We report the analysis of CPI-613, the first member of a large set of analogs of lipoic acid (lipoate) we have investigated as potential anticancer agents. CPI-613 strongly disrupts mitochondrial metabolism, with selectivity for tumor cells in culture. This mitochondrial disruption includes activation of the well-characterized, lipoate-responsive regulatory phosphorylation of the E1α pyruvate dehydrogenase (PDH) subunit. This phosphorylation inactivates flux of glycolysis-derived carbon through this enzyme complex and implicates the PDH regulatory kinases (PDKs) as a possible drug target. Supporting this hypothesis, RNAi knockdown of the PDK protein levels substantially attenuates CPI-613 cancer cell killing. In both cell culture and in vivo tumor environments, the observed strong mitochondrial metabolic disruption is expected to significantly compromise cell survival. Consistent with this prediction, CPI-613 disruption of tumor mitochondrial metabolism is followed by efficient commitment to cell death by multiple, apparently redundant pathways, including apoptosis, in all tested cancer cell lines. Further, CPI-613 shows strong antitumor activity in vivo against human non-small cell lung and pancreatic cancers in xenograft models with low side-effect toxicity.

Relevant tumor inhibitory concentrations were achieved without significant toxicity using doses up to 105 mg/m(2) on this single intravenous dose schedule. Prolonged administration schedules and combinations with other cytotoxic agents, strategies predicted to have greater antitumor efficacy according to preclinical studies, are under investigation.

Purpose The lipoate derivative CPI-613 is a first-in-class agent that targets mitochondrial metabolism. This study determined the effects of CPI-613 on mitochondrial function and defined the maximally tolerated dose (MTD), pharmacokinetics (PKs), and safety in patients with relapsed or refractory hematologic malignancies. Experimental Design Human leukemia cell lines were exposed to CPI-613 and mitochondrial function was assayed. A phase I trial was conducted in which CPI-613 was given as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days. Results CPI-613 inhibited mitochondrial respiration of human leukemia cells consistent with the proposed mechanism of action. In the phase I trial, 26 patients were enrolled. CPI-613 was well tolerated with no marrow suppression observed. When the infusion time was shortened to 1 hour renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities (DLTs). At a dose of 2940 mg/m2 over 2 hours, no DLTs were observed, establishing this as the MTD. Renal failure occurred in a total of 4 patients and resolved in all but 1, who chose hospice care. CPI-613 has a triphasic elimination with an alpha half-life of ~1.34 hours. Of 21 evaluable, heavily pretreated, patients, 4 achieved an objective response and 2 achieved prolonged stabilization of disease for a clinical benefit rate of 29%. Following drug exposure, gene expression profiles of peripheral blood mononuclear cells from responders demonstrated immune activation. Conclusion CPI-613 inhibits mitochondrial function and demonstrates activity in a heavily pretreated cohort of patients.

Myoepitheliomas of the breast are extremely rare; only four cases have been reported to date. It is not clear whether these tumors behave in a benign or malignant fashion, and no metastatic spread has been documented. We report a myoepithelioma of the breast with metastatic spread to an axillary lymph node. Myoepithelial cell (MEC) differentiation in the tumor was characterized using electron microscopic (EM) criteria. Immunologic investigations at the LM and EM levels showed that the tumor cells were positive for S100 protein, actin, and epidermal cytokeratin; these findings are indicative of MEC differentiation. By immuno-EM, cytokeratin filaments were present in a perinuclear location, while actin filaments were concentrated along the cell periphery. To the authors' knowledge, this is the first report of a breast myoepithelioma that has metastasized and also the first report of the immunologic characterization of a myoepithelioma at the light and electron microscopic levels.

Strassen's algorithm for fast matrix-matrix multiplication has been implemented for matrices of arbitrary shapes on the CRAY-2 and CRAY Y-MP snpercomputers. Several techniques have been used to reduce the scratch space requirement for this algorithm while simultaneously preserving a high level of performance. When the resulting Strassen-based matrix multiply routine is combined with some routines from the new LAPACK library, LU decomposition can be performed with rates significantly higher than those achieved by conventional means. We succeeded in factoring a 2048 x 2048 matrix on the CRAY Y-MP at a rate equivalent to 325 MFLOPS.