Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

Julie E. Bauman, Umamaheswar Duvvuri, William E. Gooding, Tanya J. Rath, Neil D. Gross, John Song, Antonio Jimeno, Wendell G. Yarbrough, Faye M. Johnson, Lin Wang, Simion Chiosea, Malabika Sen, Jason Kass, Jonas T. Johnson, Robert L. Ferris, Seungwon Kim, Fred R. Hirsch, Kimberly Ellison, John T. Flaherty, Gordon MillsJennifer R. Grandis

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

Original languageEnglish (US)
Pages (from-to)e90449
JournalJCI insight
Volume2
Issue number6
DOIs
StatePublished - Mar 23 2017
Externally publishedYes

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Head and Neck Neoplasms
Placebos
Biomarkers
Neoplasms
Protein Array Analysis
National Cancer Institute (U.S.)
src-Family Kinases
Therapeutics
Dasatinib
Erlotinib Hydrochloride
Carcinoma, squamous cell of head and neck
Health
Research

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Bauman, J. E., Duvvuri, U., Gooding, W. E., Rath, T. J., Gross, N. D., Song, J., ... Grandis, J. R. (2017). Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer. JCI insight, 2(6), e90449. https://doi.org/10.1172/jci.insight.90449

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer. / Bauman, Julie E.; Duvvuri, Umamaheswar; Gooding, William E.; Rath, Tanya J.; Gross, Neil D.; Song, John; Jimeno, Antonio; Yarbrough, Wendell G.; Johnson, Faye M.; Wang, Lin; Chiosea, Simion; Sen, Malabika; Kass, Jason; Johnson, Jonas T.; Ferris, Robert L.; Kim, Seungwon; Hirsch, Fred R.; Ellison, Kimberly; Flaherty, John T.; Mills, Gordon; Grandis, Jennifer R.

In: JCI insight, Vol. 2, No. 6, 23.03.2017, p. e90449.

Research output: Contribution to journalArticle

Bauman, JE, Duvvuri, U, Gooding, WE, Rath, TJ, Gross, ND, Song, J, Jimeno, A, Yarbrough, WG, Johnson, FM, Wang, L, Chiosea, S, Sen, M, Kass, J, Johnson, JT, Ferris, RL, Kim, S, Hirsch, FR, Ellison, K, Flaherty, JT, Mills, G & Grandis, JR 2017, 'Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer', JCI insight, vol. 2, no. 6, pp. e90449. https://doi.org/10.1172/jci.insight.90449
Bauman, Julie E. ; Duvvuri, Umamaheswar ; Gooding, William E. ; Rath, Tanya J. ; Gross, Neil D. ; Song, John ; Jimeno, Antonio ; Yarbrough, Wendell G. ; Johnson, Faye M. ; Wang, Lin ; Chiosea, Simion ; Sen, Malabika ; Kass, Jason ; Johnson, Jonas T. ; Ferris, Robert L. ; Kim, Seungwon ; Hirsch, Fred R. ; Ellison, Kimberly ; Flaherty, John T. ; Mills, Gordon ; Grandis, Jennifer R. / Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer. In: JCI insight. 2017 ; Vol. 2, No. 6. pp. e90449.
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abstract = "BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.",
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T1 - Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

AU - Bauman, Julie E.

AU - Duvvuri, Umamaheswar

AU - Gooding, William E.

AU - Rath, Tanya J.

AU - Gross, Neil D.

AU - Song, John

AU - Jimeno, Antonio

AU - Yarbrough, Wendell G.

AU - Johnson, Faye M.

AU - Wang, Lin

AU - Chiosea, Simion

AU - Sen, Malabika

AU - Kass, Jason

AU - Johnson, Jonas T.

AU - Ferris, Robert L.

AU - Kim, Seungwon

AU - Hirsch, Fred R.

AU - Ellison, Kimberly

AU - Flaherty, John T.

AU - Mills, Gordon

AU - Grandis, Jennifer R.

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N2 - BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

AB - BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

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