ABSTRACT
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 MTD, pharmacokinetics, 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 3,780 mg/m(2), there were two dose-limiting toxicities (DLT). At a dose of 2,940 mg/m(2) 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 approximately 1.34 hours. Of the 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.
Subject(s)
Antineoplastic Agents/therapeutic use , Caprylates/therapeutic use , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/pathology , Sulfides/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Caprylates/pharmacology , Cell Line, Tumor , Drug Administration Schedule , Female , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/mortality , Humans , Leukemia/drug therapy , Leukemia/metabolism , Leukemia/pathology , Male , Middle Aged , Mitochondria/drug effects , Mitochondria/metabolism , Neoplasm Staging , Positron-Emission Tomography , Sulfides/pharmacology , Tomography, X-Ray Computed , Treatment Outcome , Young AdultSubject(s)
Acute-Phase Proteins/genetics , Antibiotics, Antineoplastic/pharmacology , Doxorubicin/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Lipocalins/genetics , Matrix Metalloproteinase 9/genetics , Paclitaxel/pharmacology , Proto-Oncogene Proteins/genetics , Acute-Phase Proteins/agonists , Acute-Phase Proteins/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Female , Humans , Inhibitory Concentration 50 , Lipocalin-2 , Lipocalins/agonists , Lipocalins/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Proto-Oncogene Proteins/agonists , Proto-Oncogene Proteins/metabolism , Signal Transduction/drug effectsABSTRACT
Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs is clearly important as these are frequently used therapeutic approaches. A signaling pathway often involved in chemo- and hormonal-resistance is the Ras/PI3K/PTEN/Akt/mTOR cascades. In the studies presented in this report, we have examined the effects of constitutive activation of Akt on the sensitivity of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs as well as mTOR inhibitors. MCF-7 cells which expressed a constitutively-activated Akt-1 gene [∆Akt-1(CA)] were more resistant to doxorubicin, etoposide and 4-OH-tamoxifen (4HT) than cells lacking ∆Akt-1(CA). Cells which expressed ∆Akt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC50s for doxorubicin, etoposide and 4HT in the cells which expressed ∆Akt-1(CA), demonstrating a potential improved method for treating certain breast cancers which have deregulated PI3K/PTEN/Akt/mTOR signaling. Understanding how breast cancers respond to chemo- and hormonal-based therapies and the mechanisms by which they can become drug resistant may enhance our ability to treat breast cancer. These results also document the potential importance of knowledge of the mutations present in certain cancers which may permit more effective therapies.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm , Molecular Targeted Therapy , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Doxorubicin/pharmacology , Etoposide/pharmacology , Female , Humans , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/drug effects , Sirolimus/pharmacology , Tamoxifen/pharmacologyABSTRACT
BACKGROUND: The phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/v-akt murine thymoma viral oncogene homolog (Akt)/mammalian target of rapamycin (mTOR) pathway is central in the transmission of growth regulatory signals originating from cell surface receptors. OBJECTIVE: This review discusses how mutations occur that result in elevated expression the PI3K/PTEN/Akt/mTOR pathway and lead to malignant transformation, and how effective targeting of this pathway may result in suppression of abnormal growth of cancer cells. METHODS: We searched the literature for articles which dealt with altered expression of this pathway in various cancers including: hematopoietic, melanoma, non-small cell lung, pancreatic, endometrial and ovarian, breast, prostate and hepatocellular. RESULTS/CONCLUSIONS: The PI3K/PTEN/Akt/mTOR pathway is frequently aberrantly regulated in various cancers and targeting this pathway with small molecule inhibitors and may result in novel, more effective anticancer therapies.
