Metabolic response to pegylated arginine deiminase in mesothelioma with promoter methylation of argininosuccinate synthetase

Our plain-English summary of Metabolic response to pegylated arginine deiminase in mesothelioma with promoter methylation of argininosuccinate synthetase, by P.W. Szlosarek, P. Luong, M.M. Phillips, et al (Journal of Clinical Oncology, 2013).

The study

• Authors: P.W. Szlosarek, P. Luong, M.M. Phillips, M. Baccarini, E. Stephen, T. Szyszko, M.T. Sheaff, N. Avril
• Journal: Journal of Clinical Oncology
• Published: 2013;31(7):e111-3
• Type of article: Case report
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Summary of the article

This case report described a patient with malignant pleural mesothelioma treated with the arginine-depleting enzyme pegylated arginine deiminase (ADI-PEG20). A 57-year-old man with previous asbestos exposure in the power-plant industry was diagnosed with epithelioid malignant mesothelioma in June 2010 after breathlessness and a left-sided pleural effusion. His disease progressed after three cycles of cisplatin and pemetrexed, and again after 2 months in a phase III trial of vorinostat versus placebo. In March 2011 he entered the ADAM trial, a randomized phase II study of ADI-PEG20 plus best supportive care versus best supportive care alone in mesothelioma lacking the enzyme argininosuccinate synthetase 1 (ASS1). Immunohistochemistry showed his tumor was ASS1-deficient, and methylation-specific polymerase chain reaction confirmed ASS1 promoter methylation. He was randomly assigned to 320 IU/m2/wk of ADI-PEG20 by intramuscular injection. After 3 doses, FDG-PET showed a partial metabolic response, with a 40% reduction in maximum standardized uptake value (5.5 to 3.5), while CT showed stable disease. Plasma arginine fell from 63 µmol/L at baseline to 2 µmol/L by the second week and returned to pretreatment levels by the fourth week, as anti-ADI-PEG20 antibody titers rose to a plateau. Symptoms remained stable for an additional 3 weeks, then breathlessness, chest-wall pain and subdiaphragmatic extension of disease developed. He died in August 2011, 14 months after diagnosis. The authors concluded that resistance was likely due to neutralizing antibodies, and that FDG-PET may provide a sensitive method for early evaluation of response to arginine deprivation in tumors with ASS1 methylation.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This was a case report about one patient. A 57-year-old man exposed to asbestos in the power-plant industry was diagnosed in June 2010 with epithelioid malignant mesothelioma, after breathlessness and a left-sided pleural effusion. His disease progressed after cisplatin and pemetrexed chemotherapy, and again after 2 months in a trial of vorinostat. In March 2011 he entered the ADAM trial. His tumor lacked the enzyme ASS1, a loss traced to methylation of the gene's promoter. He received weekly injections of the arginine-depleting drug ADI-PEG20. After three doses, a PET scan showed a partial metabolic response, with a 40% fall in tracer uptake (5.5 to 3.5). A CT scan showed stable disease. Blood arginine fell from 63 to 2 micromoles per liter by week two, then returned to pretreatment levels by week four. The authors said the brief stable period was consistent with resistance from neutralizing antibodies to the drug, which rose in his blood. Symptoms stayed stable for 3 more weeks, then worsened. He died in August 2011, 14 months after diagnosis. The authors suggested that FDG-PET may offer a sensitive early way to judge response to arginine deprivation in such tumors.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report (single patient treated within a randomized phase II trial)
• Who was studied: One 57-year-old man in London, United Kingdom, diagnosed in June 2010 with epithelioid malignant mesothelioma after breathlessness and a left-sided pleural effusion. The discussion calls his disease malignant pleural mesothelioma.
• Exposure: Previous asbestos exposure in the power-plant industry; no fiber type is given. The treatment studied was pegylated arginine deiminase (ADI-PEG20), 320 IU/m2 per week by intramuscular injection, given within the ADAM trial.
• Main results:
  • Before the ADAM trial, his disease progressed after three cycles of cisplatin and pemetrexed, and again after 2 months in the VANTAGE 014 trial (vorinostat versus placebo).
  • The tumor lacked ASS1 on immunohistochemistry. This was due to ASS1 promoter methylation, confirmed by methylation-specific PCR.
  • After 3 doses, FDG-PET showed a partial metabolic response, with a 40% reduction in maximum standardized uptake value (5.5 decreasing to 3.5). CT by modified RECIST showed stable disease.
  • Plasma arginine fell from a baseline of 63 micromoles per liter to 2 by the second week, then recovered to pretreatment levels by the fourth week.
  • The authors judged the brief period of stable disease consistent with the known resistance mechanism of antidrug neutralizing antibodies. In this patient the anti-ADI-PEG20 antibody titer rose to a plateau.
  • Symptoms were stable for an additional 3 weeks, then breathlessness and chest-wall pain increased, with disease spreading below the diaphragm on CT. The patient died in August 2011, 14 months after diagnosis.
• The authors' conclusion: The authors suggested that FDG-PET imaging may provide a sensitive method for early evaluation of response to L-arginine deprivation in tumors with ASS1 promoter methylation. They noted that such analyses are ongoing in the mesothelioma trial.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Pegargiminase (ADI-PEG20), Asbestos Exposure, Epithelioid, Pleural Effusion, Cisplatin, Pemetrexed (Alimta).

Related studies

• Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer — D.H. Kim, H.H. Nelson, et al. (2001)
• Aberrant methylation of the CDKN2a/p16INK4a gene promoter region in preinvasive bronchial lesions: a prospective study in high-risk patients without invasive cancer — A. Lamy, R. Sesboüé, et al. (2002)
• Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma — H. Kohno, V.J. Amatya, et al. (2010)
• Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP — L.S. Kristensen, H.M. Nielsen, et al. (2011)
• MGMT promoter methylation is a rare epigenetic change in malignant effusions — M. Brunetti, I. Panagopoulos, et al. (2020)
• Continued pemetrexed and platin-based chemotherapy in patients with malignant pleural mesothelioma (MPM): value of 18F-FDG-PET/CT — N.G. Schaefer, P. Veit-Haibach, et al. (2012)

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