Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer

Andreas Varkaris, Paul G. Corn, Nila U. Parikh, Eleni Efstathiou, Jian H. Song, Yu Chen Lee, Ana Aparicio, Anh G. Hoang, Sanchaika Gaur, Lynnelle Thorpe, Sankar N. Maity, Menashe Bar Eli, Bogdan A. Czerniak, Yiping Shao, Mian Alauddin, Sue Hwa Lin, Christopher J. Logothetis, Gary E. Gallick

Research output: Contribution to journalArticle

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Abstract

Purpose: We performed parallel investigations in cabozantinib-treated patients in a phase II trial and simultaneously in patient-derived xenograft (PDX) models to better understand the roles of MET and VEGFR2 as targets for prostate cancer therapy. Experimental Design: In the clinical trial, radiographic imaging and serum markers were examined, as well as molecular markers in tumors from bone biopsies. In mice harboring PDX intrafemurally or subcutaneously, cabozantinib effects on tumor growth, MET, PDX in which MET was silenced, VEGFR2, bone turnover, angiogenesis, and resistance were examined. Results: In responsive patients and PDX, islets of viable pMETpositive tumor cells persisted, which rapidly regrew after drug withdrawal. Knockdown of MET in PDX did not affect tumor growth in mice nor did it affect cabozantinib-induced growth inhibition but did lead to induction of FGFR1. Inhibition of VEGFR2 and MET in endothelial cells reduced the vasculature, leading to necrosis. However, each islet of viable cells surrounded a VEGFR2-negative vessel. Reduction of bone turnover was observed in both cohorts. Conclusions: Our studies demonstrate that MET in tumor cells is not a persistent therapeutic target for metastatic castrate-resistant prostate cancer (CRPC), but inhibition of VEGFR2 and MET in endothelial cells and direct effects on osteoblasts are responsible for cabozantinib-induced tumor inhibition. However, vascular heterogeneity represents one source of primary therapy resistance, whereas induction of FGFR1 in tumor cells suggests a potential mechanism of acquired resistance. Thus, integrated cross-species investigations demonstrate the power of combining preclinical models with clinical trials to understand mechanisms of activity and resistance of investigational agents.

Original languageEnglish (US)
Pages (from-to)107-121
Number of pages15
JournalClinical Cancer Research
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2016

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Prostatic Neoplasms
Clinical Trials
Heterografts
Growth
Neoplasms
Bone Remodeling
Endothelial Cells
Tumor Biomarkers
cabozantinib
Osteoblasts
Islets of Langerhans
Blood Vessels
Research Design
Necrosis
Therapeutics
Biomarkers
Biopsy
Bone and Bones
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer. / Varkaris, Andreas; Corn, Paul G.; Parikh, Nila U.; Efstathiou, Eleni; Song, Jian H.; Lee, Yu Chen; Aparicio, Ana; Hoang, Anh G.; Gaur, Sanchaika; Thorpe, Lynnelle; Maity, Sankar N.; Eli, Menashe Bar; Czerniak, Bogdan A.; Shao, Yiping; Alauddin, Mian; Lin, Sue Hwa; Logothetis, Christopher J.; Gallick, Gary E.

In: Clinical Cancer Research, Vol. 22, No. 1, 01.01.2016, p. 107-121.

Research output: Contribution to journalArticle

Varkaris, A, Corn, PG, Parikh, NU, Efstathiou, E, Song, JH, Lee, YC, Aparicio, A, Hoang, AG, Gaur, S, Thorpe, L, Maity, SN, Eli, MB, Czerniak, BA, Shao, Y, Alauddin, M, Lin, SH, Logothetis, CJ & Gallick, GE 2016, 'Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer', Clinical Cancer Research, vol. 22, no. 1, pp. 107-121. https://doi.org/10.1158/1078-0432.CCR-15-0235
Varkaris, Andreas ; Corn, Paul G. ; Parikh, Nila U. ; Efstathiou, Eleni ; Song, Jian H. ; Lee, Yu Chen ; Aparicio, Ana ; Hoang, Anh G. ; Gaur, Sanchaika ; Thorpe, Lynnelle ; Maity, Sankar N. ; Eli, Menashe Bar ; Czerniak, Bogdan A. ; Shao, Yiping ; Alauddin, Mian ; Lin, Sue Hwa ; Logothetis, Christopher J. ; Gallick, Gary E. / Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 1. pp. 107-121.
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T1 - Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer

AU - Varkaris, Andreas

AU - Corn, Paul G.

AU - Parikh, Nila U.

AU - Efstathiou, Eleni

AU - Song, Jian H.

AU - Lee, Yu Chen

AU - Aparicio, Ana

AU - Hoang, Anh G.

AU - Gaur, Sanchaika

AU - Thorpe, Lynnelle

AU - Maity, Sankar N.

AU - Eli, Menashe Bar

AU - Czerniak, Bogdan A.

AU - Shao, Yiping

AU - Alauddin, Mian

AU - Lin, Sue Hwa

AU - Logothetis, Christopher J.

AU - Gallick, Gary E.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Purpose: We performed parallel investigations in cabozantinib-treated patients in a phase II trial and simultaneously in patient-derived xenograft (PDX) models to better understand the roles of MET and VEGFR2 as targets for prostate cancer therapy. Experimental Design: In the clinical trial, radiographic imaging and serum markers were examined, as well as molecular markers in tumors from bone biopsies. In mice harboring PDX intrafemurally or subcutaneously, cabozantinib effects on tumor growth, MET, PDX in which MET was silenced, VEGFR2, bone turnover, angiogenesis, and resistance were examined. Results: In responsive patients and PDX, islets of viable pMETpositive tumor cells persisted, which rapidly regrew after drug withdrawal. Knockdown of MET in PDX did not affect tumor growth in mice nor did it affect cabozantinib-induced growth inhibition but did lead to induction of FGFR1. Inhibition of VEGFR2 and MET in endothelial cells reduced the vasculature, leading to necrosis. However, each islet of viable cells surrounded a VEGFR2-negative vessel. Reduction of bone turnover was observed in both cohorts. Conclusions: Our studies demonstrate that MET in tumor cells is not a persistent therapeutic target for metastatic castrate-resistant prostate cancer (CRPC), but inhibition of VEGFR2 and MET in endothelial cells and direct effects on osteoblasts are responsible for cabozantinib-induced tumor inhibition. However, vascular heterogeneity represents one source of primary therapy resistance, whereas induction of FGFR1 in tumor cells suggests a potential mechanism of acquired resistance. Thus, integrated cross-species investigations demonstrate the power of combining preclinical models with clinical trials to understand mechanisms of activity and resistance of investigational agents.

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