Bio-Cancer Treatment International Limited.

Arginine deprivation using arginase emerges as a potential cancer treatment approach, as some cancers have been found to be arginine-auxotrophic, relying on exogenous arginine for their growth. In this study, we evaluated the combination of a PEGylated recombinant human arginase (PEG-BCT-100), which is currently undergoing clinical trials, with a toxic arginine analog, canavanine, in pancreatic cancer. Remarkable synergistic antitumor effect was observed both in vitro and in vivo. Specifically, the combination treatment induced apoptotic cell death in pancreatic cancer cells, whereas normal fibroblast cells remained viable. Our findings also suggested that pancreatic tumors lacking the key enzymes in arginine biosynthesis, argininosuccinate synthetase 1 (ASS1) and ornithine transcarbamylase (OTC), were more susceptible to the treatment. From our in-house cohort and online database analysis, we found that the majority of the patients with pancreatic cancer exhibited deficiencies in both ASS1 and OTC enzymes, suggesting that the combination of arginine deprivation and canavanine could be particularly effective in these patients. The ASS1 and OTC negativity could also serve as predictive biomarkers for the response in other arginine-dependent cancers.

This study investigates the synergistic antitumor effect of PEG-BCT-100, an arginase, in clinical trials, with canavanine in pancreatic cancer, in vitro and in vivo. The treatment induces cancer cell apoptosis while sparing normal fibroblasts. Our findings suggest heightened susceptibility of pancreatic tumors deficient in arginine biosynthesis enzymes ASS1 and OTC.

To fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which can result in specific nutrient dependencies. Here, we perform an amino acid drop‐out screen and apply pre‐clinical models of chronic phase chronic myeloid leukaemia (CML) to identify arginine as a nutrient essential for primary human CML cells. Analysis of the Microarray Innovations in Leukaemia (MILE) dataset uncovers reduced ASS1 levels in CML compared to most other leukaemia types. Stable isotope tracing reveals repressed activity of all urea cycle enzymes in patient‐derived CML CD34+ cells, rendering them arginine auxotrophic. Thus, arginine deprivation completely blocks proliferation of CML CD34+ cells and induces significantly higher levels of apoptosis when compared to arginine‐deprived cell lines. Similarly, primary CML cells, but not normal CD34+ samples, are particularly sensitive to treatment with the arginine‐depleting enzyme, BCT‐100, which induces apoptosis and reduces clonogenicity. Moreover, BCT‐100 is highly efficacious in a patient‐derived xenograft model, causing > 90% reduction in the number of human leukaemic stem cells (LSCs). These findings indicate arginine depletion to be a promising and novel strategy to eradicate therapy resistant LSCs.

We investigated the safety and efficacy of a pegylated arginase (PEG-BCT-100) in combination with chemotherapy (oxaliplatin and capecitabine) [PACOX] in advanced HCC patients.

This was a single centre phase 1 trial to assess the safety and tolerability of PACOX. All the enrolled subjects received treatment in 3-weekly cycles: intravenous PEG-BCT-100 2.7 mg/kg on days 1, 8 and 15 of each cycle; oral capecitabine 1000 mg/m² twice daily on day 1-14 of each cycle and intravenous oxaliplatin on day 1. Three dose levels of oxaliplatin (85 mg/m², 100 mg/m² or 130 mg/m²) were studied to define the maximum tolerated dose (MTD). Adverse events (AEs), efficacy by RECIST v1.1, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were studied.

Seventeen patients were enrolled at 3 dose levels of oxaliplatin: 85 mg/m² (8 patients), 100 mg/m² (3 patients), and 130 mg/m² (6 patients). The median age was 55 years; all had had locoregional chemotherapy or targeted therapy such as sorafenib, but no systemic chemotherapy. The most common AEs were nausea (82%), injection site reaction (76%), palmar-plantar erythrodysesthesia (59%), oral mucositis (53%) and vomiting (53%). There was no dose-limiting toxicity (DLT). Median duration on study was 8 weeks overall. In 14 evaluable cases, one achieved partial response (PR), 4 had stable disease (SD); disease control rate was 36%; most responses were observed in the 130 mg/m² cohort with 1 PR and 2 SDs. Median TTP and PFS were both 7.0 weeks. Overall median OS was 10.7 months; the median OS was not reached at 19.4 months of follow-up in the 130 mg/m2 cohort.

The PACOX regimen demonstrated good anti-cancer activity and survival advantage in advanced pre-treated HCC with favourable safety profile. It warrants further phase II/III studies.