Identifying and inhibiting cancers driven by wnt

Paul G. Polakis, Ph.D., Genentech, Inc., South San Francisco, CA.

Session Title:

Therapeutic Cancer Targets in the Wnt Pathway

Session Type:

Educational Session

Session Start:

4/14/2007 8:00:00 AM

Session End:

4/14/2007 10:00:00 AM

Location:

Room 403 A-B, Los Angeles Convention Center

Session Description:

The Wnt signaling pathway controls many developmental decisions during embryogenesis, but also regulates self-renewal in adult tissues, such as the intestine or bone. Mutational activation of the Wnt pathway is a common cause of many cancers, particularly of colorectal cancer. Genes that are typically mutated encode the Wnt pathway components APC, axin or beta-catenin. Other tmors can secrete modulators of the Wnt pathway thus contributing to the pathology of the disease: For instance, multiple myeloma cells can secrete soluble Wnt inhibitors resulting in local loss of bone. Modulation of the Wnt pathway may therefore be applied to a variety of therapeutic purposes. Blocking deregulated Wnt signaling presents a therapeutic strategy in colon cancers or breast cancers. Enhancing physiological Wnt signaling by administration of R-spondins may support post-radiation or post-chemotherapy repair of the intestinal mucosa. Bone loss in multiple myeloma may be blocked by interfering with the secreted Wnt inhibitors.

Session Leader:

Hans Clevers, Hubrecht Laboratory, Utrecht, The Netherlands



Targeting the hedgehog pathway in cancer


Frederic J. de Sauvage, Ph.D., Genentech, Inc., South San Francisco, CA.

Session Title:

Developmental Signaling Pathways in Cancer

Session Type:

Symposium

Session Start:

4/16/2007 10:30:00 AM

Session End:

4/16/2007 12:30:00 PM

Location:

Room 403 A-B, Los Angeles Convention Center

Session Description:

The myriad cell fate decisions that occur in the lifetime of any animal are governed by only a handful of signaling pathways. Five of these are the Notch, Hedgehog, Wnt. PDGF and TGFbeta pathways. In mammals, these pathways not only dicate embryonic development, but also control stem cell biology and homeostatic self-renewal in adult tissues. It therefore comes as no surprise that components of these pathways are mutated in specific human malignancies. Thus, activating mutations in Notch are associated with T cell leukemias, activating mutations in the Wnt pathway cause colorectal cancer and activating Hedgehog pathway mutations are found in Basal Cell Carcinoma and medullablastoma. In this session, signaling pathway activation in cancer is discussed in the context of the physiological role of these pathways in adult tissue homeostasis.

Session Leader:



Abstract Number:

5693

Presentation Title:

The soluble wnt receptor Frizzled 8-CRD inhibits wnt activity in vitro and has has anti-tumor activity in vivo.

Presentation Start/End Time:

Wednesday, Apr 18, 2007, 9:55 AM -10:10 AM

Location:

Room 515 A, Los Angeles Convention Center

Author Block:

Venita DeAlmeida, Li Miao, Hartmut Koeppen, James Ernst, Paul Polakis, Bonnee Rubinfeld. Genentech, Inc, South San Francisco, CA

Wnt signaling is important for normal cell growth and proliferation, and mutations in pathway components are associated with human cancers. Recent studies suggest that altered wnt ligand/receptor interactions might contribute to human tumorigenesis, therefore agents that antagonize wnt signaling at the extracellular level would be attractive therapeutics for these cancers. We have generated a soluble wnt receptor containing the cysteine rich domain (CRD) of the Frizzled 8 receptor fused to the human Fc domain (F8CRDhFc) that downregulates wnt signaling in vitro and exhibits favorable phamacologic properties in vivo. Potent efficacy was demonstrated using the MMTV-Wnt1 tumor model under dosing conditions that did not produce notable toxicity in regenerating tissue compartments such as skin and intestine. We have also determined that, similar to the PA-1 cells, the teratoma cell lines NCCIT, Tera-2 and NTera-2 have a functional autocrine wnt pathway. In vitro F8CRDhFc inhibited both basal and wnt3a stimulated signaling in these teratoma cells and in vivo, systemic administration of F8CRDhFc significantly retarded the growth of tumor xenografts derived from two of these cell lines, PA-1 and NTera-2. Pharmacodynamic markers of wnt signaling, identified by gene expression analysis of cultured teratoma cells treated with wnt3a and F8CRDhFc, were also modulated in the tumor xenografts following treatment with F8CRDhFc. The identified pharmacodynamic markers can thus be used both to follow treatment efficacy as well as to identify patients that will benefit from the therapeutic agent. This is the first report showing the efficacy of a soluble wnt receptor as an anti-tumor agent, and suggests that further development of soluble wnt antagonists will have utility in treating human cancer.





Paul G. Polakis, Ph.D.,



Genentech, Inc., South San Francisco, CA.

Session Title:

Targeting the WNT Pathway in Cancer

Session Type:

Meet-the-Expert Sunrise Session

Session Start:

4/16/2007 7:00:00 AM

Session End:

4/16/2007 8:00:00 AM

Location:

Room 304 A-C, Los Angeles Convention Center

Session Description:

Activation of wnt signaling occurs in a significant percentage of human malignancies. Strategies for therapy rely upon the identification of those cancers activated by wnt signaling, the mechanism by which they are activated and the identification of the appropriate druggable target. Additional assets include a means to monitor drug response in both the tumor and the normal tissues in which toxicities might be anticipated. Examples relating to these facets of drug discovery in wnt signaling will be discussed.

Session Leader:

Paul G. Polakis, Genentech, Inc., South San Francisco, CA





This one below is sorta confusing if you want an explanation let me know



Abstract Number:

2802

Presentation Title:

Inhibition of tumor-stromal signaling by specific small molecule hedgehog antagonists delays growth of primary human pancreatic cancer xenografts

Presentation Start/End Time:

Monday, Apr 16, 2007, 1:00 PM - 5:00 PM

Location:

Exhibit Hall, Los Angeles Convention Center

Poster Section:

11

Poster Board Number:

26

Author Block:

Stephen Gould, Bob L. Yauch, Ling Fu, Tracy Tang, Hua Tian, Derek Marshall, Leslie B. Lee, Christian Dibble, Hui Qu, James C. Marsters Jr., Lee Rubin, Fred De Sauvage. Genentech Inc., South San Francisco, CA, Curis Inc., Cambridge, MA

Abstract Body:

Ectopic or overexpression of sonic hedgehog (Shh) has recently been implicated as a contributing factor in several solid tumors including pancreatic, prostate, upper gastrointestinal, and small cell lung cancers. The observation that high concentrations (>3 mM) of cyclopamine, a natural product that antagonizes the hedgehog (Hh) pathway, blocks proliferation of cells that exhibit a Hh signature has been used as evidence of an autocrine growth requirement of these cells for Hh. We find that this concentration of cyclopamine is ³10-fold in excess of what is required to inhibit the Hh pathway in cell lines that exhibit pathway activation in response to exogenously added sonic hedgehog (Shh). This suggests that additional off-target effects may be responsible for the observed growth inhibition. Furthermore, using a specific small molecule Hh antagonist we fail to demonstrate inhibition of proliferation of the majority of cell lines tested including SCLC, NSCLC, pancreatic, and colon cell lines (15/112 or 13%) by concentrations that are 50-fold greater than the IC50 for inhibition of the Hh pathway for this compound. In addition, no correlation between the relative sensitivity to growth inhibition and the expression levels of SMO, GLI1, GLI2, PTCH1, SHH, or IHH, were detected at these high concentrations. An analysis of gene expression data from a database of solid tumor cancers reveals that pancreatic cancers exhibited elevated transcript levels for indian hedgehog and sonic hedgehog relative to either normal adjacent tissue, or normal tissues. Based on these results we have used a potent synthetic small molecule antagonist of the Hh pathway to treat primary human pancreatic cancer xenografts. We find that blockade of the hedgehog pathway results in growth delay of a subset of these primary human xenografts. Analysis of these xenograft tumors via species-specific PCR primers fails to detect any alteration in Hh target genes in human cells, but detects robust changes in murine Hh target genes including mGli1 and mPtch1. Thus inhibition of tumor growth is accompanied by blockade of Hh signaling between tumor and stromal cell populations suggesting a paracrine requirement for the Hh pathway. These data support the use of specific Hh antagonists to treat pancreatic tumors and provide a mechanistic basis for the selection of additional cancer indications that rely on paracrine Hh signaling between tumor and stromal cells for growth.