K Podar

....

..To prevent relapse of MM in patients treated with Bortezomib, we therefore recommend the combination of Bortezomib with agents that induce MM cell death independent of Mcl-1...

..This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents - small molecules as well as therapeutic antibodies - that hold promise to further improve outcome in MM...

..Our own and others' work suggest that VEGF-inhibitors e.g., the small molecule VEGF receptor inhibitor pazopanib, may also improve patient outcome in MM...

..Important contributing effectors are tumor cell-stroma cell and cell-extracellular matrix contacts, the bone marrow vasculature, and a variety of cytokines and growth factors in the bone marrow milieu...

..Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors...

....

..Ongoing studies are further delineating MM pathogenesis in the BM to enhance cytotoxicity, avoid drug resistance and improve patient outcome...

..Close collaboration between basic researchers and clinicians will be required to further improve our knowledge of MM pathophysiologically in order to translate advances from the bench to the bedside and improve patient outcome...

..In this mini-review, we characterize the functional role of caveolin-1 in multiple myeloma, and present the preclinical rationale for novel potential therapeutic approaches targeting caveolin-1 in multiple myeloma...

..Importantly, early studies already demonstrate promising preclinical of novel agents, predominantly small molecules, which target c-Myc, HIF or both...

..Our data therefore provide the rationale for the clinical evaluation of Natalizumab, preferably in combination with novel agents (e.g. bortezomib) to enhance MM cytotoxicity and improve patient outcome...

..Therefore, it is necessary to further dissect the relative contribution of PKC isozymes in the development and progression of specific tumors in order to identify therapeutic opportunities, using either PKC inhibitors or PKC activators...

..These data demonstrate the importance of stromal-MM cell interactions in regulating VEGF and IL-6 secretion, and suggest additional mechanisms whereby thalidomide and IMiD1-CC4047 act against MM cells in the BM millieu...

..Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM...

..These observations provide the framework for novel therapeutic strategies targeting VEGF signaling cascades in MM...

..These data indicate that VEGF plays a pivotal role not only in neoangiogenesis in MM BM but also in proliferation and migration of tumor cells...

....

..Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies...

..These studies may therefore allow improved therapeutic uses of Dex, based upon targeting genes that regulate MM cell growth and survival...

..Combining NPI-0052 and Bortezomib induces synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating NPI-0052, alone and together with Bortezomib, to improve patient outcome in MM...

..These studies provide the framework for clinical evaluation of MLN120B, alone and in combined therapies, trials of these novel agents to improve patient outcome in multiple myeloma...

..CONCLUSION: These studies provide a framework for clinical evaluation of beta-lapachone to improve the outcome for patients with MM...

....

....

..Thus in vitro and in vivo data support the hypothesis that Thal may mediate its anti-MM effect, at least in part, by modulating NK cell number and function...

..These studies may therefore allow improved therapeutic use of 2ME2, based upon targeting genes that regulate MM cell growth and survival...

..Together, these findings provide the framework for clinical evaluation of CDDO-Im, either alone or in combination with bortezomib, to overcome drug resistance and improve patient outcome in MM...

..Together, these preclinical studies suggest that combining bortezomib with PK may enhance its clinical efficacy, reduce attendant toxicity, and overcome conventional and bortezomib resistance in patients with relapsed refractory MM...

..Our studies therefore demonstrate that LPAAT-beta inhibitor CT-32615 triggers necrosis, even in PS-341-resistant DHL-4 cells, providing the framework for its evaluation to overcome clinical PS-341 resistance and improve patient outcome...

..Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM...

..Moreover, IKKbeta inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-kappaB activity in MM cells...

....

....

..Coupled with a recent report that Ku86 activity correlates with resistance to radiation and chemotherapy, these results have implications for the potential role of Ku86 as a novel therapeutic target...

..Time-lapse phase contrast video microscopy (TLVM) studies confirm the importance of these signaling components in VEGF-triggered MM cell migration on fibronectin...

....

..Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti-MM agents, to improve patient outcome...

....

..The demonstrated anti-MM activity of PTK787, coupled with its antiangiogenic effects, provides the framework for clinical trials of this agent to overcome drug resistance and improve outcome in MM...

..Our data, therefore, identify Hif-1alpha as a novel molecular target in MM and add another facet to anti-MM drug activity...

....

..Our study therefore provides the rationale for clinical protocols evaluating LBW242, alone and together with other anti-MM agents, to improve patient outcome in MM...

....

..These preclinical studies provide the framework for clinical trials of bortezomib with Perifosine to improve patient outcome in MM...

....

..Moreover, they define the functional association of IGF-IR and beta1 integrin in mediating MM cell homing, providing the preclinical rationale for novel treatment strategies targeting IGF-I/IGF-IR in MM...

..Our data, therefore, indicate that R-etodolac circumvents drug resistance in MM cells at clinically relevant concentrations, targets Mcl-1, and can be synergistically combined with Dex...

....

..Finally, blockade of Hsp27 by anti-sense strategy enhanced anti-MM activity of both 2ME2 and PS-341. These findings provide the clinical application of novel therapeutics targeting Hsp27 to improve patient outcome in MM...

..This treatment framework promises to improve outcome not only for patients with multiple myeloma, but also with other haematological malignancies and solid tumours...

..These findings provide the first evidence that Hsp27 confers PS-341 resistance...

..These results suggest that FTY720 overcomes drug resistance in multiple myeloma cells and provide the rationale for its clinical evaluation to improve patient outcome in multiple myeloma...

..Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM...

..Our studies therefore demonstrate that VEGF-induced MM cell proliferation and survival are mediated via Mcl-1, providing the preclinical framework for novel therapeutics targeting Mcl-1 and/or VEGF to improve patient outcome in MM...

..Taken together, our results provide the preclinical rationale for clinical protocols of HNK to improve patient outcome in MM...

..Taken together, these preclinical findings suggest that patupilone may be a safe and effective drug in the treatment of MM, providing the framework for clinical studies to improve patient outcome in MM...

....

..Our results therefore show that the IMiDs have more potent direct anti-tumor and anti-angiogenic effects than thalidomide in vivo, providing the framework for clinical protocols evaluating these agents in MM and other B cell neoplasms...

..1S cells and patient MM cells. Taken together, these results provide the preclinical rationale for the evaluation of SGN-40 as a potential new therapy to improve patient outcome in MM...

....

..Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells...

..These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM...

..These results provide the preclinical rationale for clinical trials of CHIR-12.12 to improve patient outcome in multiple myeloma...

..Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel etodolac analog SDX-308 can target MM cells in the BM milieu...

..They provide a framework for the use of 2ME2, either alone or in combination with Dex, to overcome drug resistance and to improve outcome in MM...

..Finally, these results hint at novel targets for drug development that may aid traditional therapy...

....

..Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM...

..Taken together, this study identifies caveolin-1 and other structural membrane components as potential new therapeutic targets in multiple myeloma...

..These studies defined the mechanisms whereby IMiDs trigger NK cell-mediated tumour-cell lysis, further supporting their therapeutic use in MM...

..Our results identify Gab2 and its associated proteins as key determinants of the lineage and severity of BCR/ABL transformation...

..Therefore, targeting Ku86 and Ku70, with blocking peptides for example, might serve as a novel treatment strategy in human MM...

..These findings demonstrate that activation of JNK is an obligatory event for the release of Smac during stress-induced apoptosis in MM cells...

..Taken together, our data provide the rationale for clinical trials of perifosine to improve patient outcome in MM...

..The characterization of SU11274 as an effective inhibitor of Met tyrosine kinase activity illustrates the potential of targeting for Met therapeutic use in cancers associated with activated forms of this kinase...

....

..Importantly, this effect on cytokine-induced gp130 signaling cascades may account, at least in part, for the remarkable preclinical sensitivity and clinical responses achieved in MM with PS-341 treatment...

..These studies therefore provide the framework for clinical trials of SCIO-469 to enhance sensitivity and overcome resistance to PS-341, thereby improving patient outcome in MM...

..Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM...

..These studies demonstrate that CD40 induces VEGF secretion and MM cell migration, suggesting a role for CD40 in regulating MM homing and angiogenesis...

..Here we discuss the regulation and function of Mcl-1 in the pathophysiology of multiple myeloma...

..These findings have clinical significance, because identification of downstream apoptotic signaling after topoisomerase I inhibition will both elucidate mechanisms of resistance and optimize future combination chemotherapy against MM...

....

..Taken together, these results show that AZD6244 targets both MM cells and OCs in the BM microenvironment, providing the preclinical framework for clinical trials to improve patient outcome in MM...

..Our studies therefore demonstrated in vitro anti-MM activity of FQPD and provide the rationale for its in vivo evaluation in animal models and derived clinical trials...

..In this study, we compare the effects of 3 tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on 2 GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib...

..These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination...

....