Could a drug used by many people to control high blood pressure play a role in the fight against pancreatic cancer? That’s the question posed by a study now underway at six clinical sites, including the University of Colorado Cancer Center on the Anschutz Medical Campus.
The drug in question is losartan, a hypertension medication that lowers blood pressure by preventing blood vessels from narrowing. Animal studies over the past decade have shown that losartan could similarly help increase blood flow into cancerous tumors. That, in turn, might improve the delivery of cancer-fighting, tumor-shrinking chemotherapy drugs.
Blood pressure drug to fight pancreatic cancer
The target of the current study is pancreatic cancer, and with good reason, said Dr. Wells Messersmith, head of the Division of Medical Oncology at the University of Colorado School of Medicine. Messersmith is the Cancer Center’s principal investigator for the trial, which is sponsored by Massachusetts General Hospital.
Messersmith noted that pancreatic tumors are typically rock hard because they are bolstered by stromal cells, the ones that produce connective tissue. The stromal cells help to make the tumors protective fortresses for the cancerous cells within.
“The concern is that no matter what drugs we give, not much gets into the tumor,” Messersmith said. He compared the problem to attempting to force a solid rock to absorb water. The trial investigates whether losartan could decrease that resistance and increase the volume of drugs penetrating the tumor and attacking cancer cells.
Losartan as a multipronged attack
Losartan is only one element of the randomized trial, which has four treatment arms. All patients receive a four-month regimen of FOLFIRINOX, which is a combination of four chemotherapy drugs; short-course precision radiation therapy that spares healthy tissue; and surgery to remove the tumor and clean out any remaining cancer cells. The control arm gets no additional therapy. The experimental arms include patients who add losartan; patients who add nivolumab, an immunotherapy drug that targets cancer cells; and patients who add both losartan and nivolumab.
The study’s primary comparison is the percentage of patients in each group who have cancer-free margins of tissue around the surgically removed tumor.
The sequence of the treatments is another important feature of the trial, Messersmith said. Patients with pancreatic cancer typically undergo surgery before getting chemotherapy and/or radiation. But up to two-thirds of patients who have their pancreatic tumors cut out see their cancer recur, Messersmith said. That’s because legions of rogue cells have spread undetected to other parts of the body.
“If you have pancreatic cancer, the tumor itself won’t kill you,” Messersmith said. “It’s the spread of it.”
The last shall be first in pancreatic cancer treatment
With that in mind, the trial moves the chemotherapy treatment to the front of the line, followed by radiation to “sterilize the field” before surgery, as Messersmith put it. “The idea is to address the killer as soon as you can instead of waiting until after surgery,” he said. He noted patients may take two months to recover from surgery – a potentially dangerous window for remaining cancer cells to spread, if surgery is done first.
The approach could also save some patients from unnecessary surgery, Messersmith added. For example, a patient who gets little or no help from the initial chemotherapy regimen has little chance of a cure, he said. “For that rare patient whose tumor spreads and grows despite chemo, we’re probably sparing them from surgery that wasn’t going to help them.”
The treatment sequence relies on the development of more effective chemotherapy drugs. FOLFIRINOX, first developed in France, nearly doubled survival in patients with pancreatic cancer after surgery, Messersmith said. “It crosses the threshold of feeling comfortable delaying surgery until after chemotherapy. Without the proven efficacy of FOLFIRINOX, we wouldn’t do the trial.”
Trial of blood pressure drug could yield helpful insight into pancreatic cancer treatment
The trial, which received important funding assistance from Wings of Hope for Pancreatic Cancer Research, a local nonprofit that supports the Cancer Center’s research, could show that the experimental treatments don’t improve patient outcomes, Messersmith emphasized.
“We have no idea if they will actually help or not,” he said. Even a “clear winner” in a trial that aims to enroll 160 patients won’t “totally answer the question” of whether a particular treatment can be a proven pancreatic cancer fighter. It could, however, provide “initial signals that inform a larger, national trial” that further tests the hypothesis, Messersmith said.
He added that a randomized study from geographically and demographically diverse institutions that pits four different approaches against one another could yield valuable information, regardless of the direct data from the trial. For example, study researchers will analyze tissue samples from study patients, looking for patterns in those who do especially well or poorly after treatment and then seeking explanations. Tumor cells could also be used to grow miniature versions of tumors in petri dishes, allowing for testing of new drugs in a controlled environment.
Subtle signals of pancreatic cancer
Late last year, Tom Fattor, 78, from Broomfield, didn’t think about the challenges of pancreatic cancer, much less consider joining a clinical trial. Although there is pancreatic cancer in his family, Fattor had never experienced any serious health issues. A certified public accountant by trade and self-described workaholic, Fattor cheerfully admits to sticking to a resolutely unhealthy diet over the years, invariably choosing hamburgers, hotdogs, popcorn, ice cream and beer over leafy green vegetables. You couldn’t argue with the results, he said, noting his weight stayed at a consistent 160 pounds.
“I’d go to my physician for my annual physical and he’d come back and say, ‘I don’t know what you’re doing, but keep it up,’” Fattor joked.
His relative health and steady work routine helped him ignore a persistent pain below his stomach that began midway through 2019. The discomfort stretched from his left side to his right “like a big old smile” for a few months, Fattor said, but he shrugged it off.
“If I get into my work, I really don’t feel any physiologic signals,” he said. As time went on, his wife, Kris, urged him to see a physician, but he didn’t do it. “I decided it was too vague,” Fattor said. “I told myself, ‘You’re 77. Get over it,’.”
A mass on the pancreas
That changed in mid-November 2019. He was at a Denver Broncos game when pain that felt like a red-hot poker struck him between his stomach and ribs. He thought he was having a heart attack. With that, Kris convinced him to seek help at a local hospital, where he got imaging tests that revealed a mass on his pancreas.
Given his family history, Fattor said he was well aware that he was a risk for cancer. Still, the news caught him off guard. He remembers feeling as if he left his body and watched the scene unfold from afar. The physician who delivered the news wasn’t sure if it had registered with him.
“It knocked me back pretty far,” Fattor said.
It turned out the tumor had closed his bile duct. He had surgery to implant a stent, which relieved the pain. Fattor stopped working for a month and a half as he made a series of physician and emergency room visits and took medications to manage his condition and the pain. Then he decided to take his life back.
“I figured they hadn’t told me I was going to die right away, so I might as well go back to work,” Fattor said. “It also gave me a chance to talk to people about having a life as well as a disease.”
Seeking expert cancer help from a high school friend
Fattor also had an important conversation with a high school friend. Dr. Martin J. Murphy and Fattor were classmates at the now-closed Abbey High School in Canõn City, Colorado. Fattor recalls accompanying Murphy to the school’s biology lab and doing his homework while his friend built the groundwork for a distinguished career in cancer research. He’s currently chief executive officer and co-founder of the CEO Roundtable on Cancer, a non-profit devoted to spearheading cancer-fighting initiatives on multiple fronts.
It turned out that Murphy knows Messersmith, and he let Fattor know about the losartan trial. Fattor said that while Murphy emphasized that the decision was completely personal, he urged him to consider enrolling in the trial at the Cancer Center. Fattor decided to do that and quickly got a referral from Kaiser Permanente. He was randomized to the losartan/nivolumab arm, began his chemotherapy treatments in January and in early March was halfway through the regimen.
The first round was especially rough, Fattor admitted, but with the second round, the Infusion Center gave him anti-anxiety and anti-nausea medications that have helped considerably. He also battled dehydration – he said he has had a hard time drinking water – but addresses that with intravenous fluids after each infusion.
He’s learning as he goes. “As a CPA, everything is process. I’m pretty optimistic about the remaining [infusions].” He added that he benefits emotionally from the upbeat professionalism of the Infusion Center staff.
The challenges of a clinical trial
Messersmith said he and his team are sympathetic to the many challenges for patients considering participating in the trial. Some, for example, may not want to delay surgical treatment. The trial requires patients to travel to the Anschutz Medical Campus for treatment at UCHealth University of Colorado Hospital. That’s difficult for the significant number of patients who live well outside the Denver area.
“Traveling to campus every two weeks for chemo can be hard,” Messersmith said. “We’ll take care of you no matter what and we totally understand if you don’t want to do this trial.”
Tom Fattor understands. He considered doing nothing after his diagnosis. “I’ve done everything I want to do in life,” he said. Then he considered the older of his two granddaughters (now 14) and how much he’d like to be there for her wedding someday. He thought of Martin Murphy’s contributions to medical science and how much his longtime friend has done to help people. He understands that the trial promises nothing, but he decided nonetheless to move ahead.
“I thought that this is the right thing to do,” Fattor said. “Maybe it will help somebody.”
For more information on the trial, contact Wells Messersmith: [email protected].