Characterization of mice deficient in the Src family nonreceptor tyrosine kinase Frk/rak.

Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Although developmental expression patterns and functional overexpression in vitro have associated these kinases with growth suppression and differentiation, their physiological functions remain largely unknown. We therefore generated mice carrying a null mutation in iyk, the mouse homolog of Frk/rak. We report here that frk/rak(-/-) mice are viable, show similar growth rates to wild-type animals, and are fertile. Furthermore, a 2-year study of health and survival did not identify differences in the incidence and spectrum of spontaneous tumors or provide evidence of hyperplasias in frk/rak(-/-) epithelial tissues. Histological analysis of organs failed to reveal any morphological changes in epithelial tissues that normally express high levels of Frk/rak. Ultrastructural analysis of intestinal enterocytes did not identify defects in brush border morphology or structural polarization, demonstrating that Frk/rak is dispensable for intestinal cytodifferentiation. Additionally, frk/rak-null mice do not display altered sensitivity to intestinal damage induced by ionizing radiation. cDNA microarray analysis revealed an increase in c-src expression and identified subtle changes in the expression of genes regulated by thyroid hormones. Significant decreases in the circulating levels of T3 but not T4 hormone are consistent with this observation and reminiscent of euthyroid sick syndrome, a stress-associated clinical condition.

Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers.

BACKGROUND: Germline mutations in BRCA1 and BRCA2 are responsible for 5%-10% of epithelial ovarian cancers, but the molecular pathways affected by these mutations are unknown. We used complementary DNA (cDNA) microarrays to compare gene expression patterns in ovarian cancers associated with BRCA1 or BRCA2 mutations with gene expression patterns in sporadic epithelial ovarian cancers and to identify patterns common to both hereditary and sporadic tumors. METHODS: Tumor samples from 61 patients with pathologically confirmed epithelial ovarian adenocarcinoma with matched clinicopathologic features were studied, including 18 with BRCA1 founder mutations, 16 with BRCA2 founder mutations, and 27 without either founder mutation (termed sporadic cancers). The cDNA microarrays contained 7651 sequence-verified features. Gene expression data were analyzed with a modified two-sided F test, with P<.0001 considered statistically significant. The expression level of six genes was also studied with reverse transcription-polymerase chain reaction. RESULTS: The greatest contrast in gene expression was observed between tumors with BRCA1 mutations and those with BRCA2 mutations; 110 genes showed statistically significantly different expression levels (P<.0001). This group of genes could segregate sporadic tumors into two subgroups, "BRCA1-like" and "BRCA2-like," suggesting that BRCA1-related and BRCA2-related pathways are also involved in sporadic ovarian cancers. Fifty-three genes were differentially expressed between tumors with BRCA1 mutations and sporadic tumors; six of the 53 mapped to Xp11.23 and were expressed at higher levels in tumors with BRCA1 mutations than in sporadic tumors. Compared with the immortalized ovarian surface epithelial cells used as reference, several interferon-inducible genes were overexpressed in the majority of tumors with a BRCA mutation and in sporadic tumors. CONCLUSIONS: Mutations in BRCA1 and BRCA2 may lead to carcinogenesis through distinct molecular pathways that also appear to be involved in sporadic cancers. Sporadic carcinogenic pathways may result from epigenetic aberrations of BRCA1 and BRCA2 or their downstream effectors.

An early examination of access to select orphan drugs treating rare diseases in health insurance exchange plans.

BACKGROUND: Patients with rare diseases often face significant health care access challenges, particularly since the number of available treatment options for rare diseases is limited. The implementation of health insurance exchanges promises improved access to health care. However, when purchasing a plan, patients with rare diseases need to consider multiple factors, such as insurance premium, access to providers, coverage of a specific medication or treatment, tier placement of drug, and out-of-pocket costs.  OBJECTIVE: To provide an early snapshot of the exchange plan landscape from the perspective of patients with select rare diseases by evaluating the degree of access to medications in a subset of exchange plans based on coverage, tier placement, associated cost sharing, and utilization management (UM) applied.  METHODS: The selection of drugs for this analysis began by identifying rare diseases with FDA-approved treatment options using the National Institutes of Health Office of Rare Diseases' webpage and further identification of a subset of drugs based on select criteria to ensure a varied sample, including the characteristics and prevalence of the condition. The medications were categorized based on whether alternative therapies have FDA approval for the same indication and whether there are comparators based on class or therapeutic area. The list was narrowed to 11 medications across 7 diseases, and the analysis was based on how these drugs are listed in exchange plan outpatient pharmacy benefit formularies. This analysis focused on 84 plans in 15 states with the highest expected exchange enrollment and included a variety of plan types to ensure that variability in the marketplace was represented. To best approximate plans that will have the greatest enrollment, the analysis focused on silver and bronze plan formularies because consumers in this market are expected to be sensitive to premiums. Data on drug coverage, tier placement, cost, and UM were collected from these plans beginning October 1, 2013, with the launch of the open enrollment period. RESULTS: Coverage and use of UM for selected medications vary within and across states. This study found that bronze plans were far less likely than silver plans to cover the 11 products included in this analysis. Results also showed that select drugs identified as the only FDA-approved product indicated for a certain rare disease experienced relatively robust coverage (at least 65% of plans) but often included some form of UM. However, coverage of selected rare disease therapies also is complicated by the fact that plans cover certain products under the medical benefit versus the pharmacy benefit. At the time of this analysis, transparency of medical benefit coverage for these products in exchange plans was limited.Selected medications are most likely to appear on the highest tiers of 4-tier formularies or are not covered at all. Although there are no requirements to designate certain tiers as "specialty tiers," more than 70% of plans in this study use coinsurance for the highest tiers of their formularies. Rates of coinsurance for medications on highest tiers range from 10% to 50% in silver plans and 15% to 50% in bronze plans. Among those plans utilizing copayments rather than coinsurance, ranges of copayments for these select products vary between $20 and $250 per prescription across both silver plans and bronze plans. CONCLUSIONS: This preliminary analysis of access to treatments for patients with select rare diseases revealed the complexities involved for patients with specific needs when selecting a plan with appropriate coverage. For patients with rare diseases, the process of identifying and selecting a plan centers on understanding if and how the plan covers a specific treatment or set of treatments. Access factors will likely vary substantially across plans, as demonstrated by the findings from this analysis. With limited treatment options and the potential for cost sharing and UM barriers, increased data transparency to assist patients in navigating formularies will be a critical step for patients to fully understand their access to needed therapies in each plan.