2458 Despite dramatic improvements in treatment over the past 40 years, acute lymphoblastic leukemia (ALL) remains one of the most common causes of death from disease in childhood. Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, and patient response to treatment is an important determinant of long-term outcome in childhood ALL. In spite of its clinical significance, the molecular basis of glucocorticoid resistance is still poorly understood. The aim of this study was to develop an experimental model system to define clinically relevant mechanisms of glucocorticoid resistance in childhood ALL. An in vivo model of childhood ALL has been developed in our laboratory, using patient biopsies established as xenografts in immune-deficient nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice. This model is highly representative of the human disease (Lock et al., Blood, 99: 4100-4108, 2002). The in vivo responses of these xenografts to the glucocorticoid dexamethasone (DEX) correlated significantly with patient outcome (p 1 μM) in xenografts from six patients, five of whom died of their disease. In contrast, four DEX-sensitive xenografts (IC50 values 2-fold in sensitive xenografts within 8 hours of treatment. In contrast, Bim induction was dramatically attenuated in DEX-resistant xenografts. These results have identified a clinically significant and novel mechanism of glucocorticoid resistance in childhood ALL, which occurs downstream of receptor-ligand interactions, but upstream of the signalling pathway resulting in Bim induction and apoptosis.

Novel mechanisms of glucocorticoid resistance in childhood acute lymphoblastic leukemia.

Study of New Curcumin Analogs for the Treatment of Erα Negative Breast Cancers

Resistance to the HER2-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-overexpressing metastatic breast cancer. Increased expression or signaling of the insulin-like growth factor-I receptor (IGF-IR) has been reported in a subset of cell lines and clinical samples derived from trastuzumab-resistant breast cancers. Genetic and pharmacologic inhibition of IGF-IR signaling has been shown to improve response to trastuzumab in trastuzumab-naive and trastuzumab-resistant models. In this paper, we will discuss the role of IGF-IR signaling in trastuzumab resistance. Further, we will discuss cotargeting IGF-IR and HER2 as a potential therapeutic strategy for HER2-over-expressing breast cancers that have progressed on trastuzumab treatment.

/pdf/deciphering-the-role-of-insulin-like-growth-factor-i-217ieotkgs.pdf

Deciphering the role of insulin-like growth factor-I receptor in trastuzumab resistance.

Approximately 20-30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Elevated levels of HER2 are associated with aggressive disease, high metastatic potential, and reduced survival versus other breast cancer subtypes (Slamon, 1987). Trastuzumab (Herceptin) is a monoclonal antibody targeted against an extracellular region of HER2 (Carter, 1992). Clinical trials have shown that 15-30% of patients with HER2overexpressing metastatic breast cancer respond to single-agent trastuzumab for a median duration of approximately 10 months (Baselga, 1996; Cobleigh, 1999). Response rates improve when trastuzumab is combined with chemotherapy in patients with HER2overexpressing metastatic breast cancer (Esteva, 2002; Slamon, 2001). A subset of trastuzumab-resistant breast cancers respond to the dual EGFR/HER2 kinase inhibitor lapatinib, although the majority (70% or more) show primary resistance (Geyer, 2006). Similar to trastuzumab treatment, clinical trials with lapatinib indicated that the median duration of response to lapatinib in a heavily pre-treated, trastuzumab-refractory population was less than one year (Geyer, 2006). Hence, resistance to clinically available HER2-targeted agents is a major concern in the treatment of patients with HER2overexpressing metastatic breast cancer.

/pdf/novel-therapeutic-strategies-and-combinations-for-her2-2yyugigb5x.pdf

Novel Therapeutic Strategies and Combinations for HER2-Overexpressing Breast Cancer

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Novel Therapeutic Strategies and Combinations for HER2-Overexpressing Breast Cancer