Biomedical subjects

Robert Vessella

Publications and source records attributed to Robert Vessella.

13 recordsLinked to original sources

PubMed2006

Combined in vivo effect of A12, a type 1 insulin-like growth factor receptor antibody, and docetaxel against prostate cancer tumors.

PURPOSE: A human type 1 insulin-like growth factor receptor antibody (A12) has been shown to effectively inhibit human xenograft tumor growth, including androgen-dependent and androgen-independent prostate tumors. Docetaxel, either as a single agent or combined with others, has shown a survival benefit in prostate cancer patients. Based on these data, we investigated the combined in vivo effect of A12 and docetaxel on human androgen-independent and osseous prostate tumor growth. EXPERIMENTAL DESIGN: To study human androgen-independent prostate cancer model, LuCaP35V tumors were implanted s.c. into castrated severe combined immunodeficient mice. When tumors reached about 100 mm3, animals were treated with vehicle control docetaxel (10 or 20 mg/kg) and docetaxel in combination with A12 (40 microg/kg) for 4 weeks. To study human osseous prostate cancer model, LuCaP 23.1 tumors were implanted intratibiae. When serum prostate-specific antigen reached 5 to 10 ng/mL, treatments were initiated. RESULTS: A12 markedly augmented the inhibition of docetaxel on tumor growth. When docetaxel is combined with A12, the inhibition of tumor growth continued after treatment cessation, which was associated with continued apoptosis and decreased proliferation of tumor cells. Gene expression profiles indicated that the posttreatment suppression of tumor growth may be due to enhanced negative regulation of cell cycle progression- and/or cell survival-associated genes, some of which have been shown to induce resistance to docetaxel. CONCLUSIONS: Our findings suggest that targeting type 1 insulin-like growth factor receptor can enhance the therapeutic effect of docetaxel on advanced prostate cancer. Our findings also suggest a potential mechanism to improve the treatment efficacy of docetaxel in prostate cancer.

Animals↗

PubMed2006

Basic mechanisms responsible for osteolytic and osteoblastic bone metastases.

Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation. The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.

Bone Neoplasms↗

PubMed2006

TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer.

Prostate cancer is a common and clinically heterogeneous disease with marked variability in progression. The recent identification of gene fusions of the 5'-untranslated region of TMPRSS2 (21q22.3) with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4 (17q21), suggests a mechanism for overexpression of the ETS genes in the majority of prostate cancers. In the current study using fluorescence in situ hybridization (FISH), we identified the TMPRSS2:ERG rearrangements in 49.2% of 118 primary prostate cancers and 41.2% of 18 hormone-naive lymph node metastases. The FISH assay detected intronic deletions between ERG and TMPRSS2 resulting in TMPRSS2:ERG fusion in 60.3% (35 of 58) of the primary TMPRSS2:ERG prostate cancers and 42.9% (3 of 7) of the TMPRSS2:ERG hormone-naive lymph node metastases. A significant association was observed between TMPRSS2:ERG rearranged tumors through deletions and higher tumor stage and the presence of metastatic disease involving pelvic lymph nodes. Using 100K oligonucleotide single nucleotide polymorphism arrays, a homogeneous deletion site between ERG and TMPRSS2 on chromosome 21q22.2-3 was identified with two distinct subclasses distinguished by the start point of the deletion at either 38.765 or 38.911 Mb. This study confirms that TMPRSS2:ERG is fused in approximately half of the prostate cancers through deletion of genomic DNA between ERG and TMPRSS2. The deletion as cause of TMPRSS2:ERG fusion is associated with clinical features for prostate cancer progression compared with tumors that lack the TMPRSS2:ERG rearrangement.

5' Untranslated Regions↗

PubMed2006

A molecular correlate to the Gleason grading system for prostate adenocarcinoma.

Adenocarcinomas of the prostate can be categorized into tumor grades based on the extent to which the cancers histologically resemble normal prostate glands. Because grades are surrogates of intrinsic tumor behavior, characterizing the molecular phenotype of grade is of potential clinical importance. To identify molecular alterations underlying prostate cancer grades, we used microdissection to obtain specific cohorts of cancer cells corresponding to the most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each cancer sample with matched benign lumenal prostate epithelial cells and profiled transcript abundance levels by microarray analysis. We identified an 86-gene model capable of distinguishing low-grade (pattern 3) from high-grade (patterns 4 and 5) cancers. This model performed with 76% accuracy when applied to an independent set of 30 primary prostate carcinomas. Using tissue microarrays comprising >800 prostate samples, we confirmed a significant association between high levels of monoamine oxidase A expression and poorly differentiated cancers by immunohistochemistry. We also confirmed grade-associated levels of defender against death (DAD1) protein and HSD17 beta4 transcripts by immunohistochemistry and quantitative RT-PCR, respectively. The altered expression of these genes provides functional insights into grade-associated features of therapy resistance and tissue invasion. Furthermore, in identifying a profile of 86 genes that distinguish high- from low-grade carcinomas, we have generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.

Adenocarcinoma↗

PubMed2006

Targeted chemotherapy with cytotoxic bombesin analogue AN-215 inhibits growth of experimental human prostate cancers.

We developed a powerful cytotoxic analogue of bombesin AN-215, in which the bombesin (BN)-like carrier peptide is conjugated to 2-pyrrolino doxorubicin (AN-201). Human prostate cancers express high levels of receptors for BN/gastrin releasing peptide (GRP) that can be used for targeted chemotherapy. The effects of targeted chemotherapy with cytotoxic BN analogue AN-215 were evaluated in nude mice bearing subcutaneous xenografts of DU-145, LuCaP-35, MDA-PCa-2b and intraosseous implants of C4-2 human prostate cancers. Intraosseous growth of C4-2 tumors was monitored by serum PSA. BN/GRP receptors were evaluated by 125I-[Tyr4]BN binding assays and RT-PCR. The effects of AN-215 on apoptosis and cell proliferation were followed by histology, and the expression of Bcl-2 and Bax protein was determined by Western blot analysis. Targeted analog AN-215 significantly inhibited growth of subcutaneously implanted DU-145, LuCaP-35 and MDA-PCa-2b prostate cancers by 81% to 91% compared to controls, while cytotoxic radical AN-201 was less effective and more toxic. Serum PSA levels of mice bearing intraosseous C4-2 prostate tumors were significantly reduced. In LuCaP-35 tumors administration of BN antagonist RC-3095 prior to AN-215 blocked the receptors for BN/GRP and inhibited the effects of AN-215. High affinity receptors for BN/GRP and their m-RNA were detected on membranes of all 4 tumor models. Therapy with AN-215, but not with AN-201, decreased the ratio of Bcl-2/Bax in DU-145 and the expression of antiapoptotic Bcl-2 in LuCaP-35 tumors. The presence of BN/GRP receptors on primary and metastatic prostate cancers makes possible targeted chemotherapy with AN-215 for the treatment of this malignancy.

Animals↗

PubMed2005

Estrogen effects on tubulin expression and taxane mediated cytotoxicity in prostate cancer cells.

BACKGROUND: The present study was designed to determine if estrogens change microtubule polymerization and modulate cell cycle progression in vitro, related to modulation of tubulin expression and to determine if estrogens had antagonistic or synergistic effects with microtubule active agents. METHODS: cDNA array analysis of LNCaP cells treated with the estrogens, estradiol, estrone, diethylstilbestrol (DES), and 2-methoxyestradiol (2-ME) was carried out and the results confirmed by PCR and Western blotting. Microtubule arrays in cells treated with estrogens were assessed using indirect immunofluorescence. The effects of combining estrogens with taxane was assessed by MTT assay and flow cytometry for cell cycle kinetics. Human prostate cancer xenografts were treated with DES and docetaxel to assess the effects of combining estrogens and taxane in vivo. RESULTS: Treatment of LNCaP cells with DES and 2-ME suppressed transcripts and protein for beta-tubulin isotype IVa. This effect on tubulin synthesis was not blocked by estrogen or androgen receptor modulators. Other estrogens had no effect on beta-tubulin expression. 2-ME and DES decreased the density of microtubules. The administration of DES or 2-ME with paclitaxel enhanced cytotoxicity and G(2)-M arrest in vitro. DES enhanced tumor suppression in a human prostate cancer xenograft model when combined with the taxane docetaxel. CONCLUSION: The use of DES and 2-ME enhances the effects of taxanes and may be a novel and important means of increasing therapeutic efficacy of cytotoxic chemotherapy against prostate carcinoma.

Blotting, Western↗

PubMed2005

In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors.

PURPOSE: The type I insulin-like growth factor receptor (IGF-IR) and its ligands have been shown to play a critical role in prostate carcinoma development, growth, and metastasis. Targeting the IGF-IR may be a potential treatment for prostate cancer. A fully human monoclonal antibody, A12, specific to IGF-IR, has shown potent antitumor effects in breast, colon, and pancreatic cancers in vitro and in vivo. In this study, we tested the in vivo effects of A12 on androgen-dependent and androgen-independent prostate tumor growth. EXPERIMENTAL DESIGN: Androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate tumors were implanted s.c. into intact and castrated severe combined immunodeficient mice, respectively. When tumor volume reached about 150 to 200 mm(3), A12 was injected at 40 mg/kg body weight thrice a week for up to 5 weeks. RESULTS: We find that A12 significantly inhibits growth of androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate xenografts, however, by different mechanisms. In LuCaP 35 xenografts, A12 treatment induces tumor cell apoptosis or G(1) cycle arrest. In LuCaP 35V xenografts, A12 treatment induces tumor cell G(2)-M cycle arrest. Moreover, we find that blocking the function of IGF-IR down-regulates androgen-regulated gene expression in androgen-independent LuCaP 35V tumor cells. CONCLUSIONS: Our findings suggest that A12 is a therapeutic candidate for both androgen-dependent and androgen-independent prostate cancer. Our findings also suggest an IGF-IR-dependent activity of the androgen receptor in androgen-independent prostate cancer cells.

Androgens↗

PubMed2003

Molecular determinants of resistance to antiandrogen therapy.

Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.

Androgen Antagonists↗

PubMed2003

Elevation of cytokine levels in cachectic patients with prostate carcinoma.

BACKGROUND: Approximately 60-70% of patients with advanced prostate carcinoma (CaP) suffer from cachexia, one of the most devastating conditions associated with advanced malignant disease. The pathophysiology of cachexia is multifactorial, and several cytokines, such as tumor necrosis factor alpha (TNFalpha) and interleukin 1 (IL-1), IL-6, and IL-8, may be involved. The objective of the current study was to determine whether cachexia associated with advanced CaP is accompanied by increased serum levels of TNFalpha, IL-1beta, IL-6, and IL-8. METHODS: The levels of TNFalpha, IL-1beta, IL-6, IL-8, and prostate specific antigen (PSA) were examined in serum samples from normal donors (n = 10 donors), from patients with organ-confined CaP (n = 19 patients), from patients with advanced CaP without cachexia (n = 17 patients), and from patients with cachectic CaP (n = 26 patients). DPC Immulite and Abbott IMx Total-PSA assays were used to determine cytokine and PSA levels, respectively. RESULTS: Levels of TNFalpha, IL-6, and IL-8 were elevated significantly in the group of patients with advanced, cachectic CaP compared with patients who were without cachexia. In the cachectic patients, levels of TNFalpha were correlated positively with IL-8, and there was no correlation between PSA levels and any of the cytokine levels. IL-1beta levels were below the limit of detection in all samples. CONCLUSIONS: The current results show that levels of TNFalpha, IL-6, and IL-8 were increased in CaP patients with cachexia. Increased levels of these cytokines were not correlated with PSA levels, suggesting that they are regulated by a mechanism that is independent of PSA synthesis. Additional fundamental research is needed to determine the mechanisms involved and to identify potential therapeutic targets in patients with cachexia.

Aged↗

PubMed2003

Isolation and characterization of human and mouse WDR19,a novel WD-repeat protein exhibiting androgen-regulated expression in prostate epithelium.

Androgens regulate important processes involved in the normal development and function of the human and rodent prostate glands. Here we report the isolation and characterization of a new androgen-regulated gene, designated WDR19, that encodes repeating sequence motifs found in the WD-repeat family of proteins. The WD repeat is a conserved domain of approximately 40 amino acids that is typically bracketed by glycine-histidine and tryptophan-aspartic acid (WD) dipeptides. WD-repeat proteins are a large group of structurally related proteins that participate in a wide range of cellular functions, including transmembrane signaling, mRNA modification, vesicle formation, and vesicular trafficking. The WDR19 gene comprises 36 exons and is located on chromosome 4p15-4p11. The predicted protein contains six WD repeats, a clathrin heavy-chain repeat, and three transmembrane domains. Sequence analysis reveals that the WDR19 gene is conserved from Caenorhabditis elegans to human. WDR19 is expressed in normal and neoplastic prostate epithelium as demonstrated by RNA in situ hybridization and is regulated by androgenic hormones. WDR19 transcripts exhibit alternative splicing in which two isoforms appear to be prostate restricted, a property that could be exploited for designing diagnostic or therapeutic strategies for prostate carcinoma.

Alternative Splicing↗

PubMed2002

Prostate-specific membrane antigen directed selective thrombotic infarction of tumors.

Prostate-specific membrane antigen (PSMA), a glutamyl preferring carboxypeptidase, is found in prostate and other carcinomas present on both tumor cells and associated microvascular lining cells. We find that the channel structures delineated by PSMA-expressing cells in human and rat prostate tumors are in functional continuity with the vasculature and thus form part of tumor microvasculature. The PSMA-positive cell-outlined channels are CD31 negative and mutually exclusive of CD31-positive cell-lined channels elsewhere in the tumor consistent with tumor cells adapted to a pseudoendothelial phenotype in vasculogenic mimicry. To assess the functional potential of such PSMA-lined microvasculature to selectively direct infarctive tumor therapy, we coupled the soluble extracellular domain of tissue factor to a PSMA catalytic site inhibitor to create a PSMA-directed selective tumor vascular thrombogen (STVT). This protein induced selective local in vivo infarctive necrosis of the rat Mat Lu prostate tumor when administered i.v. The combined administration of this STVT with low-dose doxorubicin produced a profound tumoricidal effect, resulting in complete eradication of some tumors. This is consistent with the therapeutic potential for a PSMA-directed STVT and expands the potential for selective infarctive ablation of tumors.

Animals↗

PubMed2002

APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers.

Genetic alterations serve as beacons for the involvement of specific pathways in tumorigenesis. It was previously shown that 5% of prostate tumors harbor CTNNB1 mutations, suggesting that this tumor type may involve a deregulated APC/CTNNB1 pathway. To explore this possibility further, we searched for mutations in genes implicated in this pathway in 22 samples that included cell lines, xenografts, and primary tumors. We identified seven alterations: two in CTNNB1, three in APC, and two in hTRCP1 (also known as BTRC) which controls the degradation of CTNNB1. Alterations in the CTNNB1 regulatory domain, APC, and hTRCP1 were mutually exclusive, consistent with their equivalent effects on CTNNB1 stability. These results suggest that CTNNB1 signaling plays a critical role in the development of a significant fraction of prostate cancers. Moreover, they provide the first evidence that hTRCP1 plays a role in human neoplasia.

Animals↗

PubMed2002

A neuroendocrine/small cell prostate carcinoma xenograft-LuCaP 49.

The late stages of progression of prostate carcinoma are typically characterized by an androgen-insensitive, rapidly proliferative state. Some late-stage tumors are composed predominantly of neuroendocrine cells. Virtually no animal models of a neuroendocrine/small cell variant of prostate carcinoma are available for experimental studies. We report a human neuroendocrine/small cell prostate carcinoma xenograft that was developed from a nodal metastasis of a human prostate carcinoma and that has been propagated as serial subcutaneous implants in severe combined immunodeficient mice for >4 years. Designated LuCaP 49, all tumor passages exhibit a neuroendocrine/small cell carcinoma phenotype-insensitivity to androgen deprivation, expression of neuroendocrine proteins, lack of expression of prostate-specific antigen or androgen receptor, and an unusually rapid growth (a doubling time of 6.5 days) for prostate cancer xenografts. Genetically this tumor exhibits loss of heterozygosity for the short arm of chromosome 8 and has a complex karyotype. This xenograft should prove to be useful in the investigation of mechanisms underlying the androgen-insensitive state of progressive prostate carcinoma.

Aged↗