Society-Funded Researchers Take Aim at Pancreatic Cancer
Article date: January 17, 2013
By Melissa Weber
Pancreatic cancer is a seemingly unbreachable tumor, earning it a decades-long ranking as one of the most difficult cancers to treat. It is the fourth most deadly cancer among both men and women in the US, after lung, colon, breast, and prostate cancer.
But scientists funded by the American Cancer Society are finding ways to put a chink in pancreatic cancer’s armor. Researchers are exploiting weak spots in hopes of destroying the cancer and possibly preventing it altogether.
“As we better understand how pancreatic cancers develop, more and better strategies to detect and treat this disease become available,” said Karl Saxe, PhD, Director of the Society’s Program in Cancer Cell Biology and Metastasis. Saxe and his colleagues help the Society identify promising young investigators and projects to contribute to the understanding of pancreatic cancer.
Taking Away Pancreatic Cancer’s Immortality
Scientists are developing a way to tell pancreatic cancer cells it’s OK to die.
Researchers have developed drugs that specifically attach to a receptor called sigma-2. Only on the surface of fast-growing pancreatic cancer cells are these receptors exposed in high numbers, making them an easy target. When the drug binds to the sigma-2 receptor, it triggers a process of programmed cell death called apoptosis.
“The cancer cells aren’t getting enough oxygen, they’re starving for nutrients, they’re crowded. These drugs say, look, you don’t belong here. There’s a natural process by which you should be dying but you’re not because you’re a cancer cell. But we’re going to give you permission to die,” said Society-funded researcher William Hawkins, MD, associate professor of surgery at Washington University School of Medicine in St. Louis.
What’s more, Hawkins said, researchers may be able to use this target as a way to bring other cancer drugs to the cancer cells. Tens of thousands of experimental cancer drugs have proved effective in the Petri dish but too toxic in humans, often because it’s hard to get the drugs concentrated only at the tumor. But this new method to deliver a toxic payload only to rapidly growing cancer cells could bring some of those promising agents back into play.
“Many drugs that have been out there simply weren’t effectively getting to the tumor. But even if just 10% of them are viable options to hook to our delivery platform – that’s the battery of potential new therapeutics my research opens up,” Hawkins said.
The Society-funded research has led to a grant from the National Institutes of Health. Hawkins will continue testing the drugs in the lab before the treatment can move into clinical trials.
“I’ve never been more optimistic in my life that there is really good treatment on the horizon for pancreatic cancer. We’re going to turn pancreas cancer into a chronic disease,” Hawkins said.
Protein May Be Both Drug Target and Predictive Marker
A single protein may be the answer to 2 very big questions in pancreatic cancer: Which tumors are most likely to respond to the widely used chemotherapy drug gemcitabine (Gemzar)? And is there finally a drug target at which we can take aim?
The protein is called HuR, and Society grantee Jonathan Brody, PhD, is chipping away at the answers.
HuR is like a street cop in the middle of a busy intersection, directing and regulating a lot of different proteins, Brody said. HuR regulates an enzyme that makes gemcitabine work better. It also helps pancreatic cancer cells survive.
“We’re trying to figure out why HuR is such a great street cop, and can we remove the street cop and use that as a therapy,” said Brody, director of surgical research at Thomas Jefferson University in Philadelphia. He is currently testing a therapy designed to knock out the HuR gene in mice.
The researchers are also investigating HuR’s powers to predict which patients will do well on gemcitabine, a mainstay of pancreatic cancer therapy since the late 1990s. Roughly half of pancreatic cancers are so-called HuR-positive and may therefore respond better to gemcitabine, according to Brody’s findings.
For patients treated with gemcitabine, Brody found that having a HuR-positive tumor improved survival 7-fold compared to patients with HuR-negative tumors. Patients with HuR-negative tumors may therefore be better off trying another treatment, Brody said.
“When we start predicting upfront and realizing that every patient has a different tumor with a different biology and that we need to treat it differently, that’s when we’re going to really start making progress against this disease,” Brody said.
Targeting a Common Mutation in Pancreatic Cancer
There’s a process that plays out over and over again in pancreatic cancer: grow, survive, spread. But now, researchers have uncovered where the process starts – and possibly how to shut it down.
What researchers want to stop is KRAS, a gene that is mutated in more than 90% of the nearly 44,000 pancreatic cancers diagnosed each year. In its mutant form, KRAS constantly sends signals that tell pancreatic cancer cells to divide uncontrollably. So far, researchers have been unable to find a way to target KRAS.
But Society grantee Joseph Kim, MD, may have found an indirect route to flip the “off” switch on KRAS: block a protein called CXCL12 from binding to CXCR4, its receptor on the surface of pancreatic cancer cells. That subsequently prevents the activation of signals inside the cell, including signals from KRAS.
In Kim’s lab, researchers have found a drug that can bind to the CXCR4 receptor and help to turn off the KRAS protein. The result: the cancer cell stops growing. “This is the breakthrough we may need to help our patients with pancreatic cancer. Our studies try to take the first major steps to effectively target KRAS,” said Kim, associate professor in the division of surgical oncology at City of Hope in Duarte, Calif.
Thwarting mutant KRAS may not only help kill pancreatic cancer cells, it might also help avert the disease altogether. The KRAS mutation is a known culprit in the initiation of pancreatic cancer. Kim’s research team plans to investigate whether a drug to turn off KRAS can prevent cancer in mice that have KRAS mutations in their pancreas cells.
“It’s these small steps that lead to the multiple big steps that will then lead to new therapies that could double, triple, quadruple the survival rates for pancreatic cancer,” Kim said.
Reviewed by: Members of the ACS Medical Content Staff
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