Abstract 3563: Novel anticancer agents modulate multiple signal transduction pathways for cancer therapy

Cancer is remarkably heterogeneous and is associated with wide variations in biological behavior. Except for some rare cancers whose growth may depend on a single factor, no single signaling pathway drives the oncogenic behavior of all tumors. In fact, most single-target agents that have undergone development in recent years have lacked the exquisite level of effectiveness. Multitarget drugs and the network approach may thus constitute a useful means for discovering novel drugs; such drugs emerge from the sum of the interactions that, together, are the principal determinants of the system-scale behavior of the cell. A multitarget agent is not necessarily more toxic than single-target agents. These multitarget drugs have presumed low-affinity interactions with several of their targets, and do not necessarily shut down a pathway completely or activate it excessively; thus they may have lower side effects. We has developed a novel class of dietary indole analogs with oral anticancer activity against a variety of cancer in animal models, including prostate, breast, lung and ovarian tumors. Western blot analysis shows that SR13654, SRI advanced lead, is able to induce apoptosis by caspase activation and poly(ADP-ribose) polymerase (PARP) cleavages. Using the Boyden chamber assay, we showed that SR13654 significantly inhibits PC-3 cells’ invasion at low concentration, and its anti-invasive activity is not due to cell killing or simple cell growth inhibition. In vitro and in vivo mechanistic studies show that SR13654 inhibits Src activation, down-regulates survivn expression, enhances EGFR degradation. SR13654 also produced a decrease in cyclin D1 and B1, and an increase in p21 levels in cancer cells. Screening a full panel of 285 kinases shows that SR13654 is not a kinase inhibitor. More in-depth mechanistic studies are undergoing. Preclinical safety studies indicate that this class of compounds holds great promise for extended therapeutic use to maximize disease control without compromising quality of life. SR13654 has relatively poor water solubility, which could limit its use in intravenous dosing. We have developed the second generation of water-soluble analogs, such as SR13677, which has significantly improved water solubility and is at least 5-fold more potent than SR13654 against various cancer cell lines. With support from the 2009 DOD/Prostate Cancer Research Program (PCRP) “Laboratory-Clinical Transition” Award, we will advance the optimized candidate through preclinical development and future IND filing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3563.