Construction of wild type PRL 3 and mutant PRL 3 protein expression vectors and

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 Construction of wild type PRL 3 and mutant PRL 3 protein expression vectors and Empty Construction of wild type PRL 3 and mutant PRL 3 protein expression vectors and

Post  jy9202 on Tue May 13, 2014 9:20 am

Other CDK inhibitors have not demonstrated similar efficacy in subjects with CLL, These results suggest that dinaciclib combin ation strategies may be especially promising in solid tumors, and dinaciclib ABT-737 as monotherapy or in combination may also be effective in hematologic malignancies. Metastatic melanoma is difficult to treat and it is only re cently that therapy has been shown to have an impact on overall survival, DTIC dacarbazine has been shown in contemporary studies to provide tumor responses in less than 15% of patients, with a median response duration of 3 4 months, Combination therapies may increase response rates, but without improvement in survival, High dose interleukin 2 and ipilimumab benefit the mi nority of patients, albeit with a subset of patients experien cing durable responses, Although many patients with BRAF mutated melanoma initially respond to vemurafenib, the only other agent approved by the FDA for this disease, most will ultimately relapse, Thus, while significant advances in both immune based and mo lecularly targeted therapies have been made, survival for many patients with metastatic melanoma remains poor.

New therapies are still needed for this disease, and the testing of new agents is being driven by an increasing knowledge of melanoma biology. The vast majority of melanomas have activating muta tions in signaling proteins involved in the RAS pathway.

Mutations in RAS occur in around 15% of melanomas, Adriamycin 価格 In addition, frequent mutations in downstream RAS effectors have been reABT-199 臨床試験 ported, the most common of which is BRAF which has been reported to be mutated in approxi mately 50% of cases, Mutated BRAF can be effectively targeted in patients with metastatic melanoma, with impressive response rates in early phase trials, Recent data now demonstrates an improvement in overall survival in patients treated with selective BRAF inhibitors when compared to dacarbazine, although many patients ultimately relapse, further highlighting the importance of understanding the molecular pathogenesis of this disease, Activation of the PI3 Kinase Akt pathway has also been implicated in melanoma tumorigenesis, potentially through downregulated expression of the negative regula tor PTEN, Interestingly, even in melanoma cells having mutations in downstream effectors, constitutive RAS activation is nonetheless seen, likely through the ac tivity of autocrine or paracrine growth factor secretion, Transgenic mouse experiments have confirmed the important contribution of activated RAS based signaling to melanomagenesis in vivo, Targeted inhibition of RAS based signaling has there fore received significant attention.

While kinase inhibi tors that interfere with the activity of the downstream molecules PI3 Kinase, RAF, and MEK are in various stages of development, it has been difficult to identify a pharmacologic strategy to inhibit RAS activity directly, However, the fact that RAS must undergo a lipid post translational modification for localization to mem brane compartments where access to its effectors occurs generated an alternative strategy for inhibiting RAS function.

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