Pancreatic cancer is one of the deadliest cancers: in the United States, only 7 percent of patients survive five years after diagnosis.
Drugs cannot easily access pancreatic tumors because the tumors have very low blood supply and secrete certain proteins that promote the growth of stroma, collagenous connective tissue that hinders drugs’ access to tumors.
Recent research has identified drug pre-treatments that boost delivery of conventional small-molecule drugs into the tumors by making their blood vessels more leaky.
But now an international partnership led by the University at Buffalo School of Pharmacy and Pharmaceutical Sciences is embarking on research based on a somewhat different principle. Since many of the pharmaceutical agents being studied in this grant already have Food and Drug Administration approval, the strategy, if proven successful, could have a rapid impact on treating pancreatic cancer, the researchers say.
The five-year, $3.8 million, grant started Sept. 1. Funding was received through the US-Ireland R&D Partnership Programme, a unique funding mechanism that supports projects across the U.S., the Republic of Ireland and Northern Ireland, with each country funding the research performed within its borders.
Under this grant, UB’s School of Pharmacy and Pharmaceutical Sciences and Roswell Park Cancer Institute (RPCI) will share $2.2 million from the National Institutes of Health, while collaborators at Queens University, Belfast, will receive the equivalent of $1.13 million from the UK Health and Social Care R&D Division and collaborators at Dublin City University will receive the equivalent of $506,000 from Science Foundation Ireland.
Instead of treating pancreatic cancer with small-molecule drugs, the team is working on using particle-based delivery systems, including liposomes, which are nano-sized, fat-soluble, drug-delivery packets; the team’s theory is that these could remain “stuck” in a tumor for days or weeks, allowing for sustained release of a drug.
“A key hypothesis we will test in this grant is that conventional small molecules are the wrong drugs to use with these ‘tumor-priming’ strategies,” said Robert M. Straubinger, PhD, professor of pharmaceutical sciences and principle investigator of the U.S. effort.
He explained that about five years ago, several important characteristics of pancreatic tumors were identified. One of them was the fact that certain pre-treatments, including drugs that inhibit cellular signaling by a pathway improbably named the “sonic hedgehog” pathway, appeared to boost efficacy of drugs by promoting tumor microvessels.
“Because the pre-treatment causes the new vessels to become leaky, it’s like opening a window,” said Straubinger. “The drugs can flow in when blood concentrations are high, but when blood concentrations fall – and many small molecules don’t circulate for very long—they can wash right back out.”
Straubinger and his colleagues will try to take advantage of that leakiness by using nanoparticles, such as liposomes, which could take hours to days to diffuse into the tumor, as opposed to minutes to hours.
“This grant will allow us to explore new ways of improving the access of drugs to tumor sites,” said Christopher J. Scott, PhD, who leads the research team at Queens University. “Using current chemotherapies, only a fraction of the drug gets to where it is needed. If this could be improved, even only incrementally, it could lead to a major advance in how we treat pancreatic cancer patients.”
The scientists will be evaluating “tumor-priming strategies,” a sequential chemotherapy approach where one agent is administered that increases tumor blood-vessel leakiness and then a second cytotoxic agent is added, such as a liposome or a therapeutic antibody that should remain in the tumor longer to fight the cancer.
Scott’s lab will test whether decorating the drug-loaded nanoparticles with tumor-homing antibodies will give the particles an additional boost in effectiveness.
But because tumor-priming strategies are poorly understood and can produce variable results, the team will use what it calls “mathematical priming” to find out what works best.
“If we capture the time course and magnitude of how an agent affects the tumor, then we can use mathematical simulation to identify the optimal timing for priming and delivery of the drug,” said Straubinger.
These chemotherapy combinations will be tested by scientists at Dublin City University and at Roswell Park Cancer Institute, including Wen Wee Ma, MD, associate professor of oncology at RPCI and assistant professor of medicine in the UB School of Medicine and Biomedical Sciences.
“We are delighted with the news of this award, which brings together complementary expertise in cancer research from three different nationally leading laboratories focused on developing new strategies to improve the treatment of pancreatic cancer,” said Robert O’Connor, PhD, now head of research for the Irish Cancer Society. Niall Barron, PhD, will head the Dublin City University group.
Straubinger, also an adjunct professor at Dublin City University and at RPCI Cancer, has been collaborating with his colleagues at the partner institutions, on this and related projects for several years.