Abstract 6109: Enzalutamide treatment of patient derived bone metastatic prostate cancer xenograft models implanted in the bone resulted in durable progression to castration resistant prostate cancer (CRPC)
Authors: Jamieson Christina A.M. , Muldong Michelle T. , Lee Sanghee , Wu Christina N. , Burner Danielle N. , Mendoza Theresa R. , Arreola Catalina , Zuniga Abril , Cacalano Nicholas A. , Jamieson Catriona H. , Kane Christopher J. , Kulidjian Anna A. 
Published: September 2020

Background: Upon diagnosis of castration-resistant prostate cancer (CRPC), 84% of patients present with metastases and their survival rate is 28% despite improvements in treatment options. PCSD1, a patient-derived xenograft from a prostate cancer bone metastasis replicated the donor patient's CRPC and was resistant to the anti-androgen drug, bicalutamide, in the bone niche. To further understand the mechanisms of androgen deprivation therapy (ADT) resistance, we treated PCSD1 and PCSD13, a novel patient derived xenograft model from a small cell prostate cancer bone metastasis, with the more potent anti-androgen, Enzalutamide.

Methods: PDX cells were implanted into male Rag2−/−γc−/− mice intra-femorally (IF) or subcutaneously (SC). Mice with established tumors were treated o.g. for 4-5 weeks with Enzalutamide (10mg/kg/day) or Vehicle control. Tumor growth was measured bi-weekly with calipers and in vivo bioluminescence (IVIS). Tumors were analyzed using FACS, RNASeq, whole exome sequencing (WES) and Oncoscan.

Results: PCSD1 and PCSD13 tumors were resistant to enzalutamide when implanted in the femur bone but not sub-cutaneously. When the enzalutamide-resistant tumor cells from the bone were re-injected sub-cutaneously they retained their enzalutamide resistance in contrast to treatment-naïve PCSD1 SC tumors. Transcriptomic analysis revealed significant modulation of WNT5A, EMT and neuronal programs. Single cell analyses revealed heterogeneous sub-populations that behave as cancer stem cells in 3D organoid cultures. Genome-wide CNV analysis of patient bone metastasis samples from the same patient obtained 10 months apart and his xenografts revealed extensive CNVs which were highly conserved between the patient samples and xenografts.

Conclusions: Our PDX models demonstrated that the bone niche promotes tumor growth and malignant progression even when treated with the potent anti-androgen, enzalutamide. These PDX models of bone metastatic prostate cancer were resistant to enzalutamide in the femur bone (IF) but sensitive in the sub-cutaneous environment (SC). Enzalutamide resistance in the bone produced a permanent change in the tumor cells that was retained when re-injected in the sub-cutaneous location. This elucidates the importance of utilizing in vivo patient derived models to gain a better understanding of why the bone niche supports tumor growth.

Citation Format: Christina A.M. Jamieson, Michelle T. Muldong, Sanghee Lee, Christina N. Wu, Danielle N. Burner, Theresa R. Mendoza, Catalina Arreola, Abril Zuniga, Nicholas A. Cacalano, Catriona H. Jamieson, Christopher J. Kane, Anna A. Kulidjian. Enzalutamide treatment of patient derived bone metastatic prostate cancer xenograft models implanted in the bone resulted in durable progression to castration resistant prostate cancer (CRPC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6109.