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ABSTRACT: Histone deacetylase (HDAC) inhibitors, including MGCD0103 and vorinostat, have led to tumor growth inhibition and apoptosis in vivo. However, with limited single-agent activity demonstrated in solid tumor trials, we examined the potential for enhanced effects in combination with topoisomerase I and II inhibitors, a staple for treatment in refractory small cell lung cancer (SCLC). SCLC cell lines were exposed to increasing concentrations of single-agent HDAC inhibitors and topoisomerase inhibitors, in various combinations, to assess for cell viability, additivity or synergy, and apoptosis. We found that MGCD0103 and vorinostat decreased cell viability by at least 60% and 80%, respectively. In the majority of cell lines, the strongest synergism was seen when vorinostat was followed by either etoposide or topotecan; concurrent therapy led to antagonism in most cell lines. Synergistic effects were seen when MGCD0103 was given concurrently or sequentially with both amrubicin and epirubicin. Enhanced additive effects leading to caspase activation were noted for the combination of MGCD0103 or vorinostat with a topoisomerase inhibitor vs. either agent alone. Thus, the combination of HDAC inhibitors and topoisomerase inhibitors showed enhanced cytotoxic effects in SCLC cell lines. Further evaluation in a clinical setting may be warranted.
Cancer biology & therapy 06/2012; 13(8):614-22. · 2.64 Impact Factor
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ABSTRACT: Triciribine phosphate is a potent, small-molecule inhibitor of activation of all three isoforms of AKT in vitro. AKT is an intracellular protein that, when activated, leads to cellular division; it is dysregulated in a large number of malignancies, and constitutively activating AKT mutations are present in a minority of cancers.
In this phase I study triciribine phosphate monohydrate (TCN-PM) was administered to subjects whose tumors displayed evidence of increased AKT phosphorylation (p-AKT) as measured by immunohistochemical analysis (IHC). TCN-PM was administered over 30 min on days 1, 8 and 15 of a 28-day cycle. Tumor biopsy specimens, collected before treatment and on day +15, were assessed for p-AKT by IHC and western blot analyses.
Nineteen subjects were enrolled; 13 received at least one cycle of therapy, and a total of 34 complete cycles were delivered. One subject was treated at the 45 mg/m(2) dose before the study was closed due to its primary objective having been met. No dose-limiting toxic effects were observed. Modest decreases in tumor p-AKT following therapy with TCN-PM were observed at the 35 mg/m(2) and 45 mg/m(2) dose levels, although definitive conclusions were limited by the small sample size.
These preliminary data suggest that treatment with TCN-PM inhibits tumor p-AKT at doses that were tolerable. Although single agent activity was not observed in this enriched population, further combination studies of TCN-PM with other signal transduction pathway inhibitors in solid tumors is warranted.
Investigational New Drugs 12/2011; 29(6):1381-9. · 3.36 Impact Factor
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Jeffrey E Lancet,
Vu H Duong,
Elliott F Winton,
Robert K Stuart,
Michelle Burton,
Shumin Zhang, Christopher Cubitt,
Michelle A Blaskovich,
John J Wright,
Said Sebti,
Daniel M Sullivan
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ABSTRACT: To determine the safety, target inhibition, and signals of clinical activity of tipifarnib in combination with bortezomib in patients with advanced acute leukemias.
In a "3 + 3" design, patients received escalating doses of tipifarnib (days 1-14) and bortezomib (days 1, 4, 8, 11) every 3 weeks until maximum tolerated dose was reached. Peripheral blood mononuclear cells (PBMC) were collected at days 1, 8, and 22 for measurement of chymotrypsin-like and farnesyltransferase activity. Purified bone marrow leukemic blasts were collected at baseline and at day 8 for measurement of NF-κB activity.
The combination was well-tolerated, and maximum tolerated dose was not reached. Dose-limiting toxicities included diarrhea, fatigue, and sensorimotor neuropathy. Chymotrypsin-like and farnesyltransferase activity within PBMCs were decreased in a majority of patients at day 8. NF-κB activity within leukemic blasts was decreased in a majority of patients at day 8. Complete response with incomplete count recovery was observed in 2 patients, and additional 5 patients had stable disease.
Tipifarnib and bortezomib combination in patients with advanced leukemias was well-tolerated, demonstrated relevant target inhibition, and was associated with signals of clinical activity in patients with advanced and refractory acute leukemias. Future studies of this combination may be warranted in more selected groups of patients in whom these molecular targets are of particular importance.
Clinical Cancer Research 01/2011; 17(5):1140-6. · 7.74 Impact Factor
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ABSTRACT: Src signaling has been implicated in several malignancies including melanoma. The prevalence of Src activation in human melanoma and the effect of the newer Src inhibitors, dasatinib, and bosutinib (SKI-606), as single agents or in combination, on melanoma cell lines is not well established. In the melanoma cell lines, A-375, SK-Mel-5, and SK-Mel-28, activity of Src inhibitors was assessed alone or in combination with standard chemotherapy agents; 50% growth inhibitory concentration was determined by MTS assay and immunoblotting was used to measure Src activation and downstream signaling. Staining for Src activation was measured by Src-phosphotyrosine 416. Immunohistochemistry was performed on primary cutaneous, mucosal, and metastatic melanoma. Src inhibitors blocked the growth of melanoma cell lines; furthermore, Src inhibitor treatment was synergized with cisplatin but not temozolomide or paclitaxel. Treatment with dasatanib increased the levels of pS473 Akt in A-375 melanoma cells but not in the other two cell lines. Forty-eight percent (17 of 35) of all melanoma stained weakly, moderately, or strongly for pY416 Src: cutaneous 61% (eight of 13), mucosal 31% (four of 13), metastatic 55% (five of nine). Most positive biopsies stained weakly and only one metastatic melanoma specimen stained strongly for Src-phosphotyrosine 416. pY416 Src is expressed in cutaneous, mucosal, and metastatic melanoma in various degrees. Src inhibitors may be a promising therapy in melanoma, either by themselves or in combination with chemotherapy (especially with platinum compounds) or inhibitors of the Akt/PI3k pathway.
Melanoma research 07/2009; 19(3):167-75. · 2.06 Impact Factor
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Christopher L Cubitt
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ABSTRACT: The BK Virus (BKV) genome is a double-stranded, circular DNA molecule with genetic organization similar to other polyomaviruses, and high homology to JC Virus (JCV) and SV40. The archetypal form of BKV noncoding regulatory region (NCRR) is the infectious form of BKV that replicates in the urothelium and is excreted in the urine. Rearranged forms of the NCRR are found in kidney and other tissues often in association with disease. BKV strains can be assigned to genotype/serotype groups based on sequence variation in the VP1 gene. Sequencing of the complete genomes from patient samples will enhance BKV phylogenetic studies and identify genotypic differences and naturally occurring mutations in BKV that may correlate with incidence and/or severity of a disease. This chapter is a review of the molecular genetics of the BK virus in respect to BKV disease.
Advances in experimental medicine and biology 02/2006; 577:85-95. · 1.09 Impact Factor
