2. Academic Validation
  3. Lenvatinib inhibits the growth of gastric cancer patient-derived xenografts generated from a heterogeneous population

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

  • J Transl Med. 2022 Mar 7;20(1):116. doi: 10.1186/s12967-022-03317-7.
John D Karalis  # 1 2,  Lynn Y Yoon  # 1 2,  Suntrea T G Hammer 3,  Changjin Hong 4,  Min Zhu 2,  Ibrahim Nassour 5,  Michelle R Ju 1,  Shu Xiao 2,  Esther C Castro-Dubon 1 2,  Deepak Agrawal 6,  Jorge Suarez 7,  Scott I Reznik 8,  John C Mansour 1,  Patricio M Polanco 1,  Adam C Yopp 1,  Herbert J Zeh 3rd 1,  Tae Hyun Hwang 4,  Hao Zhu 2,  Matthew R Porembka  # 1,  Sam C Wang  # 9 10 11
Affiliations

Affiliations

  • 1 Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2 Children's Research Institute, Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 4 Department of Artificial Intelligence and Informatics, Department of Immunology, Mayo Clinic, Jacksonville, FL, USA.
  • 5 Department of Surgery, University of Florida, Gainesville, FL, USA.
  • 6 Department of Internal Medicine, University of Texas at Austin, Austin, TX, USA.
  • 7 Department of Gastroenterology and Hepatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 8 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 9 Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA. sam.wang@utsouthwestern.edu.
  • 10 Children's Research Institute, Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. sam.wang@utsouthwestern.edu.
  • 11 Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA. sam.wang@utsouthwestern.edu.
  • # Contributed equally.
PMID: 35255940 DOI: 10.1186/s12967-022-03317-7
Abstract

Background: 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.

Methods: PDXs were established by implanting gastric Cancer tissue into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) or Foxn1nu (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 (%Δvtumor) was calculated.

Results: 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 %Δvtumor: -33%) significantly reduced tumor growth as compared to vehicle treatment (mean %Δvtumor: 190%; p < 0.0001).

Conclusions: 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.

Keywords

Gastric cancer; Lenvatinib; NSG mice; Nude mice; PDX; Patient-derived xenograft.

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