Background. Platinum-based neoadjuvant chemotherapy has been shown to improve survival outcomes in muscle-invasive bladder cancer patients.Weperformed a systematic review and meta-analysis to provide updated results of previous findings. We also summarized published data to compare clinical outcomes of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) versus gemcitabine and cisplatin/carboplatin (GC) in the neoadjuvant setting. Methods. A meta-analysis of 15 randomized clinical trials was performed to compare neoadjuvant chemotherapy plus local treatment with the same local treatment alone. Because no randomized trials have investigated MVAC versus GC in the neoadjuvant setting, a meta-analysis of 13 retrospective studies was performed to compare MVAC with GC. Results. A total of 3,285 patients were included in 15 randomized clinical trials. There was a significant overall survival

Hematopoietic growth factors mediate the survival and proliferation of blood-forming cells, but the mechanisms through which these proteins produce their effects are incompletely known. Recent studies have identified the pim family of kinases as mediators of cytokinedependent survival signals. Several studies have identified substrates for the pim-1 kinase, but little is known about the other family members, pim-2 and pim-3. We have investigated potential functions for the pim-2 kinase in factor-dependent murine hematopoietic cells. We find that pim-2 mRNA and protein expression are regulated by cytokines similarly to pim-1. Three PIM-2 protein isoforms are produced in cytokinetreated cells. All three forms are active kinases, and the short (PIM-2(34 kDa)) form is the most active at enhancing survival of FDCP1 cells after cytokine withdrawal. This pro-survival function involves inhibition of apoptosis and caspase activation. Enforced expression of PIM-2(34 kDa) kinase does not appear to regulate expression of BCL-2, BCL-xL, BIM, or BAX proteins. However, the kinase can phosphorylate the pro-apoptotic protein BAD on serine 112, which accounts in part for its ability to reverse Bad-induced cell death. Our results indicate that pim-2 functions similarly to pim-1 as a pro-survival kinase and suggest that BAD is a legitimate PIM-2 substrate.

The pim-1 kinase is a true oncogene that has been implicated in the development of leukemias, lymphomas, and prostate cancer, and is the target of drug development programs. We have used experimental approaches to identify a selective, cell-permeable, small-molecule inhibitor of the pim-1 kinase to foster basic and translational studies of the enzyme. We used an ELISA-based kinase assay to screen a diversity library of potential kinase inhibitors. The flavonol quercetagetin (3,3 ¶,4 ¶,5,6,7-hydroxyflavone) was identified as a moderately potent, ATP-competitive inhibitor (IC 50 , 0.34 Mmol/L). Resolution of the crystal structure of PIM1 in complex with quercetagetin or two other flavonoids revealed a spectrum of binding poses and hydrogen-bonding patterns in spite of strong similarity of the ligands. Quercetagetin was a highly selective inhibitor of PIM1 compared with PIM2 and seven other serine-threonine kinases. Quercetagetin was able to inhibit PIM1 activity in intact RWPE2 prostate cancer cells in a dose-dependent manner (ED 50 , 5.5 Mmol/L). RWPE2 cells treated with quercetagetin showed pronounced growth inhibition at inhibitor concentrations that blocked PIM1 kinase activity. Furthermore, the ability of quercetagetin to inhibit the growth of other prostate epithelial cell lines varied in proportion to their levels of PIM1 protein.Quercetagetin can function as a moderately potent and selective, cell-permeable inhibitor of the pim-1 kinase, and may be useful for proof-of-concept studies to support the development of clinically useful PIM1 inhibitors.

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PIM1 kinase is a serine/threonine kinase that has been shown to be overexpressed in multiple human malignancies, including prostate cancer. PIM1 phosphorylates multiple cellular substrates to inhibit apoptosis and promote cell cycle progression. Increased PIM1 can also facilitate genomic instability to promote neoplastic processes. PIM1 kinase is overexpressed in high-grade prostate intraepithelial neoplasia and in prostate cancer compared to normal prostatic tissue and benign prostate hyperplasia. Elevated PIM1 levels have been shown to be the direct result of oncogenic fusion proteins and active signal transduction pathways. In vitro and in vivo mouse studies indicate that PIM1 is weakly tumorigenic but synergizes dramatically when coexpressed with MYC. PIM1 kinase can also phosphorylate the androgen receptor (AR), thereby regulating AR degradation and function, in a low androgen environment. This finding implicates PIM1 in castration -resistant prostate cancer. Furthermore, expression of PIM1 has been shown to be increased in prostate tissue after docetaxel exposure, conferring partial resistance to docetaxel. Correlatively, decreased PIM1 levels sensitize prostate cancer cells to docetaxel treatment. Thus, PIM1 may be a target in docetaxel resistant disease. In summary, PIM1 kinase is involved in prostate tumorigenesis, castration resistance, and docetaxel resistance. Several PIM1 kinase inhibitors have been reported and are in varied stages of drug development. PIM1 is involved in multiple processes in the development and propagation of prostate cancer, thus a PIM1 kinase inhibitor may serve as an effective therapeutic agent in this prevalent disease.

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Multiple therapies currently exist for renal cell carcinoma, however, most do not result in cure and the development of acquired resistance is the rule rather than the exception. CDK4/6 and PIM1 kinases are potential new therapeutic targets in RCC. Abemaciclib is a potent CDK4/6 and PIM1 kinase inhibitor, thus we evaluated the effects of abemaciclib on renal cell carcinoma. In vitro, abemaciclib causes decreased cellular viability, increased apoptosis, and alterations in autophagy in renal cell carcinoma cell lines. A pre-clinical mouse model of RCC shows abemaciclib in combination with sunitinib to cause dramatic reduction in tumor sizes without overt toxicity. Thus abemaciclib is active in renal cell carcinoma and should be evaluated in a clinical trial in combination with sunitinib. Additionally, CDK4/6 and PIM1 kinase appear to be viable clinical targets in renal cell carcinoma.

Real-time, single-cell multiplex immunophenotyping of circulating tumor cells (CTCs) is hypothesized to inform diagnosis of tissue of origin in patients with carcinoma of unknown primary (CUP). In 20 to 50% of CUP patients, the primary site remains unidentified, presenting a challenge for clinicians in diagnosis and treatment. We developed a post-CellSearch CTC assay using multiplexed Q-dot or DyLight conjugated antibodies with the goal of detecting multiple markers in single cells within a CTC population. We adapted our approach to size-based CTC enrichment protocols for capturing CTCs and subsequent immunofluorescence (IF) using a minimal set of markers to predict the primary sites for common metastatic tumors. The carcinomas are characterized with cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor 1 (TTF-1), estrogen receptor (ER) or prostate-specific antigen (PSA. IF has been optimized in cultured tumor cells with individual antibodies, then with conjugated antibodies to form a multiplex antibody set. With IF, we evaluated antibodies specific to these 5 markers in lung, breast, colorectal, and prostate cancer cell lines and blood from metastatic prostate and breast cancer patients. This advanced technology provides a noninvasive, diagnostic blood test as an adjunct to routine tissue biopsy. Its further implementation requires prospective clinical testing.