givinostat-hydrochloride and Multiple-Myeloma

ITF2357, an orally effective member of the family of histone deacetylase inhibitors, is a potent inducer of apoptosis and death of multiple myeloma (MM) cells. We performed a phase-II, multiple-dose clinical trial in 19 patients with relapsed or progressive MM to determine the maximum tolerated dose (MTD) of ITF2357 administered twice daily for four consecutive days every week for 4 weeks (i.e., first cycle). The first six patients received 150 mg ITF2357 twice daily. Since two of them experienced a dose-limiting toxicity (DLT) during the first cycle, the subsequent patients received 100 mg ITF2357 twice daily. This was the MTD, as only one DLT occurred. Up to 12 weeks (i.e., three cycles) of treatment were scheduled. Oral dexamethasone was allowed to a maximum weekly amount of 20 mg. Median duration of treatment was 6 weeks, ranging from two (two patients) to 12 weeks (five patients). Four patients suffered from serious adverse events. Three patients experienced grade 3-4 gastro-intestinal toxicity and three had transient electrocardiographic abnormalities. Thrombocytopenia occurred in all but one patient (grade 3-4 in ten patients). At last follow-up, five patients were in stable disease, five had disease progression, and nine had died all of progressive MM. In conclusion, when given at a dose of 100 mg twice daily alone or combined with dexamethasone, ITF2357 proved tolerable but showed a modest clinical benefit in advanced MM.

Topics: Aged; Drug Administration Schedule; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Male; Middle Aged; Multiple Myeloma; Treatment Outcome

The histone deacetylase inhibitor ITF2357 has potent cytotoxic activity in multiple myeloma in vitro and has entered clinical trials for this disease.. In order to gain an overall view of the activity of ITF2357 and identify specific pathways that may be modulated by the drug, we performed gene expression profiling of the KMS18 multiple myeloma cell line treated with the drug. The modulation of several genes and their biological consequence were verified in a panel of multiple myeloma cell lines and cells freshly isolated from patients by using polymerase chain reaction analysis and western blotting.. Out of 38,500 human genes, we identified 140 and 574 up-regulated genes and 102 and 556 down-modulated genes at 2 and 6 h, respectively, with a significant presence of genes related to transcription regulation at 2 h and to cell cycling and apoptosis at 6 h. Several of the identified genes are particularly relevant to the biology of multiple myeloma and it was confirmed that ITF2357 also modulated their encoded proteins in different multiple myeloma cell lines. In particular, ITF2357 down-modulated the interleukin-6 receptor alpha (CD126) transcript and protein in both cell lines and freshly isolated patients' cells, whereas it did not significantly modify interleukin-6 receptor beta (CD130) expression. The decrease in CD126 expression was accompanied by decreased signaling by interleukin-6 receptor, as measured by STAT3 phosphorylation in the presence and absence of inter-leukin-6. Finally, the drug significantly down-modulated the MIRHG1 transcript and its associated microRNA, miR-19a and miR-19b, known to have oncogenic activity in multiple myeloma.. ITF2357 inhibits several signaling pathways involved in myeloma cell growth and survival.

Topics: Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukocytes, Mononuclear; MicroRNAs; Multiple Myeloma; Receptors, Interleukin-6; Signal Transduction

Preclinical evidence supports the investigation of histone deacetylase inhibitors for the treatment of myeloma. Results from early studies demonstrate clinical activity and further studies investigating combination strategies should be explored.

Topics: Antineoplastic Agents; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Treatment Outcome

We have investigated the activity of ITF2357, a novel hydroxamate histone deacetylase inhibitor, on multiple myeloma (MM) and acute myelogenous leukemia (AML) cells in vitro and in vivo. ITF2357 induced apoptosis in 8/9 MM and 6/7 AML cell lines, as well as 4/4 MM and 18/20 AML freshly isolated cases, with a mean IC(50) of 0.2 microM. ITF2357 activated the intrinsic apoptotic pathway, upregulated p21 and downmodulated Bcl-2 and Mcl-1. The drug induced hyperacetylation of histone H3, H4 and tubulin. When studied in more physiological conditions, ITF2357 was still strongly cytotoxic for the interleukin-6 (IL-6)-dependent MM cell line CMA-03, or for AML samples maximally stimulated by co-culture on mesenchymal stromal cells (MSCs), but not for the MSCs themselves. Interestingly, ITF2357 inhibited the production of IL-6, vascular endothelial growth factor (VEGF) and interferon-gamma by MSCs by 80-95%. Finally, the drug significantly prolonged survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line already at the 10 mg/kg oral dose. These data demonstrate that ITF2357 has potent anti-neoplastic activity in vitro and in vivo through direct induction of leukemic cell apoptosis. Furthermore, the drug inhibits production of growth and angiogenic factors by bone marrow stromal cells, in particular IL-6 and VEGF.

Topics: Acetylation; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; In Vitro Techniques; Interleukin-6; Leukemia, Myeloid, Acute; Mice; Mice, SCID; Multiple Myeloma; Stromal Cells; Survival Rate; Tubulin; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays