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Sze Kwan Lam
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-058 - Endogenous Arginase 2 as a Biomarker for PEGylated Arginase 1 Treatment in Squamous Cell Lung Carcinoma Xenograft Models (ID 8888)
09:30 - 16:00 | Presenting Author(s): Sze Kwan Lam
- Abstract
Background:
Arginine depletion induced by PEGylated arginase 1 (BCT-100, PEG-BCT-100 or rhArg1peg5000) has shown promising anticancer effects among arginine auxotrophic cancers that are deficient in argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC). High endogenous arginase 2 (ARG2) was previously found in human lung cancers. Although high ARG2 does not induce immunosuppression nor affect disease progression, it may potentially affect the efficacy of PEGylated arginase 1 treatment. ARG2 was highly expressed in H520 squamous cell lung carcinoma (lung SCC) xenograft while undetectable in SK-MES-1 lung SCC xenograft. We postulated that high endogenous ARG2 expression might hamper anticancer effect of PEGylated arginase 1 in lung SCC.
Method:
The in vivo effect of PEGylated arginase 1 was studied using 2 lung SCC xenograft models (SK-MES-1 and H520). Protein expression, arginine concentration and apoptosis were investigated by Western blot, ELISA and TUNEL assay respectively.
Result:
PEGylated arginase 1 (60 mg/kg) suppressed tumor growth in SK-MES-1 but not in H520 xenograft. ASS1 was highly expressed in SK-MES-1 xenograft while expression of OTC remained low in both xenografts. Serum arginine level was decreased significantly by PEGylated arginase 1 in both xenograft models. On the other hand, intratumoral arginine level was reduced by PEGylated arginase 1 treatment in SK-MES-1 xenograft only. In H520 xenograft, intratumoral arginine level in control arm was already very low which could not be further lowered in PEGylated arginase 1 treatment arms. G1 arrest was indirectly evidenced by downregulation of cyclin A2, B1, D3, E1 and CDK4 with PEGylated arginase 1 in SK-MES-1 xenograft only. Moreover, suppression of proliferation factor Ki67 and activation of apoptosis were induced by PEGylated arginase 1 in SK-MES-1 xenograft only.
Conclusion:
PEGylated arginase 1 treatment was effective in lung SCC xenograft with low endogenous ARG2 expression. High endogenous ARG2 level may explain low intratumoral arginine level in lung SCC xenograft. ARG2 may serve as an additional predictive biomarker, other than ASS1 and OTC, in PEGylated arginase 1 treatment in lung SCC. Acknowledgment: This research was supported by Hong Kong Anti-Cancer Society, HKSAR.
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-006 - The Effects of Pegylated Arginase on Small Cell Lung Cancer in vitro and in vivo (ID 8883)
09:30 - 16:00 | Author(s): Sze Kwan Lam
- Abstract
Background:
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer cases. SCLC is characterized by frequent relapse, and current treatments lack tumor specificity. Arginase is an important enzyme in human, but it is deficient in some tumors. Arginine deprivation has become a potential therapeutic option in selected tumors. BCT-100 is a pegylated arginase which has demonstrated anticancer activity in arginine auxotrophic tumors, such as melanoma, hepatocellular carcinoma and acute myeloid leukemia. One of resistance mechanisms to arginase is overexpression of argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC). The aim of this study is to determine the effects of BCT-100 on SCLC in vitro and in vivo.
Method:
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell viability of different SCLC cell lines after BCT-100 treatment. Western blotting was employed to evaluate the protein expression. Knockdown of OTC was performed using specific siRNA. Xenograft models were established in nude mice for testing the anticancer effect of BCT-100.
Result:
The IC~50~ values of BCT-100 in H69, DMS79, H187, H209, H446, H510A, H526, H841 and SW1271 cells were 462.9±112.2, >1000, 24.9±6.4, 8.6±0.8, 18.0±0.7, 18.2±4.0, 10.1±0.7, >1000 and 49.2±7.4 mU/mL respectively. Knockdown of OTC increased sensitivity to BCT-100 in H841 cells, partially mediated via apoptosis. Mitochondrial membrane depolarization was observed in BCT-100 treatment and cytochrome c and SMAC were released from mitochondria to cytosol. N-acetylcysteine (NAC), the reactive oxygen species (ROS) scavenger, could reverse the apoptosis induced by BCT-100 significantly. Besides, cell cycle specific proteins, cyclin A2, cyclin B1 and CDK4, were downregulated in a time-dependent manner. The tumor growth was inhibited and median survival of mice was prolonged in BCT-100 group in H446 and H510A xenograft models. Serum and intratumoral arginine level was sharply decreased, associated with G1 arrest and apoptosis in H446 and H510A xenografts.
Conclusion:
The SCLC cell lines with low expression of ASS1 and OTC were susceptible to BCT-100 treatment. ROS was involved in BCT-100 induced-apoptosis. BCT-100 showed potential anticancer activity in SCLC xenograft models.
