Pharma Strategy Blog

In April at the AACR annual meeting, Bert Vogelstein talked about 12 critically aberrant pathways in cancer and we have talked about a few of these on this blog this year. Today, I want to take a look at another one of those key pathways, Wnt (pron. wint).

Background

Wnt is well known for it's network of proteins playing key roles in both development and cancer.  In simple terms, the process begins when Wnt proteins bind to cell-surface receptors of the Frizzled family, causing the receptors to activate the Dishevelled (dvl) family proteins, leading to a change in the amount of B-catenin that reaches the nucleus.

The basic pathway is described in the schematic below:

Source: Cell Signal

Previously, we have discussed the simplicity of Hh signalling driving medulloblastoma and KRAS mutations (WT, wild-type) being critical for deciding EGFR therapy in colorectal cancer, but in pancreatic ductal adenocarcinoma (PDAC) things are a lot more complex.  Morris et al., noted that:

"Analysis of PDAC mouse models driven by targeted pancreatic expression of oncogenic KRAS suggest that both temporal and spatial control of Hh and Wnt–B-catenin activity are involved in specifying a cell lineage that can progress to PDAC."

For those of you interested in more detailed biology associated with PDAC, I urge you to check out Hezel et al's excellent review on the topic (see reference link below).

Wnt–B-catenin signalling in PDAC

An interesting observation in the literature is that the KRAS mutation is nearly universal (>95%) in human PDAC. Furthermore, Morris et al., observed that:

"Wnt–β-catenin signalling is frequently activated in PDAC and contributes to tumour cell proliferation and biology.  Genetic models that allow Wnt–β-catenin deregulation reveal that this pathway can transform pancreatic cells but is insufficient to drive PDAC initiation."

So what else is going on?

In their review, the authors specifically look at:

• the ability of KRAS to alter cell fate in the pancreas
• how the timing and location of Hh and Wnt–B-catenin signalling contribute to PDAC development.

It's well worth a read with lots of helpful schematic diagrams to illustrate the underlying biology.

Clearly, we have a long way to go before we know more about the molecular basis of what is happening in this disease.  Some of the many factors that still need to be elucidated include:

• which components of the complex pathway are activated in cancer
• how they interact
• whether there are differences in the tumour epithelium and the microenvironment
• determine which Hh and B-catenin targets are ‘mission critical’ for maintaining proliferation, viability and differentiation
• how can we block the critical signalling proteins?

Wnt in multiple Myeloma

Other research has focused on the role of Wnt in multiple myeloma (see Guiliani et al., in the references).  Their results results supported the link between the production of Wnt antagonists by multiple myeloma cells and the presence of bone lesions in multiple myeloma patients. They also demonstrated that myeloma cells do not inhibit canonical Wnt signaling in human bone microenvironment.

Targeting different parts of the Wnt pathway has, however, produced some interesting results. Studies with an orally bioavailable GSK-3a/B dual inhibitor increased markers of cellular differentiation in vitro and bone mass in vivo, proving that we have much to learn about this complex pathway before a likely pharmacologic agent will emerge commercially.

Wnt inhibitors in the pipeline

While several inhibitors of Notch and Hedgehog pathways have reached the clinical trial stage, drugable targets for Wnt inhibitors seem to have have proven elusive so far. I haven't come across too many agents inhibiting Wnt, although I was amused to hear from a friend that one is called Soggy-1.  

The Novartis Institute of Biomedical Research (NIBR) reported on XAV939 in a Nature article.  XAV939 selectively inhibits B-catenin-mediated transcription and acts via tankyrase inhibition. Huang et al., (2009) succinctly noted:

"The development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition."

Given that few first generation inhibitors hit the mark first time, we may have to test quite a few different generations of Wnt inhibitors or even inhibitors of different parts of the pathway in combination, before a successful strategy finally emerges from R&D pipelines in the future.

Morris JP 4th, Wang SC, & Hebrok M (2010). KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nature reviews. Cancer PMID: 20814421

Giuliani, N., Morandi, F., Tagliaferri, S., Lazzaretti, M., Donofrio, G., Bonomini, S., Sala, R., Mangoni, M., & Rizzoli, V. (2007). Production of Wnt Inhibitors by Myeloma Cells: Potential Effects on Canonical Wnt Pathway in the Bone Microenvironment Cancer Research, 67 (16), 7665-7674 DOI: 10.1158/0008-5472.CAN-06-4666

Hezel, A. (2006). Genetics and biology of pancreatic ductal adenocarcinoma Genes & Development, 20 (10), 1218-1249 DOI: 10.1101/gad.1415606

Huang, S., Mishina, Y., Liu, S., Cheung, A., Stegmeier, F., Michaud, G., Charlat, O., Wiellette, E., Zhang, Y., Wiessner, S., Hild, M., Shi, X., Wilson, C., Mickanin, C., Myer, V., Fazal, A., Tomlinson, R., Serluca, F., Shao, W., Cheng, H., Shultz, M., Rau, C., Schirle, M., Schlegl, J., Ghidelli, S., Fawell, S., Lu, C., Curtis, D., Kirschner, M., Lengauer, C., Finan, P., Tallarico, J., Bouwmeester, T., Porter, J., Bauer, A., & Cong, F. (2009). Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling Nature, 461 (7264), 614-620 DOI: 10.1038/nature08356