Antineoplastic
activity of subtype-specific histone-deacetylase inhibitors (HDACi)
Histone
deacetylases (HDACs) are key enzymes involved in the epigenetic regulation of
oncogenes and tumor suppressor genes. Furthermore, HDACs play a critical role
in DNA repair processes. Thus, HDAC inhibitors (HDACi) are promising candidates
for epigenetically based tumor therapeutics. The protein family of HDACs
comprises 18 distinct subtypes, and most HDACi impair multiple HDAC subtypes
(so-called pan HDACi). In the clinical setting, HDACi have been established
mainly in the field of hematological malignancies so far. In contrast, these
agents did not improve clinical outcomes in solid neoplasms owing to therapy
resistance and systemic toxicity. In order to increase the antineoplastic
efficacy of HDACi-based therapies, we will follow two approaches: (1) the
testing of subtype-specific HDACi, which may show a more favorable therapeutic
index and (2) the establishment of synergistic combination treatments with
other targeted therapeutics. We are currently investigating class-I-specific
HDACi, which predominantly inhibit subtypes HDAC1 and HDAC2, with respect to
their anti-tumor activity as compared to clinically established Pan-HDACi.
Remarkably, these novel HDAC1/2 inhibitors exhibit equivalent or even superior
effects in gastrointestinal and gynecological tumors as well as in glioblastoma
in classical two dimensional cell culture models and in complex tumor slice
cultures. In addition, treatment with HDACi results in the adaptive
upregulation of a number of druggable oncogenes. This provides the basis for targeted
combination therapies (HDACi plus inhibitors of upregulated oncogenes) based on
the concept of an acquired vulnerability of tumor cells, which is not studied
in greater detail.
