These New Discoveries Are Raising Hope For Pancreatic Cancer Treatment

This blog was originally posted on Stat News.

Pancreatic cancer is deadly: It’s difficult to detect and bedeviling to treat. Just 20 percent of patients survive a year after diagnosis. Less than 10 percent make it to the five-year mark.

But recent discoveries — both in the lab and in patients — are raising hope. They’re still early stage. Yet they offer new insight into the causes and progression of the disease — and they may ultimately help doctors better detect, and treat, this difficult cancer.

Here, a look at four key findings:

Pancreatic tumors are often studded with bacteria that deflect chemo

We’re learning more and more that the billions of microbes in our body have profound effects on how tumors grow — and on whether treatments have a shot at working. Just this fall, researchers reported in Science that they’d found bacteria in colon and pancreatic cancers that actually break down chemotherapy drugs, rendering them ineffective.

Here’s why that matters: One of the few drugs that can be used to treat some pancreatic cancers is the chemotherapy gemcitabine — but it only works in a fraction of cases. We now are beginning to understand why. A class of microbes, called Gammaproteobacteria, actually “protects” tumor cells from the chemotherapy’s poison. The study found these bacteria in 76 percent of the pancreatic tumors they studied.

Some of the bacteria, in fact, could be found inside the actual tumor cells — not just lurking somewhere in the tumor microenvironment, said Dr. Ravid Straussman, the study’s principal investigator. And when these bacteria were introduced to tumors that didn’t have them beforehand, they quickly conferred drug resistance.

“We did find bacteria inside the cancer cells, and it can metabolize chemotherapy and inactivate it,” said Straussman, who studies the cancer microbiome at Israel’s Weizmann Institute of Science.

He cautioned that “we still can’t tell exactly how much this effect contributes to the clinical resistance we see in pancreatic cancer.”

But if it holds up, the finding could help doctors identify those patients most likely to respond to chemotherapy. What’s less clear: Whether killing these bacteria with antibiotics could help improve the efficacy of cancer drugs. After all, many bacteria are good, and might even help cancer drug efficacy — so wiping them out with a broad spectrum antibiotic might harm more than help.

However, if researchers were able to identify a drug that specifically targeted just the bacteria that neutralize the chemo, “we might be able to minimize the bacteria’s effect without risking the generation of antibiotic-resistant bacterial strains or changing the gut microbiome in a profound way,” Straussman said.

Diabetes can be a warning sign for pancreatic cancer

We know smoking and obesity are risk factors for pancreatic cancer, and about 10 percent of cases have a genetic or familial link. Researchers are now trying to spread the word about another risk factor: “There’s a link between new-onset diabetes and pancreatic cancer,” said Dr. Anirban Maitra, a professor of pathology at MD Anderson Cancer Center. “Many physicians don’t know this, but it could have a profound effect in early detection.”

Diabetes, of course, is a disease of the pancreas, in which the cells that produce the hormone insulin malfunction and the body fails to process sugars appropriately. But there’s evidence that, in a small portion of people with diabetes, this is actually caused by cancer growing in the organ. Maitra wagers that about 30 to 40 percent of pancreatic cancer patients have diabetes as well. So he’s leading a consortium to try to develop a more sensitive test for people with diabetes to figure out the root cause of their illness.

(The consortium also includes the National Institutes of Health, the National Cancer Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases.)

The plan is to track 10,000 patients with diabetes over several years, and see who develops pancreatic cancer. From there, Maitra’s team plans to analyze what, precisely, sets that cohort apart. The researchers hope to use that information to develop an early diagnostic test for the disease.

“We don’t want to cause widespread panic, because there are more than 2 million new-onset diabetics in the U.S.,” Maitra said. “We’re thinking that only 1 percent, or less, actually have an underlying pancreatic cancer.”

Still, any new diagnostic would be welcome in this field, where the disease is often detected too late to treat.

Genetic markers might help predict patient outcomes

Even when pancreatic cancer is removed surgically, it has a high rate of recurrence — and researchers haven’t found good ways to predict when this will happen, said Dr. Brian Wolpin, director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute.

Wolpin’s team sequenced the DNA of tumors from 356 pancreatic cancer patients and delved deep into the intricacies of when, and where, they recurred — and how long the patients lived. The work, published earlier this month in JAMA Oncology, found that the status of the KRAS gene — which has also been implicated in colon and lung cancer — “was a clear indicator of patient outcomes,” Wolpin said.

More than 90 percent of pancreatic cancer patients have a KRAS mutation of some sort, but different variations were linked to different outcomes regarding tumor recurrence and survival, Wolpin said. The same goes for three other genes. For example, patients whose tumors didn’t express a gene called CDKN2A had considerably lower disease-free survival rates — and they died faster.

Untangling the genetics of these tricky tumors could help doctors tailor therapies better. Some patients benefit from radiation, for instance, while others do well if prophylactically treated with chemotherapy, but it’s not clear in advance which patients are in which group. The nuances in these four genes could help pinpoint treatment approaches.

“One place this work will continue is really trying to move from a place where everybody gets the same therapy, to where we can use the genetics of the tumor to tailor therapy more appropriately to the individual,” Wolpin said.

Immunotherapy might actually help metastatic pancreatic cancer

Outside of gemcitabine and a handful of other chemotherapies, few drugs have been effective in treating pancreatic cancer. Immunotherapy, which has proven powerful in many other tumor types, hasn’t shown effect here — until now.

A tiny Phase 1 study found that combining two immunotherapy drugs — nivolumab, marketed as Opdivo by Bristol-Myers Squibb, and cabiralizumab, an experimental monoclonal antibody drug from FivePrime Therapeutics and BMS — may help a sliver of patients with metastatic pancreatic cancer. The results, presented this month at the Society for Immunotherapy in Cancer conference in Maryland, showed that four out of 31 patients responded to the combination therapy.

Each patient in the study had already received intense treatment for their pancreatic cancers, and the experimental immunotherapy could be considered a last resort. The therapy appeared to shrink the tumor in these patients, as well as reduce the levels of certain proteins found in the blood that are correlated with the volume of cancer in the body.

“This is a glimmer of hope into using immunotherapy,” said Dr. Zev Wainberg, co-director of the GI Oncology Program at University of California, Los Angeles. “That’s why this study is provocative: Until this point, there have been no responses with any immunotherapy drugs for pancreatic cancer.”

Wainberg said they have guesses, but still no clear understanding as to why the four patients did respond to the immunotherapy. But the experimental drug, cabiralizumab, is designed to block “bad” immune cells, called tumor-associated macrophages, that live within the pancreatic tumors. These cells secrete hormones and growth factors that help cancers grow. The second drug, nivolumab, helps direct the body’s defense system to attack the tumor cells.

The researchers are now enrolling another 30 patients in this Phase 1 trial, with plans to publish the research. It’ll then move onto a Phase 2 trial, where researchers are looking to recruit 160 patients.

Pancreatic cancer is the third-leading cause of cancer-related death in the U.S., recently surpassing breast cancer. Only lung and colon cancers have higher mortality rates. The new findings will take years to reach the clinic, but researchers say they could, perhaps, finally start to improve patients’ odds.