Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model

• DOI: 10.18632/oncotarget.15823
• Publication Date: 2017-03-04T19:26:05Z
• Authors: Takashi Murakami; Shukuan Li; Qinghong Han; Yuying Tan; Tasuku Kiyuna; Kentaro Igarashi; Kei Kawaguchi; Ho Kyoung Hwang; Kentaro Miyake; Arun S. Singh; Scott D. Nelson; Sarah M. Dry; Yunfeng Li; Yukihiko Hiroshima; Thinzar M. Lwin; Jonathan C. DeLong; Takashi Chishima; Kuniya Tanaka; Michael Bouvet; Itaru Endo; Fritz C. Eilber; Robert M. Hoffman
• Keywords: Male; Pediatric Research Initiative; Antimetabolites, Antineoplastic; Antimetabolites; Pediatric Cancer; Biopsy; Nude; Oncology and Carcinogenesis; 610; Mice, Nude; Sarcoma, Ewing; Mice; 03 medical and health sciences; Rare Diseases; 0302 clinical medicine; Ewing; Animals; Humans; patient-derived orthotopic xenograft; Cancer; methionine dependence; Pediatric; Animal; Sarcoma; recombinant methioninase; Ewing's sarcoma; Antineoplastic; Immunohistochemistry; Xenograft Model Antitumor Assays; nude mice; Recombinant Proteins; Brain Disorders; Tumor Burden; 3. Good health; Carbon-Sulfur Lyases; Disease Models, Animal; Disease Models; Ewing’s sarcoma; recalcitrant cancer; Biotechnology; Research Paper

Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma.