Bone scan as a stratification variable in advanced prostate cancer

Knudson, Gregory; Grinis, Gedas; Lopéz-Majano, V.; Sansi, Pratiba; Targonski, Paul V.; Rubenstein, Marvin; Sharifi, Rohallah; Guinan, Patrick

doi:10.1002/1097-0142(19910715)68:2<316::aid-cncr2820680218>3.0.co;2-0

Cited by 33 publications

(12 citation statements)

References 14 publications

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“…This bone metastasis pattern is similar to sites of prostate cancer bone metastasis in humans, with the lumbar vertebrae being most common, followed by ribs, pelvis, and long bones (51). Greater than 80% of mice injected with cells overexpressing ARAF (7/8 mice) and MERTK (5/6 mice) developed bone metastasis, whereas BRAF, CRAF, and NTRK2 promoted bone metastasis in at least 50% of mice.…”

Section: Discussionsupporting

confidence: 55%

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Faltermeier

Drake

Clark

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.kinases | metastasis | prostate cancer | bone metastasis M etastatic prostate cancer is responsible for the deaths of ∼30,000 men in the United States each year (1, 2). Ninety percent of patients develop bone metastases, and other major sites of metastases include lymph nodes, liver, adrenal glands, and lung (3). First-line treatments for metastatic disease are androgen deprivation therapies that block androgen synthesis or signaling through the androgen receptor (AR) (2). Inevitably, metastatic prostate cancer becomes resistant to androgen blockade. Second-line treatments such as chemotherapy (docetaxel, cabazitaxel) and radiation only extend survival 2-4 mo (4, 5).Identifying new therapeutic targets for metastatic prostate cancer has proven difficult. Exome and whole-genome sequencing of human metastatic prostate cancer tissues have found frequent mutations and/or chromosomal aberrations in numerous genes, including AR, TP53, PTEN, BRCA2, and MYC (6-11). The precise functional contribution of these genes to prostate cancer metastasis remains unknown. Genomic and phosphoproteomic analyses have also revealed that metastatic prostate cancer is molecularly heterogeneous, which has complicated the search for common therapeutic targets (12). Few murine models of prostate cancer develop metastases. Mice having prostate-specific homozygous deletions in SMAD4 and PTEN or expression of mutant KRAS develop metastases in visceral organs but rarely in bone (13-15).Targeting genetically altered constitutively active protein kinases such as BCR-ABL in chronic myelogenous leukemia and BRAF V600E in melanoma has led to dramat...

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Section: Discussionsupporting

confidence: 55%

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Faltermeier

Drake

Clark

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Liver involvement was reported to associate with an unfavorable prognosis [ 21 , 22 ], and lung metastasis alone was a favorable prognostic factor among patients with metachronous metastatic NPC [ 13 ]. By contrast, few studies addressed the issue of the prognostic values of metastatic locations among patients with synchronous metastatic NPC.…”

Section: Discussionmentioning

confidence: 99%

Subdivision of M category for nasopharyngeal carcinoma with synchronous metastasis: time to expand the M categorization system

et al. 2015

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IntroductionThe current metastatic category (M) of nasopharyngeal carcinoma (NPC) is a “catch-all” classification, covering a heterogeneous group of tumors ranging from potentially curable to incurable. The aim of this study was to design an M categorization system that could be applied in planning the treatment of NPC with synchronous metastasis.MethodsA total of 505 NPC patients diagnosed with synchronous metastasis at Sun Yat-sen University Cancer Center between 2000 and 2009 were involved. The associations of clinical variables, metastatic features, and a proposed M categorization system with overall survival (OS) were determined by using Cox regression model.ResultsMultivariate analysis showed that Union for International Cancer Control (UICC) N category (N1–3/N0), number of metastatic lesions (multiple/single), liver involvement (yes/no), radiotherapy to primary tumor (yes/no), and cycles of chemotherapy (>4/≤4) were independent prognostic factors for OS. We defined the following subcategories based on liver involvement and the number of metastatic lesions: M1a, single lesion confined to an isolated organ or location except the liver; M1b, single lesion in the liver and/or multiple lesions in any organs or locations except the liver; and M1c, multiple lesions in the liver. Of the 505 cases, 74 (14.7%) were classified as M1a, 296 (58.6%) as M1b, 134 (26.5%) as M1c, and 1 was not specified. The three M1 subcategories showed significant difference in OS [M1b vs. M1a, hazard ratio (HR) = 1.69, 95% confidence interval (CI) = 1.16–2.48, P = 0.007; M1c vs. M1a, HR = 2.64, 95% CI = 1.75–3.98, P < 0.001].ConclusionsWe developed an M categorization system based on the independent factors related to the prognosis of patients with metastatic NPC. This system may be helpful to further optimize individualized care for NPC patients.

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“…Patients with multiple bone metastases were associated with poor prognosis in various kinds of malignancies [13,26,[28][29][30]; however, no previous study had specifically analyzed the prognostic value of the number of metastatic sites among patients with bone-only metastasis. It is intriguing that in our study, univariate analysis showed that both the number of metastases (multiple vs. single) and the number of metastatic sites (more than three vs. three or fewer) were associated with OS of patients with bone-only metastatic NPC; multivariate analysis including all significant covariates showed that the number of metastatic sites (more than three vs. three or fewer) but not the number of metastases (multiple vs. single) was an independent predictor for OS.…”

Section: Cmementioning

confidence: 99%

M1 Stage Subdivision and Treatment Outcome of Patients With Bone-Only Metastasis of Nasopharyngeal Carcinoma

et al. 2015

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Background. The current M1 stage in nasopharyngeal carcinoma (NPC) does not differentiate patients based on metastatic site and number of metastases. This study aims to subdivide the M1 stage of NPC patients with bone-only metastases and to identify the patients who may benefit from combined chemoradiotherapy (CRT). Methods. Between 1998 and 2007, 312 patients diagnosed with bone-only metastasis at Sun Yat-sen University Cancer Center were enrolled.Various possible subdivisions of M1 stage were considered, including by the time order of metastasis (synchronous vs. metachronous), involvement of specific bone metastatic site, the number of metastatic sites, and the number of metastases. The correlation of the subdivisions of M1 stage with overall survival (OS) was determined by Cox regression. Results. The median OS was 23.4 months. Patients with more than three metastatic sites had significantly poorer OS than patients with three or fewer metastatic sites (16.2 vs. 32.4

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Bone scan as a stratification variable in advanced prostate cancer

Cited by 33 publications

References 14 publications

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Subdivision of M category for nasopharyngeal carcinoma with synchronous metastasis: time to expand the M categorization system

M1 Stage Subdivision and Treatment Outcome of Patients With Bone-Only Metastasis of Nasopharyngeal Carcinoma

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