scholarly journals Targeting the BMP Pathway in Prostate Cancer Induced Bone Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Desiree M. Straign ◽  
Claire L. Ihle ◽  
Meredith D. Provera ◽  
Philip Owens
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Bone Disease ◽  
Bone Health ◽  
Metastatic Prostate Cancer ◽  
Bone Lesions ◽  
Prostate Cell ◽  
Prostate Cell Line ◽  
Lytic Bone Lesions

From the 33,000 men in the U.S. who die from prostate cancer each year, the majority of these patients exhibit metastatic disease with bone being the most common site of metastasis. Prostate cancer bone metastases are commonly blastic, exhibiting new growth of unhealthy sclerotic bone, which can cause painful skeletal related events. Patient’s current care entails androgen deprivation therapy, anti-resorptive agents, radiation, and chemotherapy to help control the spread of the cancer but little intervention is available to treat blastic bone disease. The transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) pathways are known to regulate bone growth and resorption of destructive lytic bone lesions, yet the role of TGFβ/BMP signaling in prostate cancer blastic vs lytic bone lesions are not fully understood. We hypothesized that to target the BMP/TGFβ pathway, a useful biomarker of bone lytic or blastic pathology would have superior response. We show distinct BMP vs. TGFβ signaling in clinical samples of human prostate cancer bone metastases with either lytic or blastic pathologies. BMPs exhibit distinct effects on bone homeostasis, so to examine the effect of BMP inhibition on healthy bone, we treated mice with the BMP receptor small molecule antagonist DMH1 and saw a modest temporary improvement in bone health, with increased trabecular bone. We next sought to use the BMP inhibitor DMH1 to treat bone metastasis engraftment seeded by a caudal artery injection of the lytic human prostate cell line PC3 in immunodeficient mice. The colonization by PC3 cells to the bone were restricted with DMH1 treatment and bone health was importantly preserved. We next proceeded to test BMP inhibition in an injury model of established bone metastasis via intratibial injection of the MYC-CaP mouse prostate cell line into FVBN syngeneic mice. DMH1 treated mice had a modest decrease in trabecular bone and reduced lymphocytes in circulation without affecting tumor growth. Taken together we show unique responses to BMP inhibition in metastatic prostate cancer in the bone. These studies suggest that profiling bone lesions in metastatic prostate cancer can help identify therapeutic targets that not only treat the metastatic tumor but also address the need to better treat the distinct tumor induced bone disease.

scholarly journals Prostate Cancer Presenting with Parietal Bone Metastasis

2017 ◽  
Vol 2017 ◽  
pp. 1-3
Author(s):  
Brahima Kirakoya ◽  
Abdoul Karim Pare ◽  
Babagana Mustapha Abubakar ◽  
Moussa Kabore
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Metastatic Prostate Cancer ◽  
Axial Skeleton ◽  
Parietal Bone ◽  
Cranial Bone ◽  
Bone Lesions ◽  
Urological Symptoms ◽  
Left Parietal Bone

Bone metastases from prostate cancer are very common. They are usually located on the axial skeleton. However, cranial bone metastases especially to the parietal bone are rare. We report a case of metastatic prostate cancer presenting with left parietal bone metastasis in a patient with no urological symptoms or signs. We should consider prostate cancer in any man above 60 years presenting unusual bone lesions.

Clinical Insignificance of [18F]PSMA-1007 Avid Non-specific Bone Lesions: A Retrospective Evaluation

2021 ◽  
Author(s):  
Evyn G. Arnfield ◽  
Paul A. Thomas ◽  
Matthew J. Roberts ◽  
Anita M. Pelecanos ◽  
Stuart C. Ramsay ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Clinical Outcomes ◽  
Gleason Score ◽  
Malignant Lesion ◽  
Common Finding ◽  
Bone Lesions ◽  
Retrospective Audit

Abstract Purpose: [18F]PSMA-1007 offers advantages of low urinary tracer excretion and improved resolution for imaging prostate cancer. However, non-specific bone lesions (NSBLs), defined as mild to moderate focal bone uptake without a typical morphological correlate on CT, are a common finding on [18F]PSMA-1007 PET/CT. The purpose of this study was to investigate the clinical outcomes of patients with [18F]PSMA-1007 avid NSBLs, to determine whether patients with NSBLs represent a higher risk clinical cohort, and to determine whether SUVmax can be used as a classifier of bone metastasis.Methods: A retrospective audit of 214 men with prostate cancer was performed to investigate the clinical outcomes of [18F]PSMA-1007 avid NSBLs according to defined criteria. We also compared the serum PSA, Gleason score and uptake time of patients with [18F]PSMA-1007 avid NSBLs to patients without [18F]PSMA-1007 avid bone lesions. Finally, we assessed whether SUVmax is a good classifier of bone metastases using ROC curve analysis.Results: No [18F]PSMA-1007 avid NSBLs met criteria for a likely malignant or definitely malignant lesion after a median 15.8-month follow-up interval (11.9% definitely benign, 50.3% likely benign, and 37.7% equivocal). There were no statistically significant differences in serum PSA, Gleason score and uptake time between patients with [18F]PSMA-1007 avid NSBLs and those without [18F]PSMA-1007 avid bone lesions. All NSBLs with adequate follow-up had SUVmax ≤11.1. When comparing NSBLs to definite prostate cancer bone metastases, the highest SUVmax value recorded was a good classifier of bone metastasis, and an SUVmax cut-point of ≥7.2 maximised the Youden’s index.Conclusion: [18F]PSMA-1007 avid NSBLs rarely represent prostate cancer bone metastases. When identified in the absence of definite metastatic disease elsewhere, it is appropriate to classify those with SUVmax <7.2 as likely benign. NSBLs with SUVmax 7.2-11.1 may be classified as equivocal or metastatic, with patient clinical risk factors, scan appearance, and potential management implications used to guide interpretation.

Pain as an Indicator of Bone Metastasis

1988 ◽  
Vol 29 (4) ◽  
pp. 445-449 ◽  
Author(s):  
E. Palmer ◽  
B. Henrikson ◽  
K. McKusick ◽  
H. W. Strauss ◽  
F. Hochberg
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Disease ◽  
Bone Pain ◽  
Metastatic Prostate Cancer ◽  
Metastatic Bone Disease ◽  
Common Finding ◽  
Breast Metastases ◽  
Skeletal Pain ◽  
Self Administered Questionnaire

Patients with breast or prostate cancer routinely referred for bone scintigraphy were evaluated for the presence of skeletal pain, as determined by a self administered questionnaire. Pain was a common finding, whether or not metastatic disease was present, and occurred in over half of patients. Although most patients with bone metastases did report bone pain, a significant fraction (21% of breast and 22% of prostate patients) were asymptomatic. A distinct minority of individual anatomic regions of metastasis were painful: pain was reported in 23 % of sites of breast metastases and 15% of metastatic prostate cancer sites. Of all sites at which pain was present, metastases were demonstrated in only about one half. These results indicate that pain is not a reliable indicator of the presence of location of metastatic bone disease.

scholarly journals A novel tool for improving the interpretation of isotope bone scans in metastatic prostate cancer

2020 ◽  
Vol 93 (1115) ◽  
pp. 20200775
Author(s):  
ALI H.D. Alshehri ◽  
Sarah O.S. Osman ◽  
Kevin M. Prise ◽  
Caoimhghin Campfield ◽  
PG Turner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Clinical Utility ◽  
Bone Scan ◽  
Metastatic Prostate Cancer ◽  
Imaging Modality ◽  
Skeletal Metastases ◽  
Bone Lesions ◽  
Subjective Interpretation ◽  
Radium 223

Objectives: The isotope bone scan (IBS) is the gold-standard imaging modality for detecting skeletal metastases as part of prostate cancer staging. However, its clinical utility for assessing skeletal metastatic burden is limited due to the need for subjective interpretation. We designed and tested a novel custom software tool, the Metastatic Bone Scan Tool (MetsBST), aimed at improving interpretation of IBSs, and compared its performance with that of an established software programme. Methods: We used IBS images from 62 patients diagnosed with prostate cancer and suspected bone metastases to design and implement MetsBST in MATLAB by defining thresholds used to identify the texture and size of metastatic bone lesions. The results of MetsBST were compared with those of the commercially available automated Bone Scan Index (aBSI) with regression analysis. Results: There was strong agreement between the MetsBST and aBSI results (R2 = 0.9189). In a subregional analysis, MetsBST quantified the extent of metastatic disease in multiple bone sites in patients receiving multimodality therapy (radium-223 and external beam radiotherapy) to illustrate the differences in bone metastatic response to different treatments. Conclusion: The results of MetsBST and the commercial software aBSI were highly consistent. MetsBST introduces novel clinical utility by its ability to differentiate between the responses of different bone metastases to multimodality therapies. Advances in knowledge: MetsBST reduces the variability in assessment of tumour burden caused by subjective interpretation. Therefore, it is a useful aid to physicians reporting nuclear medicine scans, and may improve decision-making in the treatment of metastatic prostate cancer.

scholarly journals Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Navatha Shree Polavaram ◽  
Samikshan Dutta ◽  
Ridwan Islam ◽  
Arup K. Bag ◽  
Sohini Roy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Potential Effect ◽  
Tumor Burden ◽  
Bone Lesions ◽  
Prostate Cancer Cells

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.

scholarly journals A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Erik Bovinder Ylitalo ◽  
Elin Thysell ◽  
Mattias Landfors ◽  
Maria Brattsand ◽  
Emma Jernberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Bone Metastases ◽  
Metastatic Prostate Cancer ◽  
Tumor Biology ◽  
Receptor Activity ◽  
Mrna Levels ◽  
Androgen Receptor Activity ◽  
Patient Prognosis

Abstract Background Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity. Materials and methods Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity. Results Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT. Conclusions A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

scholarly journals Prostatic Acid Phosphatase Alters the RANKL/OPG System and Induces Osteoblastic Prostate Cancer Bone Metastases

Endocrinology ◽  
2016 ◽  
Vol 157 (12) ◽  
pp. 4526-4533 ◽  
Author(s):  
Alexander Kirschenbaum ◽  
Sudeh Izadmehr ◽  
Shen Yao ◽  
Kieley L. O’Connor-Chapman ◽  
Alan Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Acid Phosphatase ◽  
Bone Metastases ◽  
Cross Talk ◽  
Bone Cells ◽  
Bone Mineralization ◽  
Critical Role ◽  
Prostatic Acid Phosphatase ◽  
Bone Lesions ◽  
Rankl Expression

Prostate cancer (PCa) is unique in its tendency to produce osteoblastic (OB) bone metastases. There are no existing therapies that specifically target the OB phase that affects 90% of men with bone metastatic disease. Prostatic acid phosphatase (PAP) is secreted by PCa cells in OB metastases and increases OB growth, differentiation, and bone mineralization. The purpose of this study was to investigate whether PAP effects on OB bone metastases are mediated by autocrine and/or paracrine alterations in the receptor activator of nuclear factor κ-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. To investigate whether PAP modulated these factors and altered the bone reaction, we knocked down PAP expression in VCaP cells and stably overexpressed PAP in PC3M cells, both derived from human PCa bone metastases. We show that knockdown of PAP in VCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cells had the inverse effect, increasing OPG while decreasing RANK/RANKL expression. Coculture of PCa cells with MC3T3 preosteoblasts also revealed a role for secretory PAP in OB-PCa cross talk. Reduced PAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating OB rather than osteolytic lesions in vivo using an intratibial model. These findings demonstrate that PAP secreted by PCa cells in OB bone metastases increases OPG and plays a critical role in the vicious cross talk between cancer and bone cells. These data suggest that inhibition of secretory PAP may be an effective strategy for PCa OB bone lesions.

Surgical treatment as option in treatment of metastatic hormone-sensitive prostate cancer after prior drug treatment

2022 ◽  
pp. 41-45
Author(s):  
Sh. G. Khakimova ◽  
G. G. Khakimova ◽  
G. A. Khakimov ◽  
J. B. Sadullaev
Keyword(s):  
Prostate Cancer ◽  
Surgical Treatment ◽  
Drug Treatment ◽  
Bone Metastases ◽  
Clinical Result ◽  
Metastatic Prostate Cancer ◽  
Clinical Case ◽  
Complex Treatment ◽  
Good Clinical Result ◽  
Hormone Sensitive

Currently, there is no consensus on the place of prostatectomy in the complex treatment of patients with metastatic prostate cancer. A description of a clinical case of complex treatment and observation of a patient with prostate cancer with an unfavorable baseline prognosis and the presence of bone metastases with a good clinical result is presented.

Impact of IGF-I and CYP19 Gene Polymorphisms on the Survival of Patients With Metastatic Prostate Cancer

2006 ◽  
Vol 24 (13) ◽  
pp. 1982-1989 ◽  
Author(s):  
Norihiko Tsuchiya ◽  
Lizhong Wang ◽  
Hiroyoshi Suzuki ◽  
Takehiko Segawa ◽  
Hisami Fukuda ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Patients ◽  
Genetic Polymorphisms ◽  
Metastatic Prostate Cancer ◽  
Genetic Factors ◽  
Response To Treatment ◽  
Logrank Test ◽  
Ca Repeat ◽  
Igf I

Purpose The prognosis of metastatic prostate cancer significantly differs among individuals. While various clinical and biochemical prognostic factors for survival have been suggested, the progression and response to treatment of those patients may also be defined by host genetic factors. In this study, we evaluated genetic polymorphisms as prognostic predictors of metastatic prostate cancer. Patients and Methods One hundred eleven prostate cancer patients with bone metastasis at the diagnosis were enrolled in this study. Thirteen genetic polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism or an automated sequencer with a genotyping software. Results Among the polymorphisms, the long allele (over 18 [CA] repeats) of insulin-like growth factor-I (IGF-I) and the long allele (over seven [TTTA] repeats) of cytochrome P450 (CYP) 19 were significantly associated with a worse cancer-specific survival (P = .016 and .025 by logrank test, respectively). The presence of the long allele of either the IGF-I or CYP19 polymorphisms was an independent risk factor for death (P = .019 or .026, respectively). Furthermore, the presence of the long allele of both the IGF-I and CYP19 polymorphisms was a stronger predictor for survival (P = .001). Conclusion The prognosis of metastatic prostate cancer patients is suggested to be influenced by intrinsic genetic factors. The IGF-I (CA) repeat and CYP19 (TTTA) repeat polymorphisms may be novel predictors in prostate cancer patients with bone metastasis at the diagnosis.

scholarly journals Comparison of PSMA PET/CT With Fluoride PET/CT for Detection of Bone Metastatic Disease in Prostate Cancer

2021 ◽  
Author(s):  
Naresh Kumar Regula ◽  
Vasileios Kostaras ◽  
Silvia Johansson ◽  
Carlos Trampal ◽  
Elin Lindström ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Node ◽  
Bone Metastasis ◽  
Soft Tissue ◽  
Diagnostic Performance ◽  
Bone Lesions ◽  
Soft Tissue Lesions ◽  
Contrast Enhanced Ct ◽  
Psma Pet ◽  
Pet Ct

Abstract 18F-NaF positron emission tomography/computed tomography (fluoride PET/CT) is considered the most sensitive technique to detect bone metastasis in prostate cancer (PCa). 68Ga-PSMA-11 (PSMA) PET/CT is increasingly used for staging of PCa. This study primarily aimed to compare the diagnostic performance of fluoride PET/CT and Gallium based PSMA PET/CT in identifying bone metastasis followed by a comparison of PSMA PET/CT with contrast-enhanced CT (CE-CT) in identifying soft tissue lesions as a secondary objective. Methods: Twenty-eight PCa patients with high suspicion of disseminated disease following curative treatment were prospectively evaluated. PET/CT examinations using fluoride and PSMA were performed. All suspicious bone lesions were counted, and the tracer uptake was measured as standardized uptake values (SUV) for both tracers. In patients with multiple findings, ten bone lesions with highest SUVmax were selected from which identical lesions from both scans were considered for direct comparison of SUVmax. Soft tissue findings of local and lymph node lesions from CE-CT were compared with PSMA PET/CT. Results: Both scans were negative for bone lesions in 7 patients (25%). Of 699 lesions consistent with skeletal metastasis in 21 patients on fluoride PET/CT, PSMA PET/CT identified 579 lesions (83%). In 69 identical bone lesions fluoride PET/CT showed significantly higher uptake (mean SUVmax: 73.1±36.8) compared to PSMA PET/CT (34.5±31.4; p<0.001). Compared to CE-CT, PSMA PET/CT showed better diagnostic performance in locating local (96% vs 61%, p=0.004) and lymph node (94% vs 46%, p<0.001) metastasis. Conclusion: In this prospective comparative study PSMA PET/CT detected the majority of bone lesions that were positive on fluoride PET/CT. Further, this study indicates better diagnostic performance of PSMA PET/CT to locate soft tissue lesions compared to CE-CT.

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