B A Teicher

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..Phase I clinical trials of an inhibitor of TGF-beta receptor type I kinase activity and a TGF-beta neutralizing antibody are under way...

..The five articles in this issue of CCR Focus present the current status of these next generation cytotoxic agents...

..Although some drug resistance developed in vivo is not genetically based or indefinitely stable, this form of therapeutic resistance may be critically important in the clinic...

..The selective expression of endosialin by tumor vasculature and stroma has been confirmed. Although the function of endosialin remains to be elucidated, the expression pattern for this protein may be favorable for cancer therapy...

..Both TNP-470 and enzastaurin have undergone clinical trials. Enzastaurin is currently in Phase III clinical trials...

..While only one antibody-drug conjugate has reached regulatory approval, there are nearly 20 of these in clinical trial. The time may have come for this technology to become a major contributor to improving treatment for cancer patients...

..Thus, there is still a distance to go in making optimal use of preclinical models to aid in the selection of combination regimens worthy of clinical trial...

..The CXCL12/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival. This pathway is a target for therapeutics that can block the CXCL12/CXCR4 interaction or inhibit downstream intracellular signaling...

..Each of these types of models has advantages and disadvantages to the "drug hunter" searching for improved treatments...

..In an effort to study the importance of stromal involvement in angiogenesis, we developed a novel, multicellular model that utilizes three of the primary cell types involved in tumor angiogenesis...

..This combination approach appears to be a powerful tool for identifying genes that may be useful as diagnostic markers and/or as therapeutic targets for invasive solid tumors...

..Specifically, Phospho-Akt-1, Phospho-Jnk-2, and Phospho-c-Jun are reduced in tumor cells that have been treated with netrin-4. Together, these data suggest a potential role for netrin-4 in regulating tumor growth...

..Anti-endosialin antibodies may have value in identifying vasculature in malignant tissues. With the appropriate agent, targeting endosialin may interfere with blood vessel growth during tumor development...

..This may be due to greater sensitivity of human bone marrow than mouse to the cytotoxicity of these agents. It may be possible to achieve similar levels of ARC-111 in patients as in mice allowing improved antitumor activity...

..The data presented here on endothelial genes that are up-regulated in tumor vasculature and in EPC support the hypothesis that the angiogenesis process in cancer can involve EPC...

..The therapeutic potential of LeTx needs to be further investigated in non-melanoma tumor models expressing the ANTXR1/TEM8 and/or ANTXR2/CMG2 protein...

..These results indicate that PRL-3 is functional in both endothelial cells and malignant cells and further validate PRL-3 as a potentially important molecular target for anticancer therapy...

..These data support the view that the 19S and 20S subunits of the proteasome have distinct biological functions and imply that targeting 19S and 20S would have distinct molecular consequences on tumor cells...

..Endosialin expression by both CAF and MSC further implies the potential contribution of MSC to tumor stroma via differentiation into tumor stromal fibroblasts...

..Bringing together bone marrow toxicity data, tumor cell line cytotoxicity data, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic...

..It is a dual targeting agent that neutralizes both VEGF and PlGF and, therefore, has potential as a next generation antiangiogenic therapeutic for oncology...

..A major focus of prostate cancer research has been to identify genes that are deregulated during tumor progression, potentially providing diagnostic markers and therapeutic targets...

..EPC may be a better model of human tumor endothelial cells than HUVEC and HMVEC and, thus, may provide an improved cell-based model for second generation antineoplastic antiangiogenic drug discovery...

..Pericytes displayed invasive action against NSCLC clusters in the absence of other cell types. Perivascular cells contribute to the progression of disease and are an attractive target for anti-angiogenic therapy...

..Additional characterization of this extensive brain endothelial cell gene expression database will provide unique molecular insights into vascular gene expression...

..These results support the notion that pericytes and EPC contribute to malignancy and that these cell types can be useful as cell-based models for tumor vascular development and selection of agents that may provide therapeutic benefit...

..The bone marrow toxicity and human tumor xenograft activity of three tubulin-binding compounds, vincristine, paclitaxel, and tasidotin were compared...

..Endosialin/CD248/tumor endothelial marker 1 is expressed in stromal cells, endothelial cells, and pericytes in various tumors; however, few studies have focused on expression in malignant cells...

..These cells can be used in in vitro angiogenesis assays for evaluating the potential antiangiogenic properties and interspecies cross-reactivity of novel compounds...

..A gene signature developed for topotecan sensitivity/resistance may have value in patient identification. Convergence of these efforts should result in clinically effective second generation TopoI inhibitors...

..Transforming growth factor-beta and its receptors are targets for antibody therapeutics and small molecule kinase inhibitors...

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..In summary, we have demonstrated that tumor cells directly convert CD4+CD25- T cells to T(reg) cells through production of high levels of TGF-beta, suggesting a possible mechanism through which tumor cells evade the immune system...

..8-fold increase in lifespan compared with carboplatin alone. 317615 x 2HCl is a promising new antiangiogenic agent that is in early phase clinical testing...

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..Plasma VEGF was a weak marker of response to LY317615, and plasma bFGF and TGFbeta were not markers of LY317615 activity...

..The results of this study demonstrate the ability of 13762 rat mammary carcinoma cells to elicit a measurable osteolysis and that bisphosphonates inhibit the tumor-induced bone resorption in this model...

..The third addressed the translation to the clinic and monitoring of antiangiogenic activity of agents in patients and novel trial designs. What follows is a summary of the discussions and findings of each session...

..The present study was conducted to determine whether removal of TGF-beta from these tumor cells would inhibit tumor progression in vivo...

..Together, our results provide unique insights into vascular regulation in breast tumors and suggest specific roles for genes in driving tumor angiogenesis...

..Protein kinase C frequently plays a central role in the intracellular signal transduction of growth factors and cytokines...

..This hypothesis is ready for testing in cancers of the breast, prostate, colon, and in sarcomas. Enlarging the therapeutic window is a major goal that would allow for an increasingly favorable therapeutic gain...

..Although malignant cells alone secreted VEGF, stromal cells secreted TGF-beta and bFGF at levels comparable with or greater than malignant cells and thus may be important contributors to tumor growth and progression...

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