Philip Beachy, PhD
The Hedgehog (Hh) cell-to-cell signaling pathway is important in the formation and development of the embryos of many animals, including humans. Philip A. Beachy, PhD, the Ernest and Amelia Gallo Professor in the School of Medicine, professor of developmental biology, found that this pathway supports and produces cancer stem cells and can also elicit supportive responses from surrounding cells. Dr. Beachy and his team continue to explore the role of the Hh signaling pathway in cancer stem cells. They are also interested in exploiting the use of Hh pathway antagonists and antibodies in combination with other agents, such as anti-CD47 antibodies, against a variety of cancers.
- Diffuse Intrinsic Pontine Glioma (DIPG)
- Anti-Shh/anti-CD47 Combination Therapy in Bladder and Other Epithelial Cancers
- Inhibition of Hedgehog Signaling for Treatment of Chronic Myelogenous Leukemia (CML)
- Combined Use of Itraconazole and Arsenic Trioxide to Cause Regression of Hh-Dependent Tumors
Diffuse Intrinsic Pontine Glioma (DIPG)
Investigators: Michelle Monje, Hans Vogel, Paul Fisher, Albert Wong, David Rowitch (University of California, San Francisco), Irving Weissman, and Philip Beachy
Diffuse intrinsic pontine glioma (DIPG), which accounts for 10-20 percent of childhood brain cancers, is uniformly lethal and arises in the ventral pons at a time coinciding with the appearance of a new population of human ventral pontine neuroglial progenitors the investigators have identified and are characterizing. They have established neurosphere cultures (spherical clusters of cells generated by neural stem cells in vitro) from the DIPG tumors of three patients and xenograft tumors in NOD-SCID-IL2, gamma-chain-deficient mice from one of these cell lines and have shown in secondary neurosphere assays that neurosphere growth is dependent on, and stimulated by, Hh pathway activity. A corresponding population of neuroglial progenitors in the mouse ventral pons also appears at a time corresponding to early childhood, and these progenitors display Hh pathway activity. Upon constitutive activation of the Hh pathway in these cells, proliferation increases approximately 50 percent, and the pons increases approximately 60 percent in volume. Using the xenograft model, the investigators will explore the possible use of Hh pathway antagonists for therapy of this tumor. In addition, as DIPG cells express CD47, they will explore the possibility of using anti-CD47 for therapy of this tumor, possibly in combination with Hh pathway antagonism. Using the xenograft model, they will explore the possible use of Hh pathway antagonists for therapy of this tumor.
The investigators have found that basal urothelial stem or progenitor cells express Sonic hedgehog (Shh) and that these cells can repopulate the entire urothelium following bacterial injury of the bladder. Shh expression thus appears to mark normal progenitors and may also be expressed on cancer stem cells (CSCs). Because CD47 antibody blockade enhances engulfment of leukemia and other CSCs and is expressed on bladder CSCs, they are interested in the possibility that combined therapy with anti-CD47 and anti-Shh antibodies may provide enhanced therapy for bladder cancer and possibly other epithelial cancers.
Previously, these scientists showed that Hh pathway inhibition by cyclopamine blocks progression of CML in a murine model. In an attempt to quickly translate these results for the benefit of patients, they have demonstrated that an approved drug, the antifungal itraconazole, potently inhibits the Hh pathway and the growth of Hh-pathway-dependent tumors. They are now testing the effect of itraconazole treatment in the murine model of CML with very promising results and in a murine model of blast crisis CML.
This team of researchers has used itraconazole and arsenic trioxide (ATO) separately in mice at serum levels comparable to those reported in human patients to block growth of mouse models of medulloblastoma and basal cell carcinoma. They have not, however, been able to cause regression of Hh pathway-dependent tumors with these FDA-approved drugs. Their in vitro evidence suggests that inhibition with multiple drugs acting at different levels in the pathway produces more potent inhibition at lower drug concentrations. They are testing this for itraconazole (which inhibits Smoothened, a protein involved in communicating the effect of the Hedgehog signal into the cell) and ATO (which inhibits Gli proteins, transcriptional activators of Hh target genes) in vitro and in vivo, to determine whether combined action of these drugs will produce more effective inhibition and cause tumor regression. These results could be immediately translated to human patients.