials on HCC with promising outcomes (12,13,20). Few studies have emphasized the role of BCT-100 on bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

Pegylated recombinant human arginase 1 induces autophagy and apoptosis via the ROS-activated AKT/mTOR pathway in bladder cancer cells

Zhao¹,

Zhang

Li³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Bladder cancer is one of the dominant cancers worldwide, especially for male. Currently, the therapeutical regimen of bladder cancer is based on surgery, radiation therapy, chemotherapy and immunotherapy, but the clinical outcome is still needed to improve. Recombinant human arginase (rhArg, BCT-100) is a novel agent to show great anticancer effect on arginine auxotrophic tumor. However, the effect of rhArg on bladder cancer still remains unclear. Methods A panel of six bladder cancer cell lines (BIU-87, EJ-1, J82, SCaBER, T24 and 5637) was employed to assess the anticancer effect of BCT-100 in vitro by MTT assay. T24 nude mice xenograft models were established to evaluate the anticancer effect of BCT-100 in vivo. Protein level (argininosuccinate synthetase 1 (ASS1), ornithine transcarbamylase, cleaved-PARP, PEG, Survivin, p62, Beclin-1, LC3B, p-AKT, p-mTOR) was detected by Western blot. Intracellular, serum and intratumoral arginine concentrations were examined by ELISA. Apoptotic rate, H2O2 and mitochondrial membrane depolarization were tested by flow cytometer. Immunoflorescence on ki67 and TUNEL assay were applied to identify cellular and tumoral apoptotic events. Results BCT-100 displayed anticancer effects on bladder cancer cells in vitro and in vivo. The expression of ASS1 varies in different bladder cancer cell lines, and ornithine transcarbamylase is almost deficient except weakly expressed in SCaBER cell line. Knockdown ASS1 in BIU-87 cells could enhance the cytotoxicity induced by BCT-100. Intracellular arginine level was sharply decreased followed by apoptotic events. Futhermore, BCT-100 induced H2O2 production and mitochondrial membrane depolarization, leading to cytochrome c and smac released from mitochondria to cytosol. The expression of LC3B and Becllin-1 was up-regulated, while p62 was down-regulated in a time dependent manner. Autophagic flux was also observed upon BCT-100 treatment. Besides, the phosphorylation of AKT/mTOR pathway was suppressed in a time dependent fashion in BCT-100-treated T24 cells. N-Acetyl-L-cystein reduced the apoptosis and autophagy induced by BCT-100, while CQ, MK-2206 and rapamycin potentiated the apoptosis triggered by BCT-100. Conclusions The present study demonstrated that BCT-100 induced autophagy and apoptosis via ROS mediated AKT/mTOR signaling pathway in bladder cancer cells.

show abstract

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

Cited by 52 publications

References 44 publications

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma

Metabolic underpinnings of leukemia pathology and treatment

Pegylated recombinant human arginase 1 induces autophagy and apoptosis via the ROS-activated AKT/mTOR pathway in bladder cancer cells

Contact Info

Product

Resources

About