PANOBINOSTAT

LBH589

Potent pan-DAC inhibitor-targeting epigenetic and multiple oncogenic pathways

Pan-DAC inhibitors have been shown to have multiple effects in tumor cell lines: decreased oncoprotein expression (eg, Bcr-Abl, HER-2), decreased angiogenesis, induction of apoptosis, induction of cell-cycle arrest, and decreased tumor cell motility and invasion.¹

By interfering with the hallmarks of cancer, pan-DAC inhibitors have potential in many hematologic and solid malignancies, including lymphomas, multiple myeloma (MM), AML, MDS, and breast and prostate cancers.

Panobinostat (LBH589) was identified as a potent DAC inhibitor, which induced cell death of tumor cell lines but not normal cells. Panobinostat has a long half-life in cells, leading to prolonged acetylation.² In phase I trials, activity has been seen with panobinostat as a single agent in several tumor types, including Hodgkin's lymphoma, multiple myeloma, AML, and prostate cancer.³ Preclinically, Panobinostat has also been shown to overcome resistance to kinase inhibition in tumor cell lines. Furthermore, preclinical synergy in combination with chemotherapy and other agents has been shown.^1,4

Additional clinical trials of Panobinostat are ongoing in all of the above malignancies.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

1. George P, Bali P, Annavarapu S, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005;105:1768-1776.
2. Prince HM, Ellis L, Johnstone R, et al. Oral LBH589, a novel histone deacetylase inhibitor, treatment of patients with cutaneous T-cell lymphoma (CTCL). Changes in skin gene expression profiles related to clinical response following therapy. Presented at: 97th American Association for Cancer Research (AACR) Annual Meeting. April 1-5, 2006; Washington DC. Abstract 1146.
3. Prince HM, George D, Patnick A, et al. Phase I study of oral LBH589, a novel deacetylase (DAC) inhibitor in advanced solid tumors and non-hodgkin’s lymphoma. Presented at: 43rd American Society of Clinical Oncology (ASCO) Annual Meeting. June 1-5, 2007; Chicago, Ill. Abstract.
4. Maiso P, Carvajal-Vergara X, Ocio EM, et al. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res. 2006;66:5781-5789.