In a recent clinical trial led by Co-Leader Dr. Smith, Cabozantinib (CABO;XL-184) showed unprecedented bone scan responses in men with castration-resistant prostate cancer (CRPC). Although marked responses are seen, patients eventually progress and about 30% of patients do not respond. CABO is a multi-tyrosine kinase inhibitor with greatest activity against MET, VEGFR2 and RET, which have been implicated in prostate cancer (PCa) progression and the bone microenvironment. Using preclinical models we have found that some PCas show differential sensitivity to CABO when in bone versus soft tissue. Furthermore, through integrative sequencing, we have found that MET activation compensates for loss of androgen receptor (AR) signaling in CRPC. These clinical and pre-clinical results provide a compelling rationale for studying the role of both the tumor itself and the tumor microenvironment in predicting tumor sensitivity and resistance to CABO. Hence, the overarching goal of this proposal is to leverage an ongoing investigator-initiated clinical trial of CABO and use in vitro and in vivo modeling to

Public Health Relevance

Prostate cancer is the most common non-skin cancer of men. When prostate cancer progresses, over 80% of men develop bone metastases which cause fracture and pain. Cabozantanib (CABO) treatment results in marked regression of prostate cancer however it is not effective in all patients and resistance eventually develops. Defining mechanisms of resistance will lead us to improve clinical effectiveness of CABO or determine which patients would or would not benefit from CABO treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA186786-01
Application #
8788150
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
2014-09-11
Project End
2019-08-31
Budget Start
2014-09-11
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$248,019
Indirect Cost
$88,106
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Yajia; Pitchiaya, Sethuramasundaram; Cie?lik, Marcin et al. (2018) Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression. Nat Genet 50:814-824
Hussain, Maha; Daignault-Newton, Stephanie; Twardowski, Przemyslaw W et al. (2018) Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol 36:991-999
Salami, Simpa S; Hovelson, Daniel H; Kaplan, Jeremy B et al. (2018) Transcriptomic heterogeneity in multifocal prostate cancer. JCI Insight 3:
Zhao, Shanshan; Leonardson, Amy; Geybels, Milan S et al. (2018) A five-CpG DNA methylation score to predict metastatic-lethal outcomes in men treated with radical prostatectomy for localized prostate cancer. Prostate :
Niknafs, Yashar S; Pandian, Balaji; Gajjar, Tilak et al. (2018) MiPanda: A Resource for Analyzing and Visualizing Next-Generation Sequencing Transcriptomics Data. Neoplasia 20:1144-1149
Xiao, Lanbo; Tien, Jean C; Vo, Josh et al. (2018) Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer. Cancer Res 78:5731-5740
Piert, Morand; Shankar, Prasad R; Montgomery, Jeffrey et al. (2018) Accuracy of tumor segmentation from multi-parametric prostate MRI and 18F-choline PET/CT for focal prostate cancer therapy applications. EJNMMI Res 8:23
Wu, Yi-Mi; Cie?lik, Marcin; Lonigro, Robert J et al. (2018) Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 173:1770-1782.e14
Rice, John D; Tsodikov, Alex (2017) Semiparametric profile likelihood estimation for continuous outcomes with excess zeros in a random-threshold damage-resistance model. Stat Med 36:1924-1935
Shen, Rex; Luo, Lan; Jiang, Hui (2017) Identification of gene pairs through penalized regression subject to constraints. BMC Bioinformatics 18:466

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