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A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer

Nature Genetics volume 45, pages 747–755 (2013)Cite this article

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Abstract

Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss–driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.

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Figure 1: Prostate tumors characterized by distinct genetic alterations differentially respond to castration.
Figure 2: Analysis of human prostate cancer unveils the relevance of ZBTB7A loss in the response to androgen deprivation.
Figure 3: Differential responses to castration in distinct genetic backgrounds.
Figure 4: Deregulation of XAF1 and SRD5A1 levels dictates prostate cancer progression and castration resistance in mice and humans.
Figure 5: Synergistic effect of ADT and embelin in mouse CRPC.
Figure 6: Genetic and molecular assessments in mice and humans dictate new experimental treatment to overcome CRPC.

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  • 03 September 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

We would like to thank current members of the Pandolfi laboratory for critical discussion and T. Garvey for insightful editing. We are grateful to the Preclinical Murine Pharmacogenetics Facility at Beth Israel Deaconess Medical Center and the Dana-Farber/Harvard Cancer Center for expert support in all aspects related to the work in mice. The Dana-Farber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support grant (US National Institutes of Health (NIH) 5 P30 CA06516). We also thank C. Abate-Shen (Columbia University) for kindly providing the antibody to Probasin and the Small-Animal Imaging Facility at Beth Israel Deaconess Medical Center for the MRI work. Additionally, we are grateful to G. Fedele and X. Wu from the Loda laboratory and the Center for Molecular Oncologic Pathology at Dana-Farber/Brigham and Women's for their technical support in the generation, staining and analysis of the TMA. U.A. has been supported by a fellowship from the Italian Association for Cancer Research (AIRC) under grant IG-9408. A.L. has been supported in part by a fellowship from the Istituto Toscano Tumori (ITT, Italy). This work has been supported through the Mouse Models of Human Cancer Consortium/National Cancer Institute grant (RC2 CA147940-01) and the A. David Mazzone Research Awards Program, Project Development Award to P.P.P.

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Authors and Affiliations

  1. Department of Medicine and Pathology, Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Andrea Lunardi, Ugo Ala, Mirjam T Epping, Leonardo Salmena, John G Clohessy, Kaitlyn A Webster, Guocan Wang, Caterina Nardella & Pier Paolo Pandolfi

  2. Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Turin, Turin, Italy

    Ugo Ala

  3. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Leonardo Salmena, John G Clohessy, Guocan Wang, Caterina Nardella & Pier Paolo Pandolfi

  4. Department of Pathology, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Leonardo Salmena, John G Clohessy, Guocan Wang, William L Gerald, Caterina Nardella & Pier Paolo Pandolfi

  5. Biochemistry, Cell & Molecular Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York, USA

    Guocan Wang

  6. Institute of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy

    Roberta Mazzucchelli & Rodolfo Montironi

  7. Clinic of Oncology, Postgraduate School in Medical Oncology, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy

    Maristella Bianconi

  8. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Edward C Stack, Rosina Lis & Massimo Loda

  9. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Edward C Stack, Rosina Lis, Sabina Signoretti & Massimo Loda

  10. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Edward C Stack & Sabina Signoretti

  11. Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Akash Patnaik & Glenn Bubley

  12. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

    Lewis C Cantley

  13. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Lewis C Cantley

  14. Department of Genetics and Genomic Sciences, The Mount Sinai School of Medicine, New York, New York, USA

    Carlos Cordon-Cardo

  15. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA

    Massimo Loda

  16. Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Caterina Nardella

Authors
  1. Andrea Lunardi
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  2. Ugo Ala
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  21. Pier Paolo Pandolfi
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Contributions

A.L., C.N. and P.P.P. designed, realized and analyzed the experiments. U.A., R. Mazzucchelli, M.B., E.C.S., R.L., A.P., L.C.C., G.B., C.C.-C., W.L.G. and R. Montironi conducted the human genetic and molecular analysis. K.A.W. performed the hematoxylin and eosin staining and immunohistochemistry on mouse prostate samples. M.T.E., L.S., J.G.C. and G.W. helped with the experiments. M.L. and S.S. reviewed all mouse pathology. A.L., C.N. and P.P.P. wrote the manuscript.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–7, Supplementary Tables 1 and 4 (PDF 7470 kb)

Supplementary Table 2

Clinical information of patient specimens used for the TMA. (XLS 50 kb)

Supplementary Table 3

List of genes co-lost with PTEN in CR metastasis. (XLS 44 kb)

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Lunardi, A., Ala, U., Epping, M. et al. A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer. Nat Genet 45, 747–755 (2013). https://doi.org/10.1038/ng.2650

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