Sanjeev Satyal

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

The Wnt/β-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting the Wnt pathway with a monoclonal antibody, OMP-18R5. This antibody, initially identified by binding to Frizzled 7, interacts with five Fzd receptors through a conserved epitope within the extracellular domain and blocks canonical Wnt signaling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, this antibody inhibits the growth of a range of tumor types, reduces tumor-initiating cell frequency, and exhibits synergistic activity with standard-of-care chemotherapeutic agents.

Biochemical events in the activation and attenuation of the heat shock transcriptional response

The expression of heat shock proteins in response to cellular stress is mediated by a family of heat shock transcription factors (HSFs). The transcriptional activity of these HSFs is regulated by multiple redundant regulatory mechanisms which ensure the fine tuned expression of heat shock genes. These mechanisms include cis-regulatory domains and trans-acting proteins which modulate HSF activity and control the heat shock response. Heat shock gene expression is also regulated by selective use of various HSFs under distinct developmental and growth conditions.

Abstract 3356: Development of a novel Wnt pathway antagonist antibody, OMP-18R5, that reduces tumor initiating cell frequency in breast cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The Wnt/beta-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several co-receptors, is known to play a critical role in several major cancer types. Mutations in the signalling pathway occur in most cases of human colon cancer, and activation of Wnt signalling through various mechanisms has been reported in multiple major tumor types. We have developed a novel Wnt pathway antagonist antibody, OMP-18R5 which was initially identified by binding to Frizzled7, and subsequently found to also bind several other human FZDs through a conserved epitope within the extracellular domain. OMP-18R5 blocks Wnt binding and canonical signalling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, OMP-18R5 inhibited the growth of a broad range of tumor types and has been found to be particularly active in breast cancer. OMP-18R5 treatment reduced tumor growth and the frequency of tumor initiating cells in combination with pacilitaxel. Furthermore, we found that OMP-18R5 treatment can restore chemosensitivity in drug resistant breast tumors. Molecular analyses indicated OMP-18R5 inhibits the expression of EMT markers in breast tumors, thus providing additional evidence linking EMT with resistance to chemotherapy and cancer stem cells. In addition to combination activity with paclitaxel, OMP-18R5 treatment also resulted in increased anti-tumor activity in combination with trastuzumab in a Her2+ breast cancer model. These data suggest that OMP-18R5, which has recently entered Phase 1 clinical testing, may be useful in the treatment of various types of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3356. doi:1538-7445.AM2012-3356