Leukemia Inhibitory Factor May Be a Promising Target Against Pancreatic Cancer
June 19, 2012
- KRAS protein is a key driver of most cases of pancreatic cancer.
- KRAS, working via leukemia inhibitory factor, promotes the generation and maintenance of pancreatic cancer stem cells.
- LIF shows promise as a target for pancreatic cancer treatment.
LAKE TAHOE, Nev. — Pancreatic cancer is one of the deadliest forms of cancer, defying most treatments. Its ability to evade therapy may be attributable to the presence of cancer stem cells, a subset of cancer cells present in pancreatic tumors that drive tumor growth by generating bulk tumor cells. Cancer stem cells are notorious for their ability to resist traditional chemotherapies.
However, scientists at the University of California, San Francisco (UCSF), have discovered that two proteins — KRAS and leukemia inhibitory factor (LIF) — help create cancer stem cells and that the latter can be targeted to block them.
These results were presented at the American Association for Cancer Research’s Pancreatic Cancer: Progress and Challenges
conference, held here from June 18-21.
In many different types of tumors, a constitutively active, mutant form of the signaling protein KRAS helps drive the uncontrolled tumor cell proliferation that is a hallmark of cancer. In fact, more than 90 percent of pancreatic cancers exhibit KRAS mutations, but the link between KRAS and cancer stem cells has been tenuous — until now.
Using human pancreatic cancer cell lines and mouse fibroblasts and pancreatic cancer cells, Man-Tzu Wang, Ph.D., a postdoctoral researcher in the McCormick lab at the Helen Diller Family Comprehensive Cancer Center at UCSF, and colleagues showed that KRAS causes cells to acquire and maintain stem cell-like properties.
“We know that KRAS is a very potent driver of pancreatic cancer, but we don’t know how to drug it,” said Wang. “Our results showed we can block KRAS-mediated cancer stem cells by blocking LIF activity.”
KRAS is difficult to target therapeutically. Taking the next logical step, the researchers began looking for proteins that function downstream of KRAS in the generation of pancreatic cancer stem cells to determine if any of them could be potential drug targets. They found a number of candidates but focused on LIF, a protein known to regulate stem cell development. Moreover, they found that LIF is “druggable,” making it a potential target for treatment.
Using neutralizing antibodies or shRNA, the team knocked down LIF activity or expression and found that each reduced the in vitro stem cell-like properties of mouse pancreatic cancer cells.
“We think our data indicate that blocking LIF can bring a significant improvement to cancer treatment,” Wang said.
Knocking down cancer stem cells is critically important. Because these cells are slow-growing, they are often resistant to traditional chemotherapies, which target fast-growing cells. In addition, they also contain mechanisms that pump drugs out of the cell. Their survival allows them to continue to differentiate into mature cancer cells, leading to recurrent tumors.
Though there are no drugs currently available that target LIF, Wang is hopeful that these new data will spur the development of such products and generate new pancreatic cancer therapies.
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Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR’s membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
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(215) 446-7109 Jeremy.Moore@aacr.org In Lake Tahoe, June 18-20: