Lenvatinib inhibits the growth of gastric cancer patient-derived xenografts generated from a heterogeneous population

• Published in: Journal of translational medicine Vol. 20; no. 1; pp. 116 - 13
• Main Authors: Karalis, John D, Yoon, Lynn Y, Hammer, Suntrea T G, Hong, Changjin, Zhu, Min, Nassour, Ibrahim, Ju, Michelle R, Xiao, Shu, Castro-Dubon, Esther C, Agrawal, Deepak, Suarez, Jorge, Reznik, Scott I, Mansour, John C, Polanco, Patricio M, Yopp, Adam C, Zeh, 3rd, Herbert J, Hwang, Tae Hyun, Zhu, Hao, Porembka, Matthew R, Wang, Sam C
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07-03-2022; BioMed Central; BMC
• Subjects: Animals; Care and treatment; Diagnosis; Gastric cancer; Heterografts; Humans; Lenvatinib; Mice; Mice, Inbred NOD; Mice, Nude; NSG mice; Nude mice; Patient-derived xenograft; PDX; Phenylurea Compounds; Quinolines; Stomach cancer; Stomach Neoplasms - drug therapy; Xenograft Model Antitumor Assays; Xenotransplantation; United States; Lenvatinib; NSG mice; Nude mice; PDX; Gastric cancer; Patient-derived xenograft
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-022-03317-7

Lenvatinib is a multitargeted tyrosine kinase inhibitor that is being tested in combination with immune checkpoint inhibitors to treat advanced gastric cancer; however, little data exists regarding the efficacy of lenvatinib monotherapy. Patient-derived xenografts (PDX) are established by engrafting human tumors into immunodeficient mice. The generation of PDXs may be hampered by growth of lymphomas. In this study, we compared the use of mice with different degrees of immunodeficiency to establish PDXs from a diverse cohort of Western gastric cancer patients. We then tested the efficacy of lenvatinib in this system.
PDXs were established by implanting gastric cancer tissue into NOD.Cg-Prkdc
Il2rg
/SzJ (NSG) or Foxn1
(nude) mice. Tumors from multiple passages from each PDX line were compared histologically and transcriptomically. PDX-bearing mice were randomized to receive the drug delivery vehicle or lenvatinib. After 21 days, the percent tumor volume change (%Δv
) was calculated.
23 PDX models were established from Black, non-Hispanic White, Hispanic, and Asian gastric cancer patients. The engraftment rate was 17% (23/139). Tumors implanted into NSG (16%; 18/115) and nude (21%; 5/24) mice had a similar engraftment rate. The rate of lymphoma formation in nude mice (0%; 0/24) was lower than in NSG mice (20%; 23/115; p < 0.05). PDXs derived using both strains maintained histologic and gene expression profiles across passages. Lenvatinib treatment (mean %Δv
: -33%) significantly reduced tumor growth as compared to vehicle treatment (mean %Δv
: 190%; p < 0.0001).
Nude mice are a superior platform than NSG mice for generating PDXs from gastric cancer patients. Lenvatinib showed promising antitumor activity in PDXs established from a diverse Western patient population and warrants further investigation in gastric cancer.