Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program

Richard Gorlick, E. Anders Kolb, Peter J. Houghton, Christopher L. Morton, Doris Phelps, Paula Schaiquevich, Clinton Stewart, Stephen T. Keir, Richard Lock, Hernan Carol, C. Patrick Reynolds, John M. Maris, Jianrong Wu, Malcolm A. Smith

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background. Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer. Methods. Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 μM. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/day). Lapatinib pharmacokinetic parameters were determined in scid-/- mice. Results. The median IC50 value for lapatinib against the entire PPTP cell line panel was 6.84 μM (range, 2.08 to >10.0 μM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5% of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values. Conclusions. Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets.

Original languageEnglish (US)
Pages (from-to)594-598
Number of pages5
JournalPediatric Blood and Cancer
Volume53
Issue number4
DOIs
StatePublished - Oct 2009

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Pediatrics
Heterografts
Cell Line
lapatinib
Neoplasms
Protein-Tyrosine Kinases
Inhibitory Concentration 50
Oral Administration
Appointments and Schedules
Pharmacokinetics
Breast Neoplasms
N-propyl-4-phenyl-1,2,3,6-tetrahydropyridine
In Vitro Techniques

Keywords

  • Developmental therapeutics
  • Lapatinib
  • Preclinical testing

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Medicine(all)

Cite this

Gorlick, R., Kolb, E. A., Houghton, P. J., Morton, C. L., Phelps, D., Schaiquevich, P., ... Smith, M. A. (2009). Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program. Pediatric Blood and Cancer, 53(4), 594-598. https://doi.org/10.1002/pbc.21989

Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program. / Gorlick, Richard; Kolb, E. Anders; Houghton, Peter J.; Morton, Christopher L.; Phelps, Doris; Schaiquevich, Paula; Stewart, Clinton; Keir, Stephen T.; Lock, Richard; Carol, Hernan; Reynolds, C. Patrick; Maris, John M.; Wu, Jianrong; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 53, No. 4, 10.2009, p. 594-598.

Research output: Contribution to journalArticle

Gorlick, R, Kolb, EA, Houghton, PJ, Morton, CL, Phelps, D, Schaiquevich, P, Stewart, C, Keir, ST, Lock, R, Carol, H, Reynolds, CP, Maris, JM, Wu, J & Smith, MA 2009, 'Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 53, no. 4, pp. 594-598. https://doi.org/10.1002/pbc.21989
Gorlick R, Kolb EA, Houghton PJ, Morton CL, Phelps D, Schaiquevich P et al. Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program. Pediatric Blood and Cancer. 2009 Oct;53(4):594-598. https://doi.org/10.1002/pbc.21989
Gorlick, Richard ; Kolb, E. Anders ; Houghton, Peter J. ; Morton, Christopher L. ; Phelps, Doris ; Schaiquevich, Paula ; Stewart, Clinton ; Keir, Stephen T. ; Lock, Richard ; Carol, Hernan ; Reynolds, C. Patrick ; Maris, John M. ; Wu, Jianrong ; Smith, Malcolm A. / Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2009 ; Vol. 53, No. 4. pp. 594-598.
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abstract = "Background. Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer. Methods. Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 μM. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/day). Lapatinib pharmacokinetic parameters were determined in scid-/- mice. Results. The median IC50 value for lapatinib against the entire PPTP cell line panel was 6.84 μM (range, 2.08 to >10.0 μM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5{\%} of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values. Conclusions. Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets.",
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AU - Kolb, E. Anders

AU - Houghton, Peter J.

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AU - Phelps, Doris

AU - Schaiquevich, Paula

AU - Stewart, Clinton

AU - Keir, Stephen T.

AU - Lock, Richard

AU - Carol, Hernan

AU - Reynolds, C. Patrick

AU - Maris, John M.

AU - Wu, Jianrong

AU - Smith, Malcolm A.

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N2 - Background. Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer. Methods. Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 μM. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/day). Lapatinib pharmacokinetic parameters were determined in scid-/- mice. Results. The median IC50 value for lapatinib against the entire PPTP cell line panel was 6.84 μM (range, 2.08 to >10.0 μM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5% of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values. Conclusions. Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets.

AB - Background. Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer. Methods. Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 μM. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/day). Lapatinib pharmacokinetic parameters were determined in scid-/- mice. Results. The median IC50 value for lapatinib against the entire PPTP cell line panel was 6.84 μM (range, 2.08 to >10.0 μM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5% of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values. Conclusions. Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets.

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