Initial Testing of VS-4718, a Novel Inhibitor of Focal Adhesion Kinase (FAK), Against Pediatric Tumor Models by the Pediatric Preclinical Testing Program

Overview

Journal Pediatr Blood Cancer

Specialties Hematology
Oncology
Pediatrics

Date 2016 Oct 28

PMID 27786412

Citations 11

Authors

Raushan T Kurmasheva

Richard Gorlick

E Anders Kolb

Stephen T Keir

John M Maris

Richard B Lock

Hernan Carol

Min Kang

C Patrick Reynolds

Jianrong Wu

Peter J Houghton

Malcolm A Smith

Affiliations

Soon will be listed here.

Abstract

VS-4718, a novel inhibitor of focal adhesion kinase (FAK), was tested against the Pediatric Preclinical Testing Program's (PPTP's) in vitro cell line panel and showed a median relative IC of 1.22 μM. VS-4718 was tested in vivo against the PPTP xenograft models using a dose of 50 mg/kg administered by the oral route twice daily for 21 days. VS-4718 induced significant differences in an event-free survival distribution compared with control in 18 of 36 of the evaluable solid tumor xenografts and in 0 of 8 acute lymphoblastic leukemia (ALL) xenografts, but no xenograft lines showed tumor regression. Future plans include further evaluation of the role of FAK inhibition in combination with ABL kinase inhibitors for Ph ALL.

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References

Frgala T, Kalous O, Proffitt R, Reynolds C . A fluorescence microplate cytotoxicity assay with a 4-log dynamic range that identifies synergistic drug combinations. Mol Cancer Ther. 2007; 6(3):886-97. DOI: 10.1158/1535-7163.MCT-04-0331. View

Kang M, Smith M, Morton C, Keshelava N, Houghton P, Reynolds C . National Cancer Institute pediatric preclinical testing program: model description for in vitro cytotoxicity testing. Pediatr Blood Cancer. 2010; 56(2):239-49. PMC: 3005554. DOI: 10.1002/pbc.22801. View

Lee B, Timpson P, Horvath L, Daly R . FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther. 2014; 146:132-49. DOI: 10.1016/j.pharmthera.2014.10.001. View

Tanjoni I, Walsh C, Uryu S, Tomar A, Nam J, Mielgo A . PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer Biol Ther. 2010; 9(10):764-77. PMC: 2933317. DOI: 10.4161/cbt.9.10.11434. View

Joshi I, Yoshida T, Jena N, Qi X, Zhang J, Van Etten R . Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia. Nat Immunol. 2014; 15(3):294-304. PMC: 4494688. DOI: 10.1038/ni.2821. View

Shapiro I, Kolev V, Vidal C, Kadariya Y, Ring J, Wright Q . Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med. 2014; 6(237):237ra68. PMC: 4165339. DOI: 10.1126/scitranslmed.3008639. View

Schaller M, Borgman C, Cobb B, Vines R, Reynolds A, Parsons J . pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci U S A. 1992; 89(11):5192-6. PMC: 49256. DOI: 10.1073/pnas.89.11.5192. View

Mullighan C, Miller C, Radtke I, Phillips L, Dalton J, Ma J . BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008; 453(7191):110-4. DOI: 10.1038/nature06866. View

Hanks S, Calalb M, Harper M, Patel S . Focal adhesion protein-tyrosine kinase phosphorylated in response to cell attachment to fibronectin. Proc Natl Acad Sci U S A. 1992; 89(18):8487-91. PMC: 49945. DOI: 10.1073/pnas.89.18.8487. View

10.

Kanner S, Reynolds A, Vines R, Parsons J . Monoclonal antibodies to individual tyrosine-phosphorylated protein substrates of oncogene-encoded tyrosine kinases. Proc Natl Acad Sci U S A. 1990; 87(9):3328-32. PMC: 53893. DOI: 10.1073/pnas.87.9.3328. View

11.

Houghton P, Morton C, Tucker C, Payne D, Favours E, Cole C . The pediatric preclinical testing program: description of models and early testing results. Pediatr Blood Cancer. 2006; 49(7):928-40. DOI: 10.1002/pbc.21078. View

12.

Parsons J . Focal adhesion kinase: the first ten years. J Cell Sci. 2003; 116(Pt 8):1409-16. DOI: 10.1242/jcs.00373. View

13.

Churchman M, Evans K, Richmond J, Robbins A, Jones L, Shapiro I . Synergism of FAK and tyrosine kinase inhibition in Ph B-ALL. JCI Insight. 2016; 1(4). PMC: 4844070. DOI: 10.1172/jci.insight.86082. View

14.

Liem N, Papa R, Milross C, Schmid M, Tajbakhsh M, Choi S . Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies. Blood. 2004; 103(10):3905-14. DOI: 10.1182/blood-2003-08-2911. View