Five Wnt-Related Questions for Heinz-Josef Lenz, MD

Heinz-Josef Lenz, MD

Professor of Medicine and Preventive Medicine, Associate Director, Clinical Research, Chair, GI Oncology Program, Co-director, Colorectal Center, Scientific Director, Cancer Genetics Unit, USC Norris Comprehensive Cancer Center Los Angeles, CA

Heinz-Josef Lenz, MD, has focused his research on a range of scientific and translational questions, including the regulation of gene expression in drug resistance and targeted therapies for the treatment of metastatic colorectal cancer. A recipient of the ASCO Young Investigator Award and other honors, Lenz has served on several National Cancer Institute committees. His current clinical trial work includes serving as the principal investigator on studies evaluating panobinostat in stage IV colorectal cancer and dasatinib in advanced liver cancer.

At the USC Center for Molecular Pathways and Drug Development, Lenz is collaborating with Michael Kahn, PhD, on exploring cancer cell-signaling pathways. Lenz, along with other USC Norris researchers, developed PRI-724, a small molecule that inhibits the Wnt pathway. Two clinical trials are under way, including a phase I/II study in advanced myeloid malignancies and a phase I trial in advanced solid tumors.

He discussed the Wnt pathway in this interview with OncologyLive.

1

Can you describe your research and its focus on the Wnt pathway?

The focus of my research is to identify predictive and prognostic markers in order to identify patients who benefit most from chemotherapy, especially focusing on the EGF and VEGF pathways. We also are very interested in early drug development, which is one of the reasons we are interested in the Wnt pathway since one of the first-in-class medications, called PRI-724, being tested in the clinic is being developed by a colleague of mine, Dr. Kahn, here at USC.

This agent has completed the first-in-human clinical trial and is a novel inhibitor that modulates the Wnt pathway in a very significant way. It inhibits CBP-catenin, which modifies the Wnt activated pathway in cancers in a way that pushes the pathway into differentiation.

2

What is the role of the Wnt pathway in colon cancer?

Wnt is a very complicated pathway that is particularly important in colon cancer, and is present in over 95% of tumors. The reason this pathway is complex is because the regeneration of the intestinal mucosum is driven by the colon stem cells; in order for the intestinal mucosa to rejuvenate every 24 hours, it first undergoes proliferation and then differentiation to result in a mature intestinal mucosa. The Wnt pathway is one of the most important pathways involved in this process. Obviously, if the Wnt pathway is altered⎯and particularly the proliferation pathway is changed⎯colon cancer can develop.

3

Can you discuss how the Wnt pathway functions in other cancer types?

The Wnt pathway is activated in many cancers, including liver cancer, breast cancer, leukemias, and liquid tumors. It is a very fundamental pathway because it is one of the pathways that are activated first in the development of a human being because it is involved in the decision point of proliferation and differentiation. It is the first pathway to be activated to decide what the cells should become—whether to proliferate and then differentiate into a specific target organ.

So because of this fundamental role, this pathway is altered in many cancers. It is also involved in many other degenerative diseases because weakening the proliferation and differentiation functions can also promote degenerative disease, chronic inflammatory diseases, aging disorders, etc.

4

How will a drug designed to target the Wnt pathway affect normal cells?

What usually happens in the aging process of human beings is that the process of stem cell rejuvenation does not work as well. This is the reason we lose hair, get wrinkles, get constipation⎯because our organs are not rejuvenating in the way they should. A Wnt pathway inhibitor can actually rejuvenate the ability for an asymmetric division to take place in normal cells, so it actually will turn back the clock and will make sure cells will do what they are supposed to do. That is the reason our Wnt inhibitor works as an anti-aging, anti-wrinkle, and hair cream, and we have a license for some cosmetic applications. So it makes sense.

The first worry about this pathway is toxicity, and the problem is pharmaceutical companies have in the past tried to develop an inhibitor because of its crucial role, but the complexity and maybe the lack of understanding of the specific differences can result in significant toxicities. So I think it depends how these drugs are developed. However, if it is possible to harness the potential of this pathway, there may be significant benefits in healthy patients, not only because of its rejuvenating potential but also in patients who are undergoing degenerative changes associated with disease, including cancer.

5

When do you expect that Wnt inhibitors will move into clinical practice?

There are now widespread clinical trials ongoing on colon cancer, pancreatic cancer, and liquid tumors, but it may be a while. I think the Wnt pathway bears unique opportunities to really impact cancer. The ultimate problem in our inefficacy to cure cancers, particularly metastatic disease, is the inability to really kill colon cancer or any cancer stem cells.

The only way to succeed with targeting stem cells, which are ultimately resistant to any of the treatments we have, including the targeted treatments, is really to differentiate these cancer stem cells out, and then kill them with chemotherapy. I think that will revolutionize the way we do treatment in the future. I think this drug, as a single agent, will probably not be effective, but in combination with chemotherapy, absolutely it will be. We see that in our preclinical models.