Histone deacetylase (HDAC) enzymes play an important part in the development and progression of cancer and HDAC inhibitors (HDACi) are currently being tested as anti-cancer agents. Early clinical trials show that these drugs have anti-tumor activity, but the response rates are low and it is unclear which patients may benefit from HDACi. There are at least 17 HDAC family members, yet very little is known about the function of individual HDACs and their relevance as specific therapeutic targets. It has been shown that HDACi cause cell cycle arrest and differentiation in cancer cells. HDACi further promote chromatin decondensation and potentiate DMA damage induced by cytotoxic agents (such as topoisomerase (topo) inhibitors). However, the effects of HDACi on tumor tissues are dependent on the dose and duration of drug treatment and the effects vary greatly between different tumor types. We hypothesized that the effects of HDACi such as chromatin decondensation, growth inhibition and sensitization to chemotherapy may not only depend on the inhibition of specific HDAC enzymes, but is also determined by the expression of specific HDAC enzymes in the target tissue. This is supported by our preliminary data showing that mainly HDAC2 was involved in chromatin de- condensation. We found that the inhibition of HDAC2 by selective siRNA depletion was sufficient to cause chromatin decondensation. Furthermore, neither HDACi-induced chromatin decondensation nor sensitization to topo inhibitors was seen in cells lacking HDAC2. In contrast, while not associated with chromatin decondensation, HDAC6 was involved in cell cycle regulation and may determine the phase of the cell cycle arrest. These findings suggest that defining the roles of individual HDAC enzymes as specific therapeutic targets could vastly improve the next generation of HDACi, the selection of patients, and the optimal design of clinical trials for these drugs either alone or in combination.
In Specific Aim 1, we will therefore define the roles of specific HDAC enzymes as therapeutic targets and the consequence of their selective inhibition in cell culture models by the depletion of specific HDACs using siRNA and in cell systems with variant HDAC expression.
In Specific Aim 2, patients with early stage breast cancer will be treated with an HDACi, prior to exposure to a topo II inhibitor. In pre- and post-treatment tumor samples, we will determine which HDACs are involved in the cellular effects induced by the HDACi and which HDACs may predict response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122657-03
Application #
7674687
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Wu, Roy S
Project Start
2007-05-18
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$271,618
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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