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 p110A, 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-; 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. [Mol Cancer Ther 2005;4(9):1349 -57]

Thioredoxin-1 (Trx-1) is a small redox protein that is overexpressed in many human tumors, where it is associated with aggressive tumor growth and decreased patient survival. Trx-1 is secreted by tumor cells and is present at increased levels in the plasma of cancer patients. PX-12 is an irreversible inhibitor of Trx-1 currently in clinical development as an antitumor agent. We have used SELDI-TOF mass spectroscopy to measure plasma Trx-1 from patients treated with PX-12 during a phase I study. Mean plasma Trx-1 levels at pretreatment were significantly elevated in the cancer patients at 182.0 ng/mL compared with 27.1 ng/mL in plasma from healthy volunteers. PX-12 treatment significantly lowered plasma Trx-1 in cancer patients having the highest plasma Trx-1 pretreatment levels. High-plasma vascular endothelial growth factor (VEGF) levels have been correlated to decreased patient survival. PX-12 treatment also significantly lowered plasma VEGF levels in cancer patients with high pretreatment VEGF levels. SELDI-TOF mass spectrometry identified seven additional plasma proteins whose levels decreased after PX-12 administration, one of which was identified as a truncated form of transthyretin. The results of this study suggest that the lowering of elevated levels of plasma Trx-1 in cancer patients may provide a surrogate for the inhibition of tumor Trx-1 by PX-12. Furthermore, PX-12 decreases plasma VEGF levels that may contribute to the antitumor activity of PX-12.

Thioredoxin-interacting protein, a putative tumor suppressor gene, is induced in response to hypoxia in a HIF-1alpha-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-1alpha.

ClinicalTrials.gov; No.: NCT00517933, NCT00650091, NCT00957242; URL: www.clinicaltrials.gov.

We identified and validated national and local key factors associated with accrual at our site. This methodology has not been previously validated broadly with the intent of trial feasibility. Model validation shows it to be an accurate and quick metric in anticipating accrual success that can be used for resource allocation.