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High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development, "Beyond the Abstract," by Dong Lin, Alexander W. Wyatt, Colin C. Collins, and Yuzhuo Wang

BERKELEY, CA (UroToday.com) - Prostate cancer discovery and drug development are severely limited by a lack of standardized preclinical models which accurately replicate the diverse molecular and biological heterogeneity of human tumors. To address this unmet need in prostate cancer research, we have created a novel bank of state-of-the-art transplantable patient-derived prostate tumor xenografts. This panel of novel models features a number of groundbreaking innovations:

  1. We used a spectrum of different tumors to capture the diverse biological and molecular characteristics of primary prostate cancers;
  2. Collectively, the panel of patient-derived prostate cancer tissue xenograft models closely mimic the original cancers in terms of histopathology, tumor heterogeneity, chromosomal aberrations, gene expression profiles and tumor aggressiveness;
  3. Transplantable tumor models were successfully developed from early stage human prostate cancer tissue, even from tiny needle biopsy specimens, which previously was not possible;
  4. Multiple models established from different biopsies of the same tumor provided a functional dissection of tumor heterogeneity;
  5. The first model of complete transformation from adenocarcinoma to neuroendocrine cancer was established and provides a first-in-field model to study the progression of the most lethal form of prostate cancer;
  6. Overall, the models mimic patient disease progression and response to therapies. As such, they can be viewed as next generation prostate cancer xenograft models.[1]

These next generation models have led to breakthroughs in several areas of research including,

  1. prostate cancer mechanisms and biomarker discovery,[2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]
  2. development of new therapies,[13, 14, 15, 16, 17, 18] and
  3. advancement of personalized oncology.[3, 19]

bta lin figure1 thumbThere is no doubt that as research continues, new discoveries will emanate from the models. One notable example is the unique model of transdifferentiation from adenocarcinoma to neuroendocrine cancer (i.e., LTL331/LTL331R) that is revealing the mechanisms of lethal NEPC transdifferentiation. This is critically important because of emerging evidence that androgen blockade can induce NEPC transdifferentiation.[20] Genetic profiling of both LTL331 and its castration-resistant NEPC counterpart, LTL331R, exhibited very similar chromosome copy number and mutation profiles, strongly suggesting that the switch to NEPC occurs through an adaptive response of adenocarcinoma cells rather than through clonal selection of existing NEPC cells. This represents the first reproducible model of neuroendocrine transdifferentiation in a pre-clinical model, and it provides strong evidence for a high degree of cellular plasticity. As an example of the potential translational relevance of this model, we presented a novel set of candidate biomarkers for neuroendocrine transdifferentiation that are highly expressed in a clinical cohort of NEPCs and are associated with poor patient outcome in an independent cohort of adenocarcinoma patients. As such, they may be useful for improved risk stratification and prediction of clinical outcome of adenocarcinoma and provide insight into the mechanisms of the malignant progression of prostate cancer. 

Recent discoveries using these models have already given researchers exciting and profound insight into prostate cancer and led to the identification of novel therapeutic targets for the disease. In the coming years we can foresee combinatorial therapeutics and strategies for “evidence based” precision oncology being evaluated using these models. As such, we believe that this resource will be transformative for advancing mechanistic understandings of disease progression, development of co-targeting strategies, and provide a powerful platform for precision oncology.

References:

  1. Lin, D., et al., Next generation patient-derived prostate cancer xenograft models. Asian Journal of Andrology, 2014.
  2. Watahiki, A., et al., MicroRNAs Associated with Metastatic Prostate Cancer. PLoS One, 2011 6(9): p. e24950.
  3. Collins, C.C., et al., Next generation sequencing of prostate cancer from a patient identifies a deficiency of methylthioadenosine phosphorylase, an exploitable tumor target. Molecular Cancer Therapeutics, 2012. 11(3): p. 775-83.
  4. Wu, C., et al., Poly-gene fusion transcripts and chromothripsis in prostate cancer. Genes, Chromosomes & Cancer, 2012.
  5. Choi, S.Y., et al., Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? The Journal of Pathology, 2013. 230(4): p. 350-5.
  6. Crea, F., et al., The non-coding transcriptome as a dynamic regulator of cancer metastasis. Cancer Metastasis Reviews, 2013.
  7. Lin, D., P.W. Gout, and Y.Z. Wang, Lessons from in-vivo models of castration-resistant prostate cancer. Current Opinion in Urology, 2013.
  8. Low, C.G., et al., BIRC6 Protein, an Inhibitor of Apoptosis: Role in Survival of Human Prostate Cancer Cells. PloS one, 2013. 8(2): p. e55837.
  9. Wyatt, A.W., et al., The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing. Asian Journal of Andrology, 2013. 15(3): p. 301-8.
  10. Chiang, Y.T., et al., GATA2 as a potential metastasis-driving gene in prostate cancer. Oncotarget, 2014.
  11. Crea, F., et al., Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer. Oncotarget, 2014.
  12. Chiang, Y.T., et al., Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification. Asian Journal of Andrology, 2014.
  13. Andersen, R.J., et al., Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell, 2010. 17(6): p. 535-46.
  14. McPherson, S.J., et al., Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated. Proc Natl Acad Sci U S A, 2010. 107(7): p. 3123-8.
  15. Beltran, H., et al., Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of Aurora Kinase as a Therapeutic Target. Cancer Discovery 2011. 1(6).
  16. Nakamura, H., et al., Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer. PLoS One, 2011. 6(5): p. e20034.
  17. Tung, W.L., et al., Use of irinotecan for treatment of small cell carcinoma of the prostate. The Prostate, 2011. 71(7): p. 675-81.
  18. Qu, S., et al., Enhanced anticancer activity of a combination of docetaxel and Aneustat (OMN54) in a patient-derived, advanced prostate cancer tissue xenograft model. Molecular Oncology, 2014. 8(2): p. 311-22.
  19. Dong, X., et al., Patient-derived first generation xenografts of non-small cell lung cancers: promising tools for predicting drug responses for personalized chemotherapy. Clin Cancer Res, 2010. 16(5): p. 1442-51.
  20. Mosquera, J.M., et al., Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia, 2013. 15(1): p. 1-10.

Written by:
Dong Lin,*# Alexander W. Wyatt,* Colin C. Collins,* and Yuzhuo Wang*# as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

*Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
#Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada

High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development - Abstract

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