Biological activity of Curis' CUDC-101 HDAC, EGFR and HER2 inhibitor published in Cancer Research

Curis, Inc.Apr 23 2010

Curis, Inc. (NASDAQ: CRIS), a drug development company seeking to develop next generation targeted small molecule drug candidates for cancer treatment, today announced that a research paper describing the biological activity of its HDAC, EGFR and HER2 inhibitor, CUDC-101, was published online in the journal Cancer Research and also will be published in an upcoming print version of the journal.

"We believe that the results described in this publication demonstrate that CUDC-101 may have the potential to increase patient response rates in certain cancers and improve the treatment of drug-resistant tumors that cannot be effectively controlled with single-target EGFR or Her2 inhibitors," stated Dan Passeri, Curis' President and Chief Executive Officer. "CUDC-101 represents the first example of an individual small molecule from our network-targeted cancer drug programs that simultaneously inhibits multiple distinct cancer targets chosen for their mechanistic synergy and ability to durably suppress cancer pathway networks. Our scientists plan to select another development candidate mid-year, which they have designed to simultaneously inhibit HDAC and PI3 kinase targets."

Following Curis' first publication of related to this molecule in the Journal of Medicinal Chemistry earlier this year, the Cancer Research publication describes preclinical data that are supportive of CUDC-101's effective and selective inhibition of HDAC, EGFR and HER2, the direct molecular targets of CUDC-101. The paper also presents data demonstrating that CUDC-101 inhibits key regulators of the EGFR and HER2 signaling pathways, including Akt. Additionally, the drug appears to effectively attenuate HER3 and MET signaling, which are often activated as a compensatory mechanism in response to EGFR and HER2 inhibition and are believed to help cancer cells escape the effects of conventional EGFR and HER2 inhibitors. CUDC-101 suppresses the progression of and induces cell death of a broad range of tumor types at low doses in in vitro and in vivo preclinical cancer models, including certain cancer cells that are resistant to approved standard-of-care single-target agents.

The paper also indicates that CUDC-101 achieves a synergistic effect through simultaneous inhibition of HDAC, EGFR and HER2 targets. The authors tested the growth-inhibitory activity of CUDC-101 in a total of 54 human cancer cell lines, with results showing that the compound effectively inhibits growth of a broad range of cancer cell types, including lung, pancreas, liver, colon, breast, prostate and head and neck. Notably, CUDC-101 exhibited equal or greater potency in these assays than vorinostat (a marketed HDAC inhibitor), erlotinib (a marketed EGFR inhibitor), lapatinib (a marketed EGFR/HER2 inhibitor) and combinations of vorinostat and erlotinib and vorinostat and lapatinib. CUDC-101 also suppressed the growth of the lapatinib-insensitive, triple-negative (estrogen receptor-, progesterone receptor- and HER2-negative) breast cancer cell line MDA-MB-231 as effectively as it did the lapatinib-sensitive, HER2-overexpressed lines BT-474 and SkBr-3. Similarly, CUDC-101 inhibits the growth of lung cancer cell lines that are not sensitive to erlotinib treatment, including H1975, which harbor an EGFR-T790M mutation. These results suggest that CUDC-101, with its synergistic inhibitions of multiple pathways, has the potential to enhance the response rates and prolong the duration of response when compared to traditional kinase inhibitors.