Target

Vascular endothelial growth factor (VEGF) receptor 2 (VEGFr2, VEGFr-2) / (FLK1, Flk-1) / KDR • Met [hepatocyte growth factor receptor (HGFr)/c-Met] • Ret proto-oncogene (RET), glial cell-line derived neurotrophic factor receptor (GDNFr)

Mechanism

Angiogenesis inhibition • Receptor tyrosine kinase (RTK) inhibition

Details

In preclinical trials, XL184 potently inhibited the hepatocyte growth factor receptor (Met) and VEGFr2 (KDr) RTK. Additionally, XL184 potently inhibited other important RTK that have been implicated in various forms of cancer, including RET, mast/stem cell growth factor (Kit), Flt3, and Tie-2. In preclinical efficacy trials, XL184 prevented tumor growth, and induced regression of large tumors in a broad range of human tumor xenograft models including breast cancer, lung cancer, and glioma. In addition, XL184 strongly inhibits cell proliferation in gastric or medullary thyroid cancer (MTC) cell lines harboring activated or overexpressed MET or activated RET. Preclinical single dose pharmacodynamic studies with XL184 demonstrate substantial inhibition of RET phosphorylation in TT (MTC model) xenograft tumors.

In laboratory trials, XL184 demonstrated significant oral bioavailability and excellent PK properties.

EXEL-7184 is a potent inhibitor of VEGFr2 and Met, with potent antitumor and antiangiogenic activity in preclinical models. In enzymatic assays, EXEL-7184 is a potent inhibitor of VEGFr2 and Met tyrosine kinase activities, with IC50 values in the sub-nanomolar and single digit nanomolar range, respectively. EXEL-7184 also exhibits potent activity in cell-based assays, inhibiting VEGF-induced activation of ERK in endothelial cells, and HGF-induced activation of Met in tumor cells. EXEL-7184 also inhibits endothelial tubule formation stimulated by VEGF, or by conditioned media derived from tumor cell lines, as well as HGF-induced responses such as invasion or chemotaxis in tumor cells. In pharmacodynamic assays, oral administration of EXEL-7184 resulted in dose-dependent and reversible inhibition of VEGFr2 in mouse lung, and of Met in xenograft tumors and in mouse liver. Following acute administration to xenograft tumor-bearing mice, EXEL-7184 caused rapid disruption of the tumor vasculature, and apoptosis of both tumor and endothelial cells. Administration of EXEL-7184 using both once daily and less frequent oral dosing schedules resulted in significant efficacy in a range of solid tumor models, causing substantial regression of large tumors. According to immunohistochemical analysis at the end of efficacy studies, the agent caused potent inhibitory effects on the tumor vasculature, and strong induction of tumor cell death (Joly A, EORTC-NCI-AACR06, Abs. 104).

Current as of

June 27, 2010

Target

Toll-like receptor 9 (TLr9), CD289

Mechanism

Immunomodulation

Details

Bacterial DNA activates the innate immune. This activity resides within the nonmethylated CpG motifs of the DNA and may be recapitulated using appropriate synthetic CpG containing oligodeoxynucleotides (CpG-ODN).

CpG oligos exert immunostimulatory effects through their interaction with Toll-like receptor 9 (TLr9). HYB2055, containing a novel structure and a synthetic CpR (R=synthetic guanosine analog) motif, was investigated as cancer therapy used alone or in combination with chemotherapy, radiation therapy and antibody therapy. Both in vivo and in vitro antitumor activities were found in various models of human malignancies, including colon, breast, lung, prostate, and brain cancer, with various p53 status. Studies with p53 and/or p21 knockout colon cancer cells (HCT116) indicate that p53 is not required for the activity of the IMO. IMO inhibited cell proliferation, induced apoptosis, and inhibited tumor growth in a dose-dependent manner compared with a control non-CpR IMO. Additionally, IMO potentiated the effects of the cytotoxic paclitaxel, the antibody-based agents Rituxan and Herceptin, as well as radiation therapy. Also, this study suggests that TLR9 is expressed in several tumor cells, in colorectal, breast, lung, pancreatic, and prostate cancer, and glioma. These results indicate that IMO may exert their effects by direct interaction with its receptor expressed in tumor cells in addition to immune cells. This study provides a basis for the development of IMO as a novel approach to human cancer therapy. HYB2055 is currently being evaluated in phase I/II clinical trials in cancer patients (Wang H, etal, AACR05, Abs. 720).

Investigators at Hybridon compared the immunostimulatory activity of three immunomers with different nucleotide sequences containing a synthetic cytosine-phosphate-2'-deoxy-7-deazaguanosine dinucleotide (CpR), referred to as immunomodulatory oligonucleotides (IMO), in mouse, humans, and monkeys. IMO induced IL-12 and IFN-gamma secretion more than a control non-CpG IMO in mice. All three IMO activated HEK293 cells expressing TLr9 but not TLr3, -7, or -8. IMO induced human B-cell proliferation and enhanced expression of CD86 and CD69 surface markers on B cells. The three IMO induced CD86 expression on human plasmacytoid DC but only IMO that contained a 5'-terminal TCR nucleotide sequence induced IFN-alpha secretion. A sequence that forms a duplex structure also was required for IFN-alpha induction in human peripheral blood mononuclear cell cultures. IMO induced chemokine and cytokine gene expression in human PBMC. In monkeys, all three IMO induced transient changes in peripheral blood leukocytes and lymphocytes and activated B and T lymphocytes. All three IMO induced IFN-alpha in vivo in monkeys with the IMO sequence that forms a stable secondary structure inducing the highest levels of IFN-alpha. These results suggest that IMO induce strong and rapid immunostimulation and that the CpR dinucleotide is recognized by TLr9, leading to immune-cell activation and cytokine secretion in vitro and in vivo (Kandimalla ER, etal, PNAS USA, 10 May 2005;102(19):6925-30).

Phosphorothioate oligonucleotides containing a CpG motif (CpG DNA) exhibit immunostimulatory properties. Appropriate chemical modifications of the CpG motif were shown to minimize immunostimulatory properties in preclinical trials.

IMOxine's mechanism of action is based on modulation of TLr9. DNA with CpG activates TLr9. B cells and dendritic cells (DC) extract TLrR9, which leads to activation of Th1. This leads to activation of NK cells, cytotoxic T cells (CTL), and more importantly, a tumor-specific memory response.

TLr9 is a first line immune system defense receptor. TLr9 agonists restore immune system balance. Activation of a specific TLr leads to defensive immune response. The mechanism of action and proof of concept of TLr were demonstrated with Aldara Cream, an agonist of TLr7.

Current as of

April 09, 2010