Plasma miRNAs as biomarkers to identify patients with castration-resistant metastatic prostate cancer.

MicroRNAs (miRNAs) have emerged as key regulators of numerous biological processes, and increasing evidence suggests that circulating miRNAs may be useful biomarkers of clinical disease. In this study, we sought to identify plasma miRNAs that differentiate patients with metastatic castration resistant prostate cancer (mCRPC) from those with localized prostate cancer (PCa). Pooled plasma samples from patients with localized PCa or mCRPC (25 per group) were assayed using the Exiqon miRNA qPCR panel, and the differential expression of selected candidates was validated using qRT-PCR. We identified 63 miRNAs upregulated in mCRPC versus localized PCa, while only four were downregulated. Pearson's correlation analysis revealed two highly correlated groups: one consisting of miR-141, miR375 and miR-200c and the other including miR151-3p, miR423-3p, miR-126, miR152 and miR-21. A third group, containing miR-16 and miR-205, showed less correlation. One miRNA from each group (miR-141, miR151-3p and miR-16) was used for logistic regression analysis and proved to increase the sensitivity of the prostate-specific antigen (PSA) test alone. While no miRNA alone differentiated localized PCa and mCRPC, combinations had greater sensitivity and specificity. The expression of these 10 candidates was assayed for association with clinical parameters of disease progression through the cBio portal. Our results demonstrate that plasma levels of selected miRNAs are potential biomarkers to differentiate localized PCa and mCRPC.

Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease.

Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. The objective of this study was to use a mouse model of prostate cancer as a tool to discover serum miRNAs that could be assessed in a clinical setting. Global miRNA profiling identified 46 miRNAs at significantly altered levels (p ≤ 0.05) in the serum of TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice with advanced prostate cancer compared to healthy controls. A subset of these miRNAs with known human homologues were validated in an independent cohort of mice and then measured in serum from men with metastatic castration-resistant prostate cancer (mCRPC; n = 25) or healthy men (n = 25). Four miRNAs altered in mice, mmu-miR-141, mmu-miR-298, mmu-miR-346 and mmu-miR-375, were also found to be at differential levels in the serum of men with mCRPC. Three of these (hsa-miR-141, hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue, suggesting that they are released into the blood as disease progresses. Moreover, the intra-tumoral expression of hsa-miR-141 and hsa-miR-375 were predictors of biochemical relapse after surgery. This study is the first to demonstrate that specific serum miRNAs are common between human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the discovery of novel biomarkers.

A Phase II Study of PX-866 in Patients With Recurrent or Metastatic Castration-resistant Prostate Cancer: Canadian Cancer Trials Group Study IND205.

BACKGROUND: In PTEN-loss models, the phosphatidylinositol 3-kinase (PI3K)/AKT and androgen receptor signaling pathways cross-regulate by reciprocal feedback whereby inhibition of one activates the other, creating a rationale for co-targeting. We studied the irreversible, pan-isoform inhibitor of Class I PI-3K PX-866 singly (part A) and with abiraterone acetate (AA) in patients on AA with rising prostate-specific antigen (PSA) (part B). PATIENTS AND METHODS: The primary endpoint was lack of progression at 12 weeks. Exploratory endpoints included changes in circulating tumor cells (CTC), pharmacodynamic studies on platelets (part A), and archival tumor exploration of PTEN as predictor of response (part B). RESULTS: A total of 43 and 25 patients accrued to parts A and B, respectively. In part A, 14 (33%) patients were progression-free at 12 weeks, with 2 partial objective responses and 1 confirmed PSA response. Favorable CTC conversion (< 5 CTC/7.5 mL) occurred in 6 (24%) of 25 evaluable patients. In part B, 11 of 25 patients had measurable disease. Six (24%) patients were progression-free at 12 weeks. No objective or PSA responses were observed. For all 68 patients, the most common toxicities were diarrhea (53 patients), nausea (36), anorexia (24), fatigue (22), and vomiting (20). Among 17 patients for whom PTEN testing was possible, 3 had PTEN homozygous deletion and 14 had no change. No correlation between PTEN status and response was seen. CONCLUSIONS: PX-866 had modest single agent activity. Adding AA to PX-866 showed no evidence of resistance reversal. Strategies to combine PI3K inhibition with androgen receptor-targeted therapies could consider initiation earlier, combination with other agents, and/or recruiting a selected population.

Lapatinib for breast cancer: a review of the current literature.

IMPORTANCE OF THE FIELD: The identification of HER-2 expression as a predictive and prognostic marker revolutionized breast cancer. Trastuzumab, a humanized mAb, improves survival in both early and advanced HER-2 overexpressing breast cancer. However, many cancers either do not respond or develop resistance to this agent. Lapatinib is an oral tyrosine kinase inhibitor which has both HER-1 and -2 activities and has been licensed for use in recurrent breast cancer that overexpresses HER-2. Studies of lapatinib in early breast cancer are ongoing. AREAS COVERED IN THIS REVIEW: A PubMed search was conducted using 'lapatinib' and 'breast cancer' as the key words. All published works up to July 2010 were reviewed. A manual review of abstracts presented at the ASCO Annual meeting and the San Antonio Breast Cancer Symposium was conducted for the last 2 years. In this review, we summarize the current knowledge of lapatinib and pose questions which need to be addressed as we further expand our knowledge of the HER-2 subtypes of breast cancer. WHAT THE READER WILL GAIN: The reader will gain an up-to-date and comprehensive review of the current literature as it pertains to the safety and efficacy of lapatinib in the treatment of breast cancer. TAKE HOME MESSAGE: Lapatinib has provided an alternative for the treatment of advanced HER-2 overexpressing breast cancer and is currently being assessed in early disease.

Novel targeted therapies for prostate cancer.

This article reviews the concepts and rationale behind targeted agents that are currently in clinical testing for patients with castration resistant prostate cancer (CRPC). Advances in our understanding of the molecular mechanisms underlying prostate cancer progression has translated into a variety of treatment approaches. Agents targeting androgen receptor activation and local steroidogenesis, angiogenesis, apoptosis, chaperone proteins, the insulinlike growth factor pathway, RANK ligand, endothelin receptors, and Src family kinases are entering, or have recently completed, accrual to phase III trials for patients with CRPC. There has also been interest generated by data from early-phase studies evaluating multitargeted tyrosine kinase inhibitors, agents effecting signal transduction pathways, and novel cytotoxics.

Rasburicase prevents tumor lysis syndrome despite extreme hyperleukocytosis.

Hyperleukocytosis [white blood cell count (WBC) >100 x 10(9)/l] occurs in 5%-22% of pediatric patients with acute leukemia. Rasburicase (recombinant urate oxidase) is very effective for the prophylaxis and treatment of hyperuricemia, but its efficacy in marked hyperleukocytosis (WBC >200 x 10(9)/l) is not well known. We describe three children with marked hyperleukocytosis (WBC of 508, 320, and 242 x 10(9)/l) at initiation of induction chemotherapy. All three received rasburicase. Minimal metabolic disturbance occurred in all patients. We conclude that WBC reduction strategies may not be required solely for the risk of tumor lysis syndrome in patients with very high WBC (>200 x 10(9)/l) who are treated with rasburicase.