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1.  Enhanced detection of metastatic prostate cancer cells in human plasma with lipid bodies staining 
BMC Cancer  2014;14:91.
Reprogramming of energy metabolism of malignant cancer cells confers competitive advantage in growth environments with limited resources. However, not every process of cancer development is associated with competition for resources. During hematogenous transport, cancer cells are exposed to high levels of oxygen and nutrients. Does energy metabolism of cancer cells change as a function of exposure to the bloodstream? Could such changes be exploited to improve the detection of circulating tumor cells (CTC)? These questions have clinical significance, but have not yet been sufficiently examined.
The energy metabolism was examined as a function of incubation in nutrient-rich plasma in prostate metastatic cancer cells LNCaP and non-transformed prostate epithelial cells RWPE1. Uptake kinetics of a fluorescent glucose analog (2-NBD) and lipophilic dyes (DiD & Bodipy) were measured in both cell lines, as well as in peripheral blood mononuclear cells (PBMC).
LNCaP cells exhibited hyper-acetylation of low molecular weight proteins compared to RWPE1 cells. Following plasma incubation, protein lysine acetylation profile was unchanged for LNCaP cells while significantly altered for RWPE1 cells. O-linked glycosylated protein profiles were different between LNCaP and RWPE1 cells and varied in both cell lines with plasma incubation. Maximal respiration or glycolytic capacities was unchanged in LNCaP cells and impaired in RWPE1 cells following plasma incubation. However, the uptake rates of 2-NBD and DiD were insufficient for discrimination of LNCaP, or RWPE1 cells from PBMC. On the other hand, both RWPE1 and LNCaP cells exhibited intracellular lipid bodies following plasma incubation; whereas, PBMC did not. The presence of lipid bodies in LNCaP cells permitted retention of Bodipy dye and allowed discrimination of LNCaP cells from PBMC with flow cytometry.
Despite clear differences in energy metabolism, metastatic prostate cancer cells could not be efficiently distinguished from non-transformed prostate epithelial cells using fluorescent glucose or lipid uptake kinetics. However, metastatic prostate cancer cells in plasma could be clearly distinguished from blood nucleated cells due to the presence of intracellular lipid bodies. Fluorescent labeling of lipid bodies permitted a simple and sensitive means for high throughput detection of metastatic prostate cancer cells in human plasma.
PMCID: PMC3931481  PMID: 24528787
Cancer energy metabolism; Coherent anti-Stokes Raman microscopy; Circulating tumor cell; Flow cytometry; Lipid bodies; Prostate cancer; Protein lysine acetylation; Protein O-linked glycosylation; Proteomics
2.  A Phase 1 Study of a Vaccine Targeting Preferentially Expressed Antigen in Melanoma and Prostate-specific Membrane Antigen in Patients With Advanced Solid Tumors 
Preferentially expressed antigen in melanoma (PRAME) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens implicated in cellular differentiation, genetic stability, and angiogenesis. MKC1106-PP is an immunotherapeutic regimen cotargeting PRAME and PSMA, comprised of a recombinant plasmid (pPRA-PSM encoding fragments derived from both antigens) and 2 peptides (E-PRA and E-PSM derived from PRAME and PSMA, respectively). This multicenter study evaluated MKC1106-PP with a fixed plasmid dose and 2 different peptide doses, administered by intralymph node injection in a prime-boost sequence in human leukocyte antigen-A*0201 and tumor-antigen-positive patients with progressing metastatic solid tumors who had failed standard therapy. Immune monitoring was done by tetramer and enzymatic-linked immune spot analysis. The treatment was well tolerated, with no significant differences in safety, immune response, and clinical outcome relative to peptide doses. Fifteen of 24 evaluable patients showed an immune response, as defined by the expansion of PRAME-specific or PSMA-specific T cells in the blood. There were no partial or complete responses by the Response Evaluation Criteria in Solid Tumors. Seven patients showed stable disease (SD) for 6 months or longer, or prostate specific antigen decline: 4 of 10 with prostate carcinoma, 2 of 2 with renal clear cell carcinoma, and 1 of 10 with metastatic melanoma. In addition, there was an association between the induction and persistence of antigen-specific T cells in blood above baseline levels and disease control, defined as SD for 6 months or longer. These results support further development of MKC1106-PP in specific clinical indications.
PMCID: PMC3709852  PMID: 21760528
active immunotherapy; PRAME; PSMA; solid tumor; intralymph node vaccination
3.  Detection of Lipid-Rich Prostate Circulating Tumour Cells with Coherent Anti-Stokes Raman Scattering Microscopy 
BMC Cancer  2012;12:540.
Circulating tumour cells (CTC) are an important indicator of metastasis and associated with a poor prognosis. Detection sensitivity and specificity of CTC in the peripheral blood of metastatic cancer patient remain a technical challenge.
Coherent anti-Stokes Raman scattering (CARS) microscopy was employed to examine the lipid content of CTC isolated from the peripheral blood of metastatic prostate cancer patients. CARS microscopy was also employed to evaluate lipid uptake and mobilization kinetics of a metastatic human prostate cancer cell line.
One hundred CTC from eight metastatic prostate cancer patients exhibited strong CARS signal which arose from intracellular lipid. In contrast, leukocytes exhibited weak CARS signal which arose mostly from cellular membrane. On average, CARS signal intensity of prostate CTC was 7-fold higher than that of leukocytes (P<0.0000001). When incubated with human plasma, C4-2 metastatic human prostate cancer cells exhibited rapid lipid uptake kinetics and slow lipid mobilization kinetics. Higher expression of lipid transport proteins in C4-2 cells compared to non-transformed RWPE-1 and non-malignant BPH-1 prostate epithelial cells further indicated strong affinity for lipid of metastatic prostate cancer cells.
Intracellular lipid could serve as a biomarker for prostate CTC which could be sensitively detected with CARS microscopy in a label-free manner. Strong affinity for lipid by metastatic prostate cancer cells could be used to improve detection sensitivity and therapeutic targeting of prostate CTC.
PMCID: PMC3519750  PMID: 23171028
4.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 number, NCT00638690.)
PMCID: PMC3471149  PMID: 21612468
5.  Carcinomatous meningitis in a patient with Her2/neu expressing bladder cancer following trastuzumab and chemotherapy: a case report and review of the literature 
Targeted therapies may impact the natural history of bladder cancer based upon their pharmacokinetics. The Her2/neu receptor tyrosine kinase, overexpressed by half of all primary urothelial carcinomas, has recently been examined as a therapeutic target in bladder cancer in a prospective phase II multicenter trial (NCI-198) that enrolled 109 patients with advanced bladder carcinomas for treatment with trastuzumab in combination with paclitaxel, carboplatin, and gemcitabine. We report on documented isolated Her2/neu positive carcinomatous meningitis in a patient treated with trastuzumab.
Case presentation
A 61-year-old Caucasian man with metastatic bladder cancer was treated with neoadjuvant chemotherapy in combination with trastuzumab with a partial response that was followed by a complete response after surgery. He relapsed with isolated Her2/neu positive carcinomatous meningitis.
Carcinomatous meningitis in bladder cancer is extremely rare. This is the first case reported of Her2/neu positive carcinomatous meningitis. Disease recurred solely at a sanctuary site, demonstrating that despite the systemic efficacy of trastuzumab in combination with chemotherapy, its inability to enter the central nervous system potentially contributes to the unusual site of disease recurrence.
PMCID: PMC2767151  PMID: 19918289
6.  Bombesin attenuates pre-mRNA splicing of glucocorticoid receptor by regulating the expression of serine-arginine protein p30c (SRp30c) in prostate cancer cells 
Biochimica et biophysica acta  2007;1773(7):1087-1094.
Although glucocorticoids are frequently administered to patients with hormone refractory prostate cancer, their therapeutic effectiveness is limited by the development of glucocorticoid resistance. The molecular mechanisms of glucocorticoid resistance are unknown but are believed to involve neuropeptide growth factors and cytokines. We examined the functional interaction between bombesin and dexamethasone in PC-3 cells and found that bombesin could act as a survival factor by interfering with dexamethasone-mediated growth inhibition. Because glucocorticoids exert their effects through glucocorticoid receptors (GRs), we measured the expression of GRα and GRβ isoforms in the presence of bombesin. Western blotting and real time PCR revealed bombesin induced expression of GRβ, but not GRα. Because GR isoforms are generated by alternative splicing of a common GR gene, we examined the expression of serine-arginine (SR) proteins involved in alternative splicing, and found that the expression of SRp30 was induced by bombesin in PC-3 cells. To characterize the role of SRp30 in splicing of GR isoforms, siRNAs specific to various SRp30 isoforms were transfected into PC-3 cells. We found that suppression of SRp30c expression by siRNA specifically antagonized bombesin’s effect on glucocorticoid-mediated inhibition of PC cells, suggesting that bombesin-induced expression of SRp30c affects GR pre-mRNA splicing, leading to increased GRβ expression and contributing to glucocorticoid resistance in PC cells.
PMCID: PMC1939980  PMID: 17540466
Glucocorticoids; glucocorticoid receptors; SRp30 proteins; bombesin; neuropeptides; prostate cancer

Results 1-6 (6)