Wendy R. Tate

The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non–small cell lung cancer xenografts

Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib show antitumor activity in a subset of non–small cell lung cancer (NSCLC) patients having mutated EGFR. Recent work shows that phosphatidylinositol-3-kinase (PI3-K) is coupled to the EGFR only in NSCLC cell lines expressing ErbB-3 and that EGFR inhibitors do not inhibit PI3-K signaling in these cells. The central role PI3-K plays in cell survival suggests that a PI3-K inhibitor offers a strategy to increase the antitumor activity of EGFR inhibitors in resistant NSCL tumors that do not express ErbB-3. We show that PX-866, a PI3-K inhibitor with selectivity for p110α, potentiates the antitumor activity of gefitinib against even large A-549 NSCL xenografts giving complete tumor growth control in the early stages of treatment. A-549 xenograft phospho-Akt was inhibited by PX-866 but not by gefitinib. A major toxicity of PX-866 administration was hyperglycemia with decreased glucose tolerance, which was reversed upon cessation of treatment. The decreased glucose tolerance caused by PX-866 was insensitive to the AMP-activated protein kinase inhibitor metformin but reversed by insulin and by the peroxisome proliferator-activated receptor-γ activator pioglitazone. Prolonged PX-866 administration also caused increased neutrophil counts. Thus, PX-866, by inhibiting PI3-K signaling, may have clinical use in increasing the response to EGFR inhibitors such as gefitinib in patients with NSCLC and possibly in other cancers who do not respond to EGFR inhibition.

Identification of thioredoxin-interacting protein 1 as a hypoxia-inducible factor 1α-induced gene in pancreatic cancer

Objective: To investigate the expression of thioredoxin-interacting protein (TXNIP) during hypoxia and its dependency on hypoxia-inducible factor 1&agr; (HIF-1&agr;) in pancreatic cancer cell lines. Methods: MiaPaCa-2 pancreatic cancer cells were transiently transfected with siRNA to HIF-1&agr; and TXNIP protein measured after growth in normoxia or hypoxia. In addition, HIF-1&agr; dependency was assessed by transiently transfecting MiaPaCa-2 pancreatic cancer cells with HIF-1&agr; with a mutated oxygen degradation domain resulting in stable HIF-1&agr; expression in normoxic conditions. Panc-1 pancreatic cancer cells with low endogenous TXNIP expression were stably transfected with TXNIP, and cell survival and response to platinum cancer agents were tested. Quantitative immunohistochemistry was utilized to measure the expression of TXNIP and thioredoxin 1 in human pancreatic cancer tissues. Results: Thioredoxin-interacting protein was induced during hypoxia in pancreatic cancer cells in a HIF-1&agr;-dependent manner. Overexpression of TXNIP in the Panc-1 cells resulted in a higher basal apoptosis and increased sensitivity to cisplatin and oxaliplatin. A negative correlation was observed between TXNIP and thioredoxin 1 expression in human pancreatic cancer tissues. Conclusions: Thioredoxin-interacting protein, a putative tumor suppressor gene, is induced in response to hypoxia in a HIF-1&agr;-dependent manner in pancreatic cancer cells, resulting in increased apoptosis and increased sensitivity to platinum anticancer therapy. Increased TXNIP may be a mechanism to counterbalance the prosurvival effects of HIF-1&agr;.

The Antitumor Agent Imexon Activates Antioxidant Gene Expression: Evidence for an Oxidative Stress Response

Purpose: The aim of this study was to identify biomarkers that may be predictive for the clinical activity of the redox-active antitumor agent imexon. Experimental Design: cDNA microarray and quantitative real-time PCR were used to identify global changes in gene expression in peripheral blood mononuclear cells (PBMC) collected from patients treated with imexon during a phase I trial. Electrophoretic mobility shift assays and Western blot analysis were done using the RPMI8226 myeloma cell line grown in vitro and PBMCs treated ex vivo to investigate the molecular mechanism responsible for these gene changes. Results: Both cDNA microarray and quantitative real-time PCR showed the up-regulation of many antioxidant genes, including thioredoxin reductase-1, glutaredoxin-2, and peroxiredoxin-3 in PBMCs collected from patients treated with imexon. Studies in PBMCs treated ex vivo and RPMI8226 myeloma cells showed that imexon increased binding to the activator protein-1 consensus sequence measured by electrophoretic mobility shift assay. Supershift analysis showed that the majority of the activator protein-1 DNA binding activity was c-Jun, with minor contribution of Jun-D. Nuclear translocation of the nuclear factor (erythroid-derived 1)-like 2 transcription factor and its binding to the antioxidant response element was also increased after imexon treatment, which correlated with an increase in the message levels for nuclear factor (erythroid-derived 1)-like 2/antioxidant response element–regulated antioxidant genes. Conclusions: Together, these results show that a predominant biological effect of imexon is a change in redox state that can be detected in surrogate normal tissues as increased redox-sensitive transcription factor binding and increased antioxidant gene expression.

Quality‐adjusted time without symptoms or toxicity (Q‐TWiST): patient‐reported outcome or mathematical model? A systematic review in cancer

Successful cancer treatment is defined as an increase in overall survival and/or progression‐free survival. Despite their importance, these metrics omit patient quality of life. Quality‐adjusted time without symptoms or toxicity (Q‐TWiST) was developed to adjust survival gained, accounting for quality of life. The purpose of this systematic review was to assess the methods reported in cancer literature to determine Q‐TWiST values and how these are currently translated to the clinic.

Clinical and economic burden of Richter syndrome in inpatient cases of chronic lymphocytic leukemia within the United States, 2001–2010

Abstract Richter syndrome (RS) is an aggressive transformation of chronic lymphocytic leukemia (CLL) characterized by poor prognoses. The purpose of this study was to assess clinical and economic characteristics of RS within inpatient hospital settings in the United States from 2001 to 2010. This retrospective cohort study employed data from the Agency for Healthcare Research and Qualitys Healthcare Cost and Utilization Project. Overall, 46 613 cases of RS were observed across 695 080 inpatient cases of CLL, representing a national bill of

Quality-adjusted time without symptoms or toxicity (Q-TWiST): patient-reported outcome or mathematical model? A systematic review in cancer: A systematic review of Q-TWiST in cancer

2.74 billion and involving a 9.3% inpatient mortality rate. Multivariate analyses found decreased national inpatient mortality from 2001 to 2010 of − 61.1% (p < 0.001), shorter length of stay of − 15.5% (p < 0.001) and higher charges of +20.9% (p = 0.003). Numerous characteristics were also associated with increased likelihoods of death, lengths of stay and charges. Clinically, the findings allow for an increased understanding of population-based RS case-mixes, outcome prediction and clinical risk assessments. The continued burden of illness of either RS or CLL ultimately remains contingent upon the comparative- and cost-effectiveness of both existing interventions and those in development.

Quality-adjusted time without symptoms or toxicity (Q-TWiST)

Successful cancer treatment is defined as an increase in overall survival and/or progression‐free survival. Despite their importance, these metrics omit patient quality of life. Quality‐adjusted time without symptoms or toxicity (Q‐TWiST) was developed to adjust survival gained, accounting for quality of life. The purpose of this systematic review was to assess the methods reported in cancer literature to determine Q‐TWiST values and how these are currently translated to the clinic.

The antitumor thioredoxin-1 inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma

Successful cancer treatment is defined as an increase in overall survival and/or progression‐free survival. Despite their importance, these metrics omit patient quality of life. Quality‐adjusted time without symptoms or toxicity (Q‐TWiST) was developed to adjust survival gained, accounting for quality of life. The purpose of this systematic review was to assess the methods reported in cancer literature to determine Q‐TWiST values and how these are currently translated to the clinic.