FRONTLINE CANCER: Working to eliminate the cancer stem cells that sustain disease
By Scott M. Lippman
Chemotherapies seek out cancer cells by targeting a fundamental characteristic of cancer cells: their rapid and frequent replication. But in doing so, these drugs can destroy healthy cells that also grow quickly. The result: adverse effects like hair loss and nausea. Worse, the benefits of chemotherapy are frequently short-lived. Seemingly beaten by chemotherapy, a cancer can suddenly return, spreading from its original site to other parts of the body with often catastrophic consequences. Ninety percent of cancer-related deaths are due to metastasis, and almost every cancer can be metastatic.
Why do cancers recur when therapeutic evidence suggests they’ve been wiped out? The answer lies in a type of cancer cell with the powerful characteristic of normal stem cells – the ability to self-renew or regenerate.
Unlike normal stem cells, however, this ability in cancer stem cells does not turn off.
Cancer stem cells are a relatively new phenomenon to cancer science. Conclusive evidence of their existence was found only in 1994, though in the years since, extraordinary efforts have been made to better understand them in order to destroy them.
It’s a daunting task. Cancer stem cells persist in small communities, often tucked away in the deep recesses of bone. They do not divide with dangerous abandon, which would make them easier targets of chemotherapy. In fact, they often lie dormant, essentially invisible until they begin again the process of self-renewal, differentiation and cancer relapse.
Toughest of all, they are very hard to kill, quickly developing resistance to existing drug therapies.
Nonetheless, progress is being made, some of it driven by researchers at UC San Diego Moores Cancer Center. Among them is Catriona Jamieson, M.D., Ph.D., an associate professor of medicine in the UC San Diego School of Medicine and director of Stem Cell Research at Moores Cancer Center.
Jamieson has devoted much of her career to deciphering the secrets of cancer stem cells and, more importantly, working to develop effective treatments to rid the body of them. She specializes in myeloproliferative neoplasms (MPNs) and leukemia.
MPNs are a family of uncommon, but not rare, degenerative disorders in which the body overproduces blood cells that may progress to leukemia. Almost 50,000 new cases of leukemia were diagnosed this year in the United States, mostly in adults. Almost 24,000 Americans die from the disease annually.
In 2008, Jamieson and colleagues formed a unique partnership between industry (TargeGen) and academia to develop a drug to counteract the JAK2 gene mutation in stem cells that causes MPN, which Jamieson had helped discover in 2006.
Traditionally, drug development takes many years, even decades. But with unprecedented speed, major contributions from TargeGen and Sanofi, from researchers at Stanford University and the Mayo Clinic and funding support from the California Institute for Regenerative Medicine (CIRM), Jamieson’s work on a JAK2-inhibitor drug has progressed to the final stage of human clinical trials.
Her efforts do not stop there.
Working with Tannistha Reya, Ph.D., professor of pharmacology at the Moores Cancer Center, and with collaborators at Pfizer and CIRM funding, Jamieson and colleagues have translated the discovery of sonic hedgehog gene activation in myeloid leukemia stem cells to Phase 2 international trials.
In addition, her lab has a $3.3 million CIRM grant to exploit newly discovered vulnerabilities in leukemia stem cells. They’ve even identified a specific compound called sabutoclax (in collaboration with John Reed and others at Sanford-Burnham Medical Research Institute) that appears to selectively target the hard-to-reach cells responsible for leukemia relapse.
There is progress elsewhere, too. Tom Kipps, M.D., Ph.D., deputy director for research at Moores Cancer Center, is spearheading an effort to target ROR1, an embryonic survival factor used by many cancers, including chronic lymphocytic leukemia – the most common blood cancer in the U.S. And Kelly Frazer, Ph.D., director of the Institute for Genomic Medicine and Genomics shared resource at Moores Cancer Center, is developing a wide array of tools to detect cancer stem cells early in the disease process.
But most notable is the latest news: Denny Sanford’s recent $100 million gift to create the Sanford Stem Cell Clinical Center at UC San Diego. The center is a bold and much-needed step toward translating the promise of stem cell-based therapies into real treatments benefitting real patients.
Cancer most often kills because it is not killed quickly enough. The work of Jamieson, Reya, Kipps, Frazer and others is inching us closer to being able to completely eliminate the cancer stem cells that sustain disease. One day soon, I hope we will be able to not just diagnose and treat each and every cancer, but declare with confidence that a cancer vanished is a cancer banished.
Scott M. Lippman, M.D., is Director of UC San Diego Moores Cancer Center. His column on medical advances from the front lines of cancer research and care appears in the La Jolla Light the end of each month. You can reach Dr. Lippman at email@example.com
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