Modulation of cabozantinib efficacy by the prostate tumor microenvironment

Manish Tripathi, Srinivas Nandana, Sandrine Billet, Karen A. Cavassani, Rajeev Mishra, Leland W.K. Chung, Edwin M. Posadas, Neil A. Bhowmick

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The tumor microenvironment (TME) is increasingly recognized as the arbiter of metastatic progression and drug resistance in advanced prostate cancer (PCa). Cabozantinib is a potent tyrosine kinase inhibitor (TKI) with reported biological activity in the PCa epithelia, but failed to provide an overall survival benefit in phase 3 clinical trials. However, the promising biologic efficacy of the drug in early trials warranted a better understanding of the mechanism of action, with the goal of improving patient selection for TKI-based therapy such as cabozantinib. We found a 100-fold lower cabozantinib IC50 in macrophages, PCa associated fibroblasts, and bone marrow fibroblasts compared to PCa epithelia. In PCa mouse models, pre-treatment with cabozantinib potentiated osseous and visceral tumor engraftment, suggesting a pro-tumorigenic host response to the drug. We further found that the host effects of cabozantinib impacted bone turnover, but not necessarily tumor expansion. Cabozantinib affected M1 macrophage polarization in mice. Analogously, circulating monocytes from PCa patients treated with cabozantinib, demonstrated a striking correlation of monocyte reprograming with therapeutic bone responsivity, to support patient selection at early stages of treatment. Thus, a re-evaluation of TKI-based therapeutic strategies in PCa can be considered for suitable patient populations based on TME responses.

Original languageEnglish (US)
Pages (from-to)87891-87902
Number of pages12
JournalOncotarget
Volume8
Issue number50
DOIs
StatePublished - Jan 1 2017

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Tumor Microenvironment
Prostate
Prostatic Neoplasms
Protein-Tyrosine Kinases
Patient Selection
Monocytes
Epithelium
Macrophages
Therapeutics
Phase III Clinical Trials
Bone Remodeling
cabozantinib
Drug Resistance
Pharmaceutical Preparations
Inhibitory Concentration 50
Neoplasms
Fibroblasts
Bone Marrow
Bone and Bones
Survival

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Tripathi, M., Nandana, S., Billet, S., Cavassani, K. A., Mishra, R., Chung, L. W. K., ... Bhowmick, N. A. (2017). Modulation of cabozantinib efficacy by the prostate tumor microenvironment. Oncotarget, 8(50), 87891-87902. https://doi.org/10.18632/oncotarget.21248

Modulation of cabozantinib efficacy by the prostate tumor microenvironment. / Tripathi, Manish; Nandana, Srinivas; Billet, Sandrine; Cavassani, Karen A.; Mishra, Rajeev; Chung, Leland W.K.; Posadas, Edwin M.; Bhowmick, Neil A.

In: Oncotarget, Vol. 8, No. 50, 01.01.2017, p. 87891-87902.

Research output: Contribution to journalArticle

Tripathi, M, Nandana, S, Billet, S, Cavassani, KA, Mishra, R, Chung, LWK, Posadas, EM & Bhowmick, NA 2017, 'Modulation of cabozantinib efficacy by the prostate tumor microenvironment', Oncotarget, vol. 8, no. 50, pp. 87891-87902. https://doi.org/10.18632/oncotarget.21248
Tripathi M, Nandana S, Billet S, Cavassani KA, Mishra R, Chung LWK et al. Modulation of cabozantinib efficacy by the prostate tumor microenvironment. Oncotarget. 2017 Jan 1;8(50):87891-87902. https://doi.org/10.18632/oncotarget.21248
Tripathi, Manish ; Nandana, Srinivas ; Billet, Sandrine ; Cavassani, Karen A. ; Mishra, Rajeev ; Chung, Leland W.K. ; Posadas, Edwin M. ; Bhowmick, Neil A. / Modulation of cabozantinib efficacy by the prostate tumor microenvironment. In: Oncotarget. 2017 ; Vol. 8, No. 50. pp. 87891-87902.
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