PTTG1 overexpression in adrenocortical cancer is associated with poor survival and represents a potential therapeutic target.

BACKGROUND: Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets. METHODS: We profiled 44 ACC and 4 normal adrenals on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by Western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation. RESULTS: Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Overexpression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average ß-actin <-3.04) was 1.8 years compared with 9.0 years if tumors expressed lower levels of PTTG1 (P < .0001). Analysis of a previously published dataset confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of 2 ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (median inhibition concentrations of 1.69 µmol/L and 0.891 µmol/L, for SW-13 and H295R, respectively). CONCLUSION: Overexpression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.

Preclinical investigation of nanoparticle albumin-bound paclitaxel as a potential treatment for adrenocortical cancer.

BACKGROUND: Traditional drug discovery methods have a limited role in rare cancers. We hypothesized that molecular technology including gene expression profiling could expose novel targets for therapy in adrenocortical carcinoma (ACC), a rare and lethal cancer. SPARC (secreted protein acidic rich in cysteine) is an albumin-binding matrix-associated protein that is proposed to act as a mechanism for the increased efficacy of a nanoparticle albumin-bound preparation of the antimicrotubular drug Paclitaxel (nab-paclitaxel). METHODS: The transcriptomes of 19 ACC tumors and 4 normal adrenal glands were profiled on Affymetrix U133 Plus2 expression microarrays to identify genes representing potential therapeutic targets. Immunohistochemical analysis for target proteins was performed on 10 ACC, 6 benign adenomas, and 1 normal adrenal gland. Agents known to inhibit selected targets were tested in comparison with mitotane in the 2 ACC cell lines (H295R and SW-13) in vitro and in mouse xenografts. RESULTS: SPARC expression is increased in ACC samples by 1.56 ± 0.44 (µ ± SD) fold. Paclitaxel and nab-paclitaxel show in vitro inhibition of H295R and SW-13 cells at IC50 concentrations of 0.33 µM and 0.0078 µM for paclitaxel and 0.35 µM and 0.0087 µM for nab-paclitaxel compared with mitotane concentrations of 15.9 µM and 46.4 µM. In vivo nab-paclitaxel treatment shows a greater decrease in tumor weight in both xenograft models than mitotane. CONCLUSIONS: Biological insights garnered through expression profiling of ACC tumors suggest further investigation into the use of nab-paclitaxel for the treatment of ACC.

Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions.

We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterol-related genes in the risk of Alzheimer's disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person's risk. In a separate study, we found that apolipoprotein E (APOE) epsilon4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE epsilon4 homozygotes, heterozygotes and noncarriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE epsilon4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk.

Adrenocortical carcinoma survival rates correlated to genomic copy number variants.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy accounting for between 0.02% and 0.2% of all cancer deaths. Surgical removal offers the only current potential for cure. Unfortunately, ACC has undergone metastatic spread in 40% to 70% of patients at the time of diagnosis. Standard chemotherapy with mitotane is often ineffective with intolerable side effects. The modern molecular technology of comparative genomic hybridization allows the examination of DNA for chromosomal alterations, which can lend biological insight into cancer processes. Genomes of 25 ACC clinical samples were queried on the Agilent 44K Human Genome comparative genomic hybridization array detecting regions of chromosomal gain and loss within the tumor population. Commonly shared amplifications appearing in > or =50% of tumors at P < or = 10(-4) include regions within chromosomes 5, 7, 12, 16q, and 20. Deleted genomic regions within ACC include portions of chromosomes 1, 3p, 10q, 11, 14q, 15q, 17, and 22q. Genomic aberrations in regions associated with differential survival (P < or = 0.05) and presence in > or =20% of tumors include amplifications of 6q, 7q, 12q, and 19p. Deletions within stratified survival groups include localized regions within 3, 8, 10p, 16q, 17q, and 19q. Statistical analysis of this genetic landscape reveals a set of chromosomal aberrations strongly associated with survival in an accumulation-dependent fashion. These regions may hold prognostic indicators and offer therapeutic targets that can be used to develop novel treatments for aggressive tumors.