Prostate Cancer Cells Preferentially Home to Osteoblast-rich Areas in the Early Stages of Bone Metastasis: Evidence From In Vivo Models

AbstractUnderstanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

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Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16534 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16534-e16534 ◽

Cited By ~ 1

Author(s):

Lisa Butler ◽

Swati Irani ◽

Margaret Centenera ◽

Natalie Ryan ◽

Neil Pegg ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Small Molecule ◽

Single Agent ◽

Specific Antigen ◽

Resistance Mechanisms ◽

Prostate Cancer Cells ◽

In Vivo Models

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.

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Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16576 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e16576-e16576

Author(s):

Marianna Kruithof-de Julio ◽

Letizia Astrologo ◽

Eugenio Zoni ◽

Sofia Karkampouna ◽

Peter C Gray ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cancer Cells ◽

Bone Cells ◽

Critical Role ◽

Prostate Cancer Cells ◽

Primary Prostate Cancer ◽

The Impact

e16576 Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.

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Potent Anti-Proliferative, Pro-Apoptotic Activity of the Maytenus Royleanus Extract against Prostate Cancer Cells: Evidence in In-Vitro and In-Vivo Models

PLoS ONE ◽

10.1371/journal.pone.0119859 ◽

2015 ◽

Vol 10 (3) ◽

pp. e0119859 ◽

Cited By ~ 13

Author(s):

Maria Shabbir ◽

Deeba N. Syed ◽

Rahul K. Lall ◽

Muhammad Rashid Khan ◽

Hasan Mukhtar

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Prostate Cancer Cells ◽

In Vivo Models ◽

Apoptotic Activity

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Radiosensitization of MYC-overexpressing prostate cancer cells by statins.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.26 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 26-26 ◽

Cited By ~ 1

Author(s):

T. Salih ◽

K. Aziz ◽

S. Thiyagarajan ◽

M. Armour ◽

B. Shanmugam ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Death ◽

Radiation Therapy ◽

Cancer Cells ◽

Radiation Treatment ◽

Statin Treatment ◽

Prostate Cancer Cells ◽

In Vivo Models

26 Background: Studies have shown a link between HMG-CoA reductase inhibitors (statins) and decreased cancer risk in various cancers including prostate cancer. Recent clinical studies have shown improved outcome for men on statin therapy receiving definitive radiation therapy compared to radiation therapy alone for prostate cancer. The oncogene Ras can be inhibited by statin treatment and in turn also result in targeted downregulation of Myc. Inactivation of Myc has been shown to induce tumor regression in transgenic mouse models of different cancers. Methods: Utilizing both in vitro and in vivo models, we studied in MYC over-expressing prostate cancer cells statin induced cytotoxicity and radiosensitization. We studied the effect of statin treatment with and without radiation treatment on in vitro cell death and clonogenic survival and correlated effects to levels of MYC and phospho-MYC. We constructed mutant cell lines to specifically examine the MYC-dependent effects of statins on prostate cancer cell cytotoxicity and radiosensitization. We performed similar studies in vivo using subcutaneous tumor grafts. Results: Statin treatment alone of prostate cancer cells resulted in increased cell death and decreased clonegenic survival. Statin treatment further sensitized prostate cancer cells to ionizing radiation as shown through colony formation assays. These cellular effects were associated with decreased levels of active MYC as confirmed by western and phospho-western analysis. Statin-induced cell death and decreased MYC levels could be rescued with the HMG-CoA bypass product mevalonate. Finally, flank tumor graft experiments demonstrated the ability of statins and radiation to delay tumor growth in vivo. Conclusions: Our preliminary data have implicated MYC as a potential critical target for the cytotoxic effects of statins on prostate cancer cells. The prevalence of MYC overexpression in human prostate cancers is as high as 80%. Thus the ability of statins to radiosensitize MYC overexpressing prostate cancer cells may provide a mechanistic explanation to the improved outcomes for men taking statins while on radiation therapy and now may afford us a molecular biomarker to examine this phenomenon in the clinic. No significant financial relationships to disclose.

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