Patient-derived, Murine Model of Prostate Cancer
In broad terms, the PCSD1 model is more representative and predictive of the bone metastatic prostate cancer tumors found in patients. Specifically: Current prostate cancer cell line (SCID mouse) xenograft models, include: - PC3, which produces purely osteolytic lesions in intra-tibial xenografts; - LAPC9, which produces purely osteoblastic lesions; and for over a decade, PCSD1 has low passage numbers with cryopreserved cells from the primary tumor and subsequent passages. Transplantation into Rag2-/-;IL2Rγc-/- immunodeficient mice (which completely lack B, T and NK cells) provides superior, highly efficient engraftment relative to SCID mice, which are not completely immunodeficient. - VCaP, which produces mixed osteoblastic/osteolytic lesions While these three collectively comprise the range of bone lesions produced by prostate cancer metastases, none recapitulates the full range of mixed osteoblastic/osteolytic lesions, observed in most patients. Where the previous models have been passaged ex vivo for over a decade, PCSD1 has low passage numbers with cryopreserved cells from the primary tumor and subsequent passages.Transplantation into Rag2-/-;IL2Rγc-/- immunodeficient mice (which completely lack B, T and NK cells) provides superior, highly efficient engraftment relative to SCID mice, which are not completely immunodeficient.
The PCSD1 xenograft model is helping unravel the complex mechanisms of interaction of prostate cancer with the bone microenvironment and patient variation in response to therapies. Enigmas that may now be addressed include: Treatments for patients with significantly lowered PSA levels after treatment with abiraterone, who still showed positive bone scans, and Treatments for patients treated with Cabozantinib (c-Met TKI, XL184), who showed dramatic reductions in positive bone scans but, paradoxically, no decrease in their PSA levels.
Injection of patient-derived prostate cancer bone metastasis specimens into femurs of immunodeficient (Rag2-/-;IL2Rγc-/-) mice engendered serially transplantable tumors, which have been used to dissect the complex interactions between prostate cancer and the bone. In addition, the model enables new approaches to understand mechanisms of therapy-resistance that inevitably arise for bone metastatic prostate cancer.
Patent Number: WO2013056174A1
Application Number: WO2012US60128A
Inventor: JAMIESON, Christina | KULIDJIAN, Anna, A. | JAMIESON, Catriona, H. | KANE, Christopher, J. | MASUDA, Koichi | WU, Christina, CN | RAHEEM, Omer, A.
Priority Date: 13 Oct 2011
Priority Number: WO2013056174A1
Application Date: 12 Oct 2012
Publication Date: 18 Apr 2013
IPC Current: A01K0067027 | C12N000510 | G01N003315
Assignee Applicant: The Regents of the University of California
Title: XENOGRAFT MODEL OF HUMAN BONE METASTATIC PROSTATE CANCER | MODÈLE DE XÉNOGREFFE DU CANCER DE LA PROSTATE AVEC MÉTASTASES OSSEUSES CHEZ L'HOMME
Usefulness: XENOGRAFT MODEL OF HUMAN BONE METASTATIC PROSTATE CANCER | MODÈLE DE XÉNOGREFFE DU CANCER DE LA PROSTATE AVEC MÉTASTASES OSSEUSES CHEZ L'HOMME
Summary: The method (M1) is useful for generating bone metastasis-derived prostate cancer xenograft model, preferably non-human animal or animal model and PCSD1 model. The method (M2) is useful for testing drug, compound, diet, therapy or treatment. The method (M3) is useful for screening therapeutic agents for prostate cancer (all claimed).
Novelty: Generating bone metastasis-derived prostate cancer xenograft model for screening therapeutic agents for prostate cancer, by providing immunodeficient non-human animal, and injecting human prostate cancer cells into animal e.g. rat
Disease Diagnostic/Treatment
Cancer/Tumor
State Of Development PCSD1 is ready for use in pre-clinical drug testing as well as basic research on castration-resistant prostate cancer and tumor growth in the bone microenvironment/niche. Validation includes: Intellectual Property Info Worldwide rights available; Pending patents available under confidentiality. Related Materials Raheem, O. et al., (2011) A novel patient-derived intra-femoral xenograft model of bone metastatic prostate cancer that recapitulates mixed osteolytic and osteoblastic lesions, J Transl Med., 9:185. Tech ID/UC Case 22747/2012-105-0 Related Cases 2012-105-0
Ma, W., et al. (2012) NOTCH1 signaling promotes human T-cell Acute Lymphoblastic Leukemia initiating cell regeneration in supportive niches, PLoS One 7(6): e39725.
Sturge J, et al., (2011) Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol., 8(6):357-68.
Mehra R, Kumar-Sinha C, et al., (2011) Characterization of bone metastases from rapid autopsies of prostate cancer patients. Clin Cancer Res.17(12):3924-32.
Lopez-Barcons, LA, (2010) Human prostate cancer heterotransplants: a review on this experimental model. Asian J Androl., 12(4):509-18.
Virk MS, et al., (2009) Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone. Bone. 44(1):160-7.
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