Argininosuccinate synthetase (ASS) deficiency in high-grade pulmonary neuroendocrine carcinoma: an opportunity for personalized targeted therapy.

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.

• Authors: Ann E Walts, John S Bomalaski, Delma Ines, Sandra Orsulic
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 141 Issue 8 Pg. 1363-9 (Aug 2015) ISSN: 1432-1335 [Electronic] Germany
• PMID: 25548129 (Publication Type: Journal Article)

Chemical References

• Polyethylene Glycols
• Hydrolases
• ADI PEG20
• Argininosuccinate Synthase

Topics

• Aged
• Aged, 80 and over
• Argininosuccinate Synthase (deficiency)
• Carcinoma, Neuroendocrine (enzymology, pathology, therapy)
• Female
• Humans
• Hydrolases (therapeutic use)
• Immunohistochemistry
• Lung Neoplasms (enzymology, pathology, therapy)
• Male
• Middle Aged
• Molecular Targeted Therapy (methods)
• Neoplasm Grading
• Patient Selection
• Polyethylene Glycols (therapeutic use)
• Precision Medicine (methods)
• Small Cell Lung Carcinoma (epidemiology, metabolism, pathology, therapy)