Emerging biological observations in prostate cancer
UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, 3rd Floor, San Francisco, CA 94115, USA.Expert Review of Anti-infective Therapy (Impact Factor: 3.46). 01/2010; 10(1):89-101. DOI: 10.1586/era.09.161
Emerging biological observations in prostate cancer provide the opportunity for the development of novel approaches to prevention, detection and treatment. Two observations selected for discussion in this review revolve around the mechanisms of action of signaling through the androgen receptor (AR) and the TMPRSS2:ERG chromosomal rearrangement, a fusion protein seen in nearly 50% of prostate cancers. Despite being called androgen-independent, these prostate cancers continue to depend on AR signaling despite low serum androgen levels. AR reactivation in recurrent tumors is hypothesized to occur through multiple mechanisms: AR amplification, AR mutation, active AR signaling (despite low levels of androgen), AR coactivators, ligand-independent AR activation, enhanced local production of androgens, alternative sources of androgen and upregulation in antiapoptotic genes in prostate cancer cells. A major breakthrough in prostate cancer was the identification of recurrent fusions between the androgen-regulated gene, TMPRSS2 and the v-ets erythroblastosis virus E26 oncogene homolog, ERG. This fusion has been identified as a common molecular event in prostate cancer, seen in approximately 50% of primary prostate cancer. It seems clear that this fusion gene plays an early role in prostate cancer development and/or progression, and ongoing work is being performed to elucidate the association between this fusion transcript and cancer aggressiveness.
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- "Chromosome loci harboring putative proto-oncogenes or tumor suppressor genes (TSGs) have been extensively evaluated toward identifying specific gene mutations and expression signatures in CaP. Mutations, amplifications or over-expression of the androgen receptor (AR), and mutations in tumor suppressors such as p53 and PTEN, are frequently identified subsets of advanced CaP.[8925–28] Among the recurrent allelic losses of 8p21-22, 6q16, 7q31, 10q23-25 and 16q24 loci detected in primary CaP, deleted 8p21-22 locus harbors a widely studied tumor suppressor gene NKX3.1. "
ABSTRACT: Prevalent gene fusions involving regulatory sequences of the androgen receptor (AR) regulated genes (primarily TMPRSS2) and protein coding sequences of nuclear transcription factors of the ETS gene family (predominantly ERG) result in unscheduled androgen dependent ERG expression in prostate cancer (CaP).Cumulative data from a large number of studies in the past six years accentuate ERG alterations in more than half of all CaP patients in Western countries. Studies underscore that ERG functions are involved in the biology of CaP. ERG expression in normal context is selective to endothelial cells, specific hematopoetic cells and pre-cartilage cells. Normal functions of ERG are highlighted in hematopoetic stem cells. Emerging data continues to unravel molecular and cellular mechanisms by which ERG may contribute to CaP. Herein, we focus on biological and clinical aspects of ERG oncogenic alterations, potential of ERG-based stratification of CaP and the possibilities of targeting the ERG network in developing new therapeutic strategies for the disease.
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ABSTRACT: Abiraterone acetate (CB7630), a pregnenolone analog, is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.
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ABSTRACT: We studied interaction of hydrophilic polymer chain and hydrophilic silica nanoparticles in a dilute aqueous system using an idealized model system comprised of a well characterized polyvinyl alcohol of 100 Å R(g) and hard spherical LUDOX® silica of 80 Å radii. Interaction among the polymer chains forming polymer clusters with collective polymer structure factor induced by the polymer-mediated potentials of mean force between the nanoparticles, was observed. However, Gaussian nature of individual polymer chain remains unaltered. The dilute system of polymer with low silica volume fraction has the scattering form which was appropriately modeled as the sum of the individual profiles of spherical silica particles and polymer cluster of interchain packing. With increasing silica volume fraction in the dilute solution, the spatial range parameter between the particles is reduced; hence there is a net increase in the mean potential force and consequently to stronger interaction between the silica and polymer. In the dilute systems of high silica with low polymer volume fraction, the polymer chain apparently attracted closer to the silica and concurrently absorbed to the silica hard surface and their scattering data were excellently fit with a model form factor as comprising of one unit forming the core of the spherical silica particles and the interacting polymer as the corona. This result of severe change in polymer interchain conformation in a dilute system corroborated with reduced polymer viscosity observed.
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