The phosphatase of regenerating liver (PRL) family, a unique class of oncogenic phosphatases, consists of three members: PRL-1, PRL-2, and PRL-3. Aberrant overexpression of PRL-3 has been found in multiple solid tumor types. Ectopic expression of PRLs in cells induces transformation, increases mobility and invasiveness, and forms experimental metastases in mice. We have now shown that small interfering RNAmediated depletion of PRL expression in cancer cells results in the down-regulation of p130Cas phosphorylation and expression and prevents tumor cell anchorage-independent growth in soft agar. We have also identified a small molecule, 7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one (thienopyridone), which potently and selectively inhibits all three PRLs but not other phosphatases in vitro. The thienopyridone showed significant inhibition of tumor cell anchorage-independent growth in soft agar, induction of the p130Cas cleavage, and anoikis, a type of apoptosis that can be induced by anticancer agents via disruption of cell-matrix interaction. Unlike etoposide, thienopyridone-induced p130Cas cleavage and apoptosis were not associated with increased levels of p53 and phospho-p53 (Ser 15 ), a hallmark of genotoxic druginduced p53 pathway activation. This is the first report of a potent selective PRL inhibitor that suppresses tumor cell three-dimensional growth by a novel mechanism involving p130Cas cleavage. This study reveals a new insight into the role of PRL-3 in priming tumor progression and shows that PRL may represent an attractive target for therapeutic intervention in cancer. [Cancer Res 2008;68(4):1162-9]

Cytogenetic and/or loss of heterozygosity studies were performed on 13 ependymomas, 11 pilocytic astrocytomas, and 18 oligodendrogliomas. Loss of chromosome 22 was the most frequent genetic abnormality among the ependymomas. We found no consistent genetic abnormality in pilocytic astrocytomas. The most common genetic abnormality in oligodendrogliomas was loss of a portion of chromosome 19. Each informative oligodendroglioma had loss of alleles mapped to the long arm (q) of chromosome 19. One oligodendroglioma had an apparent homozygous deletion of the D19S8 locus. Our results, when combined with those in the literature, indicate that chromosomes 9, 11, and 22 may harbor genes important for the pathogenesis of ependymomas and that 19q probably harbors a gene important for the pathogenesis of oligodendrogliomas.

Cytogenetic studies have shown frequent clonal abnormalities in papillary carcinoma (PFC)

No abstract

A 27-year-old man was treated for an aggressive cerebellar medulloblastoma that, at operation, exhibited dural invasion. Six months after gross total resection and radiation therapy, a "surgical metastasis" developed in the lower portion of the surgical scar. The tumor grew rapidly down into the right side of his neck. Chemotherapy failed, and he subsequently died. Cytogenetic and molecular genetic studies revealed multiple numeric and structural chromosome abnormalities, including an abnormal chromosome 17p arm, more than 100-fold N-myc amplification, a rearranged c-myc gene, and a 16-base pair deletion involving exon 7 of the p53 gene. We postulate that these genetic features may have contributed to the aggressive behavior of the tumor.

A genomics-based approach to identify pharmacodynamic biomarkers was used for a cyclin-dependent kinase inhibitory drug. R547 is a potent cyclin-dependent kinase inhibitor with a potent antiproliferative effect at pharmacologically relevant doses and is currently in phase I clinical trials. Using preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials. These candidate biomarkers were chosen based on several criteria: relevance to the mechanism of action of R547, dose responsiveness in preclinical models, and measurable expression in blood samples. We identified 26 potential biomarkers of R547 action and tested their clinical validity in patient blood samples by quantitative real-time PCR analysis. Based on the results, eight genes (FLJ44342, CD86, EGR1, MKI67, CCNB1, JUN, HEXIM1, and PFAAP5) were selected as dose-responsive pharmacodynamic biomarkers for phase II clinical trials.

β-Thalassemia is an inherited blood disorder resulting from defects in hemoglobin production, leading to premature death of red blood cells (RBCs) or their precursors. Patients with transfusion-dependent β-thalassemia often need lifelong regular RBC transfusions to maintain adequate hemoglobin levels. Frequent transfusions may lead to iron overload and organ damage. Thus, there is a large unmet need for alternative therapies. Luspatercept, a first-in-class erythroid maturation agent, is the first approved therapy in the United States for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. The population pharmacokinetics and exposure-response relationship of luspatercept were evaluated in 285 patients with β-thalassemia. Luspatercept displayed linear and time-invariant pharmacokinetics when administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept clearance, favoring weight-based dosing. Magnitude and frequency of hemoglobin increase, if not influenced by RBC transfusions, was positively correlated with luspatercept area under the serum concentration-time curve (AUC), 0.2-1.25 mg/kg, whereas a significant reduction in RBC units transfused was observed in frequently transfused patients. The probability of achieving ≥33% or ≥50% reduction in RBC transfusion burden was similar across the time-averaged AUC (0.6-1.25 mg/kg), with the 1 mg/kg starting dose sufficient for most early responders (71%-80%). Increasing luspatercept AUC (0.2-1.25 mg/kg) did not increase incidence or severity of treatment-emergent adverse events. These results provide a positive benefit-risk profile for the recommended luspatercept doses (1-1.25 mg/kg) in treating adult patients with β-thalassemia who require regular RBC transfusions.

Trastuzumab (Herceptin®) is a humanized monoclonal antibody designed to bind and inhibit the function of the human epidermal growth factor receptor 2 (HER2)/erbB2 receptor. Trastuzumab has demonstrated clinical activity in several types of HER2-overexpressing epithelial tumors, such as breast and metastatic gastric or gastroesophageal junction cancer. Relapse and therapeutic resistance, however, still occur in a subset of patients treated with regimens including trastuzumab, despite significant improvements in response rates, survival and quality of life. To investigate the potential mechanisms of acquired therapeutic resistance to trastuzumab, we developed a preclinical model of human ovarian cancer cells, SKOV-3 Herceptin-resistant (HR), and examined the corresponding changes in gene expression profiles. SKOV-3 HR cells were developed by in vivo serial passaging of parental trastuzumab-sensitive SKOV-3 cells. Following four rounds of serial transplantation of 'break-through' xenograft tumors under trastuzumab treatment, significant and reproducible differences in the effects of trastuzumab treatment between SKOV-3 HR and SKOV-3 cells in vivo and in vitro were revealed. SKOV-3 HR cells retained HER2 protein expression but were unaffected by the antiproliferative effects of trastuzumab. The trastuzumab binding affinity for SKOV-3 HR cells was diminished, despite these cells having more binding sites for trastuzumab. Microarray expression profiling (MEP) was performed to determine the genes involved in the resistance mechanism. Functional analysis revealed the differential expression of genes potentially involved in angiogenesis, metastasis, differentiation and proliferation, such as mucin1 (MUC1). Immunohistochemical staining of SKOV-3 HR cells demonstrated a marked overexpression of MUC1. Based on these data, we hypothesize that the overexpression of MUC1 may hinder trastuzumab binding to HER2 receptors, abrogating the antitumor effects of trastuzumab and thus could contribute to resistance to therapy. Moreover, the resultant MEP preclinical gene signature in this preclinical model system may provide the basis for further investigation of potential clinical mechanisms of resistance to trastuzumab.