Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both soluble factors and extracellular matrices, which may influence drug response. To address the influence of the bone marrow microenvironment on imatinib mesylate sensitivity, we used an in vitro bone marrow stroma model. Our data show culturing K562 cells, in bone marrow stroma-derived conditioned medium (CM), is sufficient to cause resistance to BCR-ABL inhibitors. Drug resistance correlated with increased pTyrStat3, whereas no increases in pTyrStat5 was noted. Moreover, resistance was associated with increased levels of the Stat3 target genes Bcl-xl, Mcl-1, and survivin. Finally, reducing Stat3 levels with small interfering RNA sensitized K562 cells cultured in CM to imatinib mesylate-induced cell death. Importantly, Stat3 dependency was specific for cells grown in CM, as reducing Stat3 levels in regular growth conditions had no effect on imatinib mesylate sensitivity. Together, these data support a novel mechanism of BCR-ABL-independent imatinib mesylate resistance and provides preclinical rationale for using Stat3-inhibitors to increase the efficacy of imatinib mesylate within the context of the bone marrow microenvironment. [Mol Cancer Ther 2008;7(10):3169 -75]
The effectiveness of BCR-ABL-dependent transformation of hematopoietic stem cells is due not to a single pathway but rather to the culmination of a network of signaling pathways.
We previously established that the class II transactivator CIITA binds GTP and disruption of the GTP binding ability of CIITA results in increased cytoplasmic CIITA, loss of nuclear CIITA, and thus diminished class II major histocompatibility complex transcription. Because of its role in facilitating nuclear localization, whether GTP binding is also required for CIITA-mediated transactivation of major histocompatibility class II genes remains unclear. We now show that recruitment of CIITA to the human leukocyte antigen (HLA)-DR promoter and activation of HLA-DR transcription is also GTP-dependent. After restoration of nuclear expression, CIITA mutants defective in GTP binding lack full transcriptional activation capacity. Although the availability of the activation domain of CIITA is unaltered, GTP mutants no longer cooperate with CREB-binding protein, p300, and pCAF and are defective in recruitment to the HLA-DR promoter.
While many anti-neoplastic drugs have a proven ability to kill cancer cells, some possess limited selectivity and high toxic effects on normal cells, which can yield marginal therapeutic indices. Antibody-drug conjugates (ADCs) represent an alternative therapeutic option being pursued by pharmaceutical companies. These therapeutic agents, also called immuno-conjugates, combine the specificity of monoclonal antibodies (mAbs) with the potency of cytotoxic molecules to deliver and release the anti-cancer agent inside tumor cells. ADCs consist of a cytotoxic agent, an antibody targeting an antigen expressed on tumor cells, and a linker that covalently binds these components together. They are designed to provide selective killing of target tumor cells while minimizing the cytotoxic effects on normal tissues. Human mAbs are one of the fastest-growing categories of therapeutics entering clinical studies. As technology improves, the rational design and optimization of chemical linkers have resulted in renewed interest in ADCs among pharmaceutical companies. Phase I studies are a critical step in oncology drug development, as they translate years of laboratory studies, non-clinical data, into clinical use. A Sponsor-submitted investigational new drug application (IND) contains non-clinical data to establish the maximum recommended starting dose in humans. This panel of non-clinical data includes those derived from laboratory animal studies and consists of pharmacology information, toxicologic profile of the compound, and the pharmacokinetics of the therapeutic agent, all of which are considered when determining the first-in-human dose. This dose is expected to exert some pharmacologic activity and have acceptable toxicities based on the patient population and the benefit:risk consideration. While the U.S. Food and Drug Administration (FDA) has established a guideline for identifying the first-in-human dose for small molecules for oncology indications (ICH S9), there is no specific FDA established approach currently for ADCs. A growing number of INDs submitted to the FDA include ADCs as the investigational drug. Our research consists of an examination of 46 INDs containing ADCs, submitted to the FDA between 2003 and 2011. Analysis of the data revealed that different approaches have been proposed by Sponsors of the INDs for selection of the human dose based on non-clinical data. During this research, these approaches are evaluated with the goal of ultimately identifying the best approach. The objectives of this research are to: 1) analyze approaches used to set the human start dose based on animal pharmacology and toxicology data, 2) examine the method and rationale for selecting the Phase I clinical start dose, and 3) identify the optimal approach for first-in-human dose selection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5391. doi:1538-7445.AM2012-5391
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