Ann E Walts1, John S Bomalaski, Delma Ines, Sandra Orsulic. 1. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA, walts@cshs.org.
Abstract
PURPOSE: Cells deficient in argininosuccinate synthetase (ASS) must absorb the arginine they need for growth from circulating blood. Treatment with pegylated arginine deiminase (ADI-PEG 20) selectively eliminates arginine from the circulation and has shown some efficacy against ASS-deficient tumors including small cell lung cancer (SCLC). We sought to assess ASS expression in a cohort of high-grade pulmonary neuroendocrine carcinomas (PNEC) which include SCLC and large cell neuroendocrine carcinoma (LCNEC). METHODS: Sixty-nine PNEC (49 SCLC and 20 LCNEC) were retrieved from our pathology archives. Formalin-fixed paraffin-embedded sections of the 54 primary tumors, 15 metastases and appropriate positive and negative controls were immunostained using an ASS-specific monoclonal antibody. Positive staining in <30 % of the tumor was scored as weak; staining in ≥30 % of the tumor was scored as strong. The absence of staining in the tumor was recorded as ASS negative. RESULTS: 58 % of the PNEC including 61.2 % of the SCLC and 50 % of the LCNEC were ASS negative. These ASS-negative tumors included 63 % of the primary and 40 % of the metastatic lesions tested. CONCLUSIONS: More than 50 % of the high-grade PNEC tested lack immunohistochemically detectable ASS, suggesting that they are auxotrophic for arginine and potential candidates for arginine deprivation therapy. PNEC comprise about 25 % of primary lung cancers and have a 5-year overall survival of only 5-10 %, underscoring the need for new and more effective therapies. Immunostaining for ASS has potential to improve the selection of patients with PNEC for arginine deprivation therapy with ADI-PEG 20.
PURPOSE: Cells deficient in argininosuccinate synthetase (ASS) must absorb the arginine they need for growth from circulating blood. Treatment with pegylated arginine deiminase (ADI-PEG 20) selectively eliminates arginine from the circulation and has shown some efficacy against ASS-deficient tumors including small cell lung cancer (SCLC). We sought to assess ASS expression in a cohort of high-grade pulmonary neuroendocrine carcinomas (PNEC) which include SCLC and large cell neuroendocrine carcinoma (LCNEC). METHODS: Sixty-nine PNEC (49 SCLC and 20 LCNEC) were retrieved from our pathology archives. Formalin-fixed paraffin-embedded sections of the 54 primary tumors, 15 metastases and appropriate positive and negative controls were immunostained using an ASS-specific monoclonal antibody. Positive staining in <30 % of the tumor was scored as weak; staining in ≥30 % of the tumor was scored as strong. The absence of staining in the tumor was recorded as ASS negative. RESULTS: 58 % of the PNEC including 61.2 % of the SCLC and 50 % of the LCNEC were ASS negative. These ASS-negative tumors included 63 % of the primary and 40 % of the metastatic lesions tested. CONCLUSIONS: More than 50 % of the high-grade PNEC tested lack immunohistochemically detectable ASS, suggesting that they are auxotrophic for arginine and potential candidates for arginine deprivation therapy. PNEC comprise about 25 % of primary lung cancers and have a 5-year overall survival of only 5-10 %, underscoring the need for new and more effective therapies. Immunostaining for ASS has potential to improve the selection of patients with PNEC for arginine deprivation therapy with ADI-PEG 20.
Authors: Paolo A Ascierto; Stefania Scala; Giuseppe Castello; Antonio Daponte; Ester Simeone; Alessandro Ottaiano; Gerardo Beneduce; Vincenzo De Rosa; Francesco Izzo; Maria Teresa Melucci; C Mark Ensor; Archie W Prestayko; Frederick W Holtsberg; John S Bomalaski; Mike A Clark; Niramol Savaraj; Lynn G Feun; Theodore F Logan Journal: J Clin Oncol Date: 2005-10-20 Impact factor: 44.544
Authors: Fuming Qiu; Yun-Ru Chen; Xiyong Liu; Cheng-Ying Chu; Li-Jiuan Shen; Jinghong Xu; Shikha Gaur; Henry Jay Forman; Hang Zhang; Shu Zheng; Yun Yen; Jian Huang; Hsing-Jien Kung; David K Ann Journal: Sci Signal Date: 2014-04-01 Impact factor: 8.192
Authors: Peter W Szlosarek; Astero Klabatsa; Arben Pallaska; Michael Sheaff; Paul Smith; Tim Crook; Matthew J Grimshaw; Jeremy P Steele; Robin M Rudd; Frances R Balkwill; Dean A Fennell Journal: Clin Cancer Res Date: 2006-12-01 Impact factor: 12.531
Authors: Michael D Allen; Phuong Luong; Chantelle Hudson; Julius Leyton; Barbara Delage; Essam Ghazaly; Rosalind Cutts; Ming Yuan; Nelofer Syed; Cristiana Lo Nigro; Laura Lattanzio; Malgorzata Chmielewska-Kassassir; Ian Tomlinson; Rebecca Roylance; Hayley C Whitaker; Anne Y Warren; David Neal; Christian Frezza; Luis Beltran; Louise J Jones; Claude Chelala; Bor-Wen Wu; John S Bomalaski; Robert C Jackson; Yong-Jie Lu; Tim Crook; Nicholas R Lemoine; Stephen Mather; Julie Foster; Jane Sosabowski; Norbert Avril; Chien-Feng Li; Peter W Szlosarek Journal: Cancer Res Date: 2013-11-27 Impact factor: 12.701
Authors: Mahmoud A Mohammad; Inka C Didelija; Barbara Stoll; Trung C Nguyen; Juan C Marini Journal: Am J Physiol Endocrinol Metab Date: 2021-01-11 Impact factor: 4.310
Authors: Yang Yuan; Mahmoud A Mohammad; Ancizar Betancourt; Inka C Didelija; Chandrasekar Yallampalli; Juan C Marini Journal: J Nutr Date: 2018-06-01 Impact factor: 4.798