title: Cabozantinib inhibits tumor growth and metastasis of a patient-derived xenograft model of papillary renal cell carcinoma with MET mutation.
abstract: MET plays an important role in the development and progression of papillary renal cell carcinoma (pRCC). Evaluation of efficacy of MET inhibitors against pRCC has been hampered by limited preclinical models depicting MET abnormalities. We established a new patient-derived xenograft (PDX) model of pRCC carrying an activating mutation of MET and tested the ability of cabozantinib, an inhibitor of receptor tyrosine kinases including MET, to inhibit tumor growth and metastasis. Precision-cut, thin tissue slices from a pRCC specimen obtained by nephrectomy were implanted under the renal capsule of RAG2-/-γC-/-mice to establish first generation TSG-RCC-030. Histologic and genetic fidelity and metastatic potential of this model were characterized by immunohistochemistry, direct DNA sequencing and quantitative polymerase chain reaction (qPCR). The effect of cabozantinib on tumor growth and metastasis was evaluated. Whether measurements of circulating tumor DNA (ctDNA) by allele-specific qPCR could be used as a biomarker of tumor growth and response to therapy was determined. Subrenal and subcutaneous tumor grafts showed high take rates and metastasized to the lung. Both primary tumors and metastases expressed typical markers of pRCC and carried the same activating MET mutation as the parental tumor. Cabozantinib treatment caused striking tumor regression and inhibited lung metastasis in TSG-RCC-030. Plasma ctDNA levels correlated with tumor volume in control mice and changed in response to cabozantinib treatment. TSG-RCC-030 provides a realistic preclinical model to better understand the development and progression of pRCC with MET mutation and accelerate the development of new therapies for pRCC.
authors.affiliation: a Department of Urology , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: a Department of Urology , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Nolley
authors.affiliation: b Department of Radiation Oncology , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Andy M W
authors.initials: AMW
authors.lastname: Chan
authors.affiliation: b Department of Radiation Oncology , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Erinn B
authors.initials: EB
authors.lastname: Rankin
authors.affiliation: a Department of Urology , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
mesh_terms: D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; D020794:Receptor Protein-Tyrosine Kinases
keywords: Cabozantinib; Circulating tumor DNA; MET mutation; Papillary renal cell carcinoma; Patient-derived xenograft; Tissue slice graft; metastasis