Abstract 2615: Antitumor activity of a dual PI3K and HDAC inhibitor in hematologic cancer models

Abstract

Abstract Recent evidence indicates that PI3K-Akt-mTOR signaling plays a crucial role in the development and progression of hematologic cancers. Therefore, inhibition of this pathway using isotype-selective or pan-PI3K inhibitors has recently been investigated extensively in hematologic malignancies. However, compensatory/feedback mechanisms in cancer cells may present a major challenge for these PI3K inhibitors. On the other hand, HDAC inhibitors, such as vorinostat and romidepsin, have been approved as a monotherapy for CTCL. Their efficacy as single agent or in combination with other approved therapeutics is being evaluated in multiple clinical trials for other types of hematologic cancers, including DLBCL, Hodgkin lymphoma, AML, ALL, CLL, and multiple myeloma. Based on the observation that synergic effects can be achieved by inhibition of both HDAC and PI3K in cancer cells as reported previously, we developed small-molecule compounds that are able to simultaneously inhibit both PI3K and HDAC. One of the lead compounds exhibits potent inhibition of all PI3K class I subtypes as well as HDAC. In cell growth inhibition assays, this compound displays potent activity in hematologic cancer cell lines, including leukemia, lymphoma, and myeloma. Besides PI3K-Akt-mTOR pathway suppression, this compound is able to up-regulate tumor suppressors p53 and p21 and simultaneously inhibit compensatory Ras-Raf-MEK signaling in cancer cells via epigenetic modifications by HDAC inhibition. In vivo experiments demonstrate this compound is orally bio-available with a long half-life in tumor tissues from xenograft models. Efficacy studies demonstrate this compound is able to inhibit tumor growth or induce tumor regression in animals implanted with various hematologic cancer cell lines. Furthermore, this compound induces apoptosis and inhibits cancer cell proliferation in these tumor xenografts. Favorable safety profile has been observed in early preclinical studies. Based on these results, this compound warrants further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2615. doi:10.1158/1538-7445.AM2011-2615