Definition from NCI Drug Dictionary:
CUDC-101 is a multi-targeted, small-molecule inhibitor of histone deacetylase (HDAC), epidermal growth factor receptor tyrosine kinase (EGFR/ErbB1), and human epidermal growth factor receptor 2 tyrosine kinase (HER2/neu or ErbB2) with potential antineoplastic activity. HDAC/EGFR/HER2 inhibitor CUDC-101 inhibits the activity of these three enzymes but the exact mechanism of action is presently unknown. This agent may help overcome resistance to inhibition of EGFR and Her2 through a simultaneous, synergistic inhibition of EGFR, Her2, and HDAC.
Further information provided by Curis, Inc. including posters from various cancer conferences at:
Clinical trials relevant to GIST:
The following phase I trial, sponsored by Curis, is currently recruiting to establish the maximum tolerated dose for CUDC-101 and to assess the safety and tolerability in subjects with advanced and refractory solid tumors:
A Phase I Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of CUDC-101 in Patients With Advanced Solid Tumors
CUDC-101 appears to be targeting 3 different pathways with the same molecule: Her2/EGFR/TargetA. Target A seems to boost the properties of Her2/EGFR. These are all validated pathways in the clinic. It is also MUCH cheaper and faster to develop these molecules that target more than one pathway, sort of like killing two birds for the price of one, or in CUDC-101 it is like 3 birds for 1.
Aberrant receptor expression or functioning of the epidermal growth factor receptor family plays a crucial part in the development and evolution of many cancers. Inhibiting the signalling activity of individual receptors in this family has advanced the treatment of a range of human cancers where overexpression is indicated.
EGFR has recently been found to be expressed in some GISTs, but there are no data yet reporting the effectiveness of targeting EGFR in GIST. The sources finding EGFR expression in GIST are the following:
Qiu X, Montgomery E. Expression of EGFR in gastric stromal tumors: a clinicopathologic study. Appl Immunohistochem Mol Morphol. 2008 Jul;16(4):310-5.
PubMed PMID: 18528288
Nakagawa M, Nabeshima K, Asano S, Hamasaki M, Uesugi N, Tani H, Yamashita Y,
Iwasaki H. Up-regulated expression of ADAM17 in gastrointestinal stromal tumors:
coexpression with EGFR and EGFR ligands. Cancer Sci. 2009 Apr;100(4):654-62. Epub
2009 Mar 1. PubMed PMID: 19298600.
This drug's primary target for GIST is probably histone deacetylase, or HDAC. HDAC is a compound causing hyperacetylation of histone deacetylase, an enzyme involved in the regulation of transcription. HDAC inhibition threfore halts the cell cycle, the method of cell proliferation by which tumors grow.
Annals of Oncology, June 10, 2009, published an article stating:
'Reversible acetylation mediated by histone deacetylase (HDAC) influences a broad repertoire of physiological processes, many of which are aberrantly controlled in tumour cells. Since HDAC inhibition prompts tumour cells to enter apoptosis, small-molecule HDAC inhibitors have been developed as a new class of mechanism-based anticancer agent, many of which have entered clinical trials. While the clinical picture is evolving and the precise utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumour types undergo a favourable response, in particular haematological malignancies."
HDAC inhibitor-based therapies and haematological malignancy.
Stimson L, Wood V, Khan O, Fotheringham S, La Thangue NB.
Laboratory of Cancer Biology, Department of Clinical Pharmacology, University of Oxford, Oxford, UK.