Patricia S Steeg

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..Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed...

..Clinical testing of agents that increase metastasis-suppressor gene expression is expected to require tailored trial designs...

..Other candidate histidine phosphorylated proteins are identified. These data suggest the existence of another series of phosphorylation patterns in signal transduction...

..So how might we use this knowledge to improve the treatment of patients with cancer?..

..Here we discuss the similarity and differences between primary tumors and metastases, pathways controlling the colonization of a distant organ, and incorporation of antimetastatic therapies into clinical testing...

..We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis...

..We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer...

..Here, we tested whether MPA treatment inhibits metastatic colonization of a hormone receptor-negative breast cancer cell line in vivo...

..The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis...

..There was a greater than additive improvement in survival in our intracranial model. Combining vorinostat with radiation may be a potential treatment option for patients with breast cancer who develop brain metastases...

..When TPI-287 treatment was delayed until days 18, 22, and 26 postinjection, efficacy was reduced (17% reduction, not significant). These data suggest that TPI-287 may have efficacy when administered early in the course of the disease...

..73; P = 0.004). The data indicate that Nm23-H1 down-regulation of EDG2 is functionally important to suppression of tumor metastasis...

..In conclusion, using pazopanib, tumor B-Raf status was identified as a significant determinant of both tumor growth and angiogenesis...

..028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target...

..CONCLUSIONS: MPA represents a first generation lead agent for the elevation of Nm23-H1 metastasis suppressor expression and the inhibition of metastatic colonization...

..To date, medroxyprogesterone acetate (MPA) has been identified as a candidate compound for clinical testing...

..001), suggesting that brain tissue secretes factors conducive to tumor cell growth. Molecules used to signal between tumor cells and the surrounding glia could provide a new avenue of therapeutic targets for brain metastases...

..These data suggest that Nm23-H1 suppresses metastasis, at least in part, through down-regulation of EDG2 expression...

..We hypothesize that the mechanism of action of Nm23 in metastasis suppression involves diminished signal transduction downstream of a particular receptor. Candidate biochemical mechanisms are identified and discussed herein...

..Metastasis suppressor expression levels can impact traditional signaling pathways, such as the Erk pathway, resulting in altered tumor cell sensitivity to cancer therapeutics...

..This review also discusses therapeutic options on the basis of reexpression of metastasis suppressors...

..However, the effects of LPA1 inhibition on primary tumor size, metastasis, and metastatic dormancy have not been investigated...

..We have tested pazopanib, a recently approved antiangiogenic drug that targets VEGFR1, VEGFR2, VEGFR3, PDGFRβ, PDGFRα, and c-kit, for prevention of experimental brain metastases and mechanism of action...

..The data provide a first demonstration that Rab11a modulates EGFR recycling, and promotes the proliferation but inhibits the motility of an immortal breast line, consistent with the DCIS phenotype...

..001). Our data indicate that Her-2 overexpression increases the outgrowth of metastatic tumor cells in the brain in this model system...

..New therapies with permeability for the blood-brain barrier are needed to counteract both types of tumor cells...

..The data also show that changes in mRNA splicing patterns accompany metastatic progression, which may contribute to proteome instability...

..Recent findings on the biology of this disease and translational leads identified by molecular studies are discussed in this article...

..Although the present study focuses on the DNA damage-repair pathway, the technique is generally useful to the study of protein signaling...

..A Phase II clinical trial of high dose MPA, alone or in combination with metronomic chemotherapy has recently opened...

..Similarly, sequence differences between DR-Nm23 and its homologs may be important for anchorage independent growth suppression...

..The contribution of alternative mRNA splicing to cancer and cancer metastasis is poorly defined. It is possible that Nm23-H1, through the regulation of RNA processing proteins, may play a role in proteome stability...

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..Our data identify a complex regulatory pattern for nm23-H1 transcription, and suggest that a mammary-specific cassette of transcription factors contribute to its elevated expression..

..Our findings establish PEDF as both a metastatic suppressor and a neuroprotectant in the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences...

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..We hypothesized that c-Met overexpression in cancer might result in increased ectodomain shedding, and that its measure could be a useful biomarker of tumor progression...

..Therapeutic approaches that either mimic the effects of MSGs or re-establish MSG expression in metastatic lesions may hold promise for the establishment or maintenance of dormancy...

..Specific, new approaches to combat brain metastatic disease are needed...

..Here, we describe and validate a transplantation strategy that circumvents some of these difficulties...

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..Based on experimental observations, we determined model parameters and generated an in silico "knockout," reflecting the experimental data, including phosphorylated proteins...

..Recently, based on the inverse correlation of Nm23 and LPA1 expression, a LPA1 inhibitor has been shown to both inhibit metastasis and induce metastatic dormancy...

..Cumulatively, the data suggest that part of the anti-metastatic function of Nm23-H1 lies in pathways that it interrupts via binding and inactivation of proteins...

..Because these drugs cause toxicities that can be associated with inhibition of Akt, an emerging target in cancer, we assessed the potential of HIV protease inhibitors as anticancer agents...

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..Proteomic analysis of DCIS revealed differential expression patterns distinct from previous nucleic acid-based studies and identified new facets of the earliest stage of breast cancer progression...

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..A liquid-liquid extraction procedure was able to recover ∼90% of drug from a small volume (50μL) of mouse plasma. This method was successfully applied to a pharmacokinetic study in mice intravenously injected with DZNep...

..Using such model systems, as well as in vitro analogs of blood-brain barrier penetration and tissue-based studies, new molecular leads into this disease are unfolding...

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..Moreover, reactions with thiol groups of critical cellular proteins could be important to the mechanism of toxicity with this class of anticancer agents...