I have written about cancer stem cells several times in this blog, but many oncologists and cancer researchers still see cancer stem cells mainly as hypothetical entities whose relevance if not very-existence is questionable. A recent article in Gen points out that a number of pharmaceutical companies are betting big on cancer therapies based on going after cancer stem cells.
As I wrote in my July 2009 post On cancer stem cells, most cancer therapies are based on killing cancer cells – as many cells as possible. But cancers frequently and persistently recur after bouts of radiation or chemotherapy. The culprit is thought to be cancer stem cells, where any surviving ones simply go about making new cancer cells. A new therapeutic concept is therefore to focus on killing the cancer stem cells. “While normal stem cells are essential for development, play a key role in tissue maintenance, and aid in repair, cancer stem cells are believed responsible for tumorigenesis, metastases, and cancer recurrence(ref).” I reported further research regarding cancer stem cells in my August 2009 blog post Update on cancer stem cells.
It turns out the way to do this is to target the same signaling pathways involved in the proliferation and differentiation of normal stem cells, pathways I have discussed previously in this blog.
Notch is one such pathway which I discussed in the post On cancer stem cells. As reported in Gen: “Different points in the (Notch) pathway have been targeted for drug development. OncoMed Pharmaceuticals’ OMP-21M18 is an antibody that blocks signals by binding to Delta-like ligand. The drug, which is in a clinical trial involving patients with advanced solid tumors, is part of a $1.4 billion collaboration with GlaxoSmithKline. Merck and Roche have inhibitors to Î³-secretase that cleaves the Notch receptor releasing the Notch intracellular domain, a transcription factor. Both companies’ drugs are in early testing against solid tumors. Finally, Trojantec is targeting the Notch pathway with a truncated version of Mastermind, a coactivator involved in chromatin-specific transcription. The drug may prove useful against tumors that overexpress Notch signaling components(ref).” The role of Notch signaling in stem cell proliferation and differentiation was touched on in my blog post Niche, Notch and nudge.
PI3K/Akt is another pathway being targeted. “The PI3K/Akt pathway’s importance in cancer is partly attributable to PI3K’s (phosphatidylinositol 3-kinase’s) association with oncogenic growth factor receptors, notably for epidermal growth factor, platelet-derived growth factor, and mesenchymal transition factor. The pathway is also prone to mutations associated with oncogenesis, including changes in the catalytic subunit of PI3K that occur in prostate, breast, endometrium, urinary tract, and colon cancers. — Similarly, mutations of the lipid phosphatase PTEN that normally serves to deactivate the PI3K/Akt pathway are found in cancers of the endometrium, brain, skin, and prostate, while mutations in the protein kinase Akt, which is downstream of PI3K, are overexpressed in head and neck squamous cell carcinoma, and in pancreatic and ovarian cancers. Eight drugs targeting the PI3K/Akt pathway are in clinical trials(ref).” I have mentioned the P13K/Akt/mTOR and its relationship to stem cells in several posts including More mTOR links to aging theories.
The Hedgehog signaling pathway is another one being targeted by new drugs in the pipeline. “The Hedgehog pathway provides an intercellular regulatory mechanism that serves essential functions in the normal proliferation and differentiation of stem cells. Mutations in this pathway figure in basal cell carcinoma, medulloblastoma, and other malignancies. Three drugs that interfere with hedgehog signaling are in clinical trials—two, Infinity Pharmaceuticals’ IPI-926 and Genentech/Curis’ GDC-0449, are derivatives of cyclopamine, which has been studied extensively(ref).”
Heavy players in the pharma industry are betting big on new therapies for going after cancer stem cells. Perhaps more cancer researchers should start watching where the “smart money” is flowing.