Lopinavir type of rationale is based on multiple factors

loped as an FGFR inhibitor. This agent, which has activity against multiple receptors Lopinavir including VEGFRs, PDGFR, and others, has shown preclinical activity in vitro and in vivo in cells expressing a variety of FGFR isoforms 9  . The agent was tolerated in a phase I trial for multiple myeloma and is currently in clinical trials for renal cell CA, breast cancer, and multiple myeloma, although no results have yet been published. A second generated FGFR-targeted TKI, termed BGJ398, has now been developed and is currently in early phase I trials for advanced solid tumors (ClinicalTrails.gov NCT00044). In Everolimus addition to small molecule TKIs, a fusion protein consisting of the FGFR ligand-binding domain coupled to the IgG Fc region was developed as a decoy receptor to block FGF signaling. This molecule, known as FP-039, had the anticipated ability to inhibit FGF-dependent activi- ties in preclinical models .

A phase I trial of this agent in advanced cancers demonstrated reasonable toler- ability and suggested some antitumor activity 3 . A phase II of this agent in endometrial cancers with known mutations in FGFR is underway (NCT044438). Wnt Inhibitors The Wnt buy flumazenil signaling system was initially discovered for its role in colon cancer associated with the inherited syndrome familial adenomatous polyposis (or adenomatous polyposis coli) 4 , 5 and has since been determined to play a role in many types of cancer 6 . Investigation into adrenal cancer has suggested that activation of Wnt/ β -catenin signaling plays a role in adrenal neoplasia, including both benign and malignant tumors 7 – 30 . Interestingly, a 3 388 reassessment of microarray expression data has identified a subset of tumors with Wnt pathway mutations that appear to behave differently than other subclasses of tumors 3 . More work is still needed to understand this phenomenon.

Nonetheless, there has been significant interest in develop- ing Wnt inhibitors for clinical use 3 . The most advanced of these agents is known as CWP39 and is currently being developed by the Choongwae Pharma Corp. in South Korea. This agent has shown activity against multiple myeloma cells in preclinical models both in vitro and in vivo by  purchase flumazenil promoting degradation of β -catenin 33 . Although there is a lot of potential for antigrowth effects of agents targeted to this pathway, the widespread use of Wnt signaling for many cellular processes means that this research must proceed with caution due to concerns about significant toxicity 34 . Rationale for Combination Chemotherapy Strategies To date, most clinical trials specifically targeted to ACC have focused on the use of single TKIs (Table ). Although this information is valuable in establishing a baseline for therapeutic efficacy, this type of treatment seems destined to provide only modest benefit to patients. A more fruitful approach may be the use of multiple agents, a practice well understood not only from oncology but also in microbiol- ogy where multiagent therapy is the norm for difficult cases.

This type of rationale is based on multiple factors. First, multiple signaling pathways stress typically are involved in cancer, such that (as discussed above) single-agent strate- gies may just shift the dominant signaling pathways to those that are not blocked. Second, resistance to single agents may occur by mutation of the target kinase, gene amplification, or upregulation of alternate pathways 35 . This latter effect could be blocked by using targeted therapies against these emerging changes. Third, strategies aimed at targeting multiple signaling pathways may benefit from therapeutic synergism and be significantly more effective than single agents used in sequential fashion. Finally, kinase inhibition may affect other factors contrib- uting to tumor growth and spread, including those in the microenvironment. In regard to synergy, there are well-documented inter- actions between the IGFR and EGFR signaling pathways 5 , 36 , 37 . It has been demonstrated that tumor

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