For Dr. Avery Posey it was a bout with chickenpox when he was in 4th grade that spurred his interest in science. He was quarantined in one room for about a week and still remembers his grandmother lovingly applying calamine lotion to his blisters. “I was miserable, itchy, missed school, missed my friends, and all I kept thinking was there had to be a way to prevent this,” Posey says. A few years later, the chickenpox vaccine was unveiled and “most kids today don’t even know what chickenpox is,” he continues. “I thought for a while I wanted to be a doctor, but I realized in undergraduate school that real important changes in how we look at disease and treat disease is due to research.”
Dr. Dannielle Engle thought she was going to be a violinist, a virtuoso maybe along the lines of Joshua Bell. She started college majoring in music, but switched gears and wound up majoring in biology. When she took a low-level job in a research lab while still an undergrad, it was the fruit fly and its simple genetic structure as well as the creativity shown by the investigators with whom she worked that made her realize science was her calling. “I was a pretty good violinist, not great,” she laughs. “But I got completely hooked on my work in the lab and I knew at that point my future was in research.”
From those rather simple beginnings, Posey and Engle are now at the forefront of trying to better understand what makes pancreatic cancer among the most lethal of malignancies and how we can better treat it, maybe even prevent it. In recognition of their efforts and success so far, Posey and Engle were named recipients of two new Career Development Awards developed by the Lustgarten Foundation and administered by the American Association for Cancer Research (AACR.)
Engle was awarded the Lustgarten Foundation-AACR Career Development Award for Pancreatic Cancer Research named in honor of Ruth Bader Ginsburg. The $300,000 grant supports the career advancement of an early-career female pancreatic cancer researcher. Posey was named the recipient of the Lustgarten Foundation-AACR Career Development Award for Pancreatic Cancer Research named in honor of John Robert Lewis. The $300,000 grant is given to members of racial or ethnic groups that have been shown to be underrepresented in the pancreatic cancer research workforce
The awards are part of an overall effort dubbed The Ruth Bader Ginsburg & John Lewis Pancreatic Cancer Research Program, developed by the Lustgarten Foundation to honor the lives and legacies of Ginsburg and Lewis, both of whom lost their lives to pancreatic cancer in 2020.The awards were presented at the 2021 AACR annual meeting by Dr. David Tuveson, President-Elect of the AACR and Chief Scientist of the Lustgarten Foundation. “These awards will encourage and support early career scientists engaged in pancreatic cancer research and address the ongoing need to advance gender equality and racial diversity within the pancreatic cancer research community,” he said.
Living Up To a Legacy
Both grantees admit they were a little shell-shocked by the win, and somewhat in awe of receiving awards named for two people they greatly admire and respect. “I am definitely thrilled by the grant and the help that it provides to my career and my lab’s research, but I’m also thrilled that that grant is named in honor of John Lewis,” says Posey, an assistant professor of Systems Pharmacology and Translational Therapeutics at the Perelman School of Medicine at the University of Pennsylvania (Philadelphia) and a Parker Institute for Cancer Immunotherapy member researcher. “There are racial disparities in science, but there are racial disparities literally everywhere,” says Posey.
“We can’t go on ignoring that fact and we can’t go on leaving people behind based on race, the color of their skin. That’s something that he (John Lewis) fought for and if I can in some way make a change in the sciences I think it will benefit those potential younger scientists who look at me and maybe see themselves. There’s still too few minorities involved in the sciences, and we need to make science a real pathway for these young, great minds.”
Engle is an assistant professor at the Salk Institute for Biological Studies (La Jolla, California). She says that although women are making strides in the sciences, the same holds true: “There is absolutely underrepresentation of women in science.” She adds, “It’s the same with women entering graduate programs. We keep losing women at early stages of their careers. I didn’t have a lot of women mentors. And I think it’s tough for some women to envision becoming a scientist, or seeing yourself in certain positions because there is no one like you in the field or in a leadership position.”
The Ginsburg fellowship grant is important to Engle for two reasons. “First, to get a grant named after RBG is so cool and so meaningful,” she says. “I sometimes doubted myself early on, asking myself if I really belonged. So this not only boosts my confidence but it also says I earned this. And second, it helps provide an opportunity for the next generation of women scientists. Maybe they won’t have to question themselves in their journey to becoming scientists because there will simply be more of us.”
Posey Focuses on the Immune Response
Posey is studying how CAR T cell therapy can help better treat pancreatic cancer. CAR T cell therapy is a type of immunotherapy called adoptive cellular therapy. T cells, which are a type of white blood cell, are extracted from a patient’s blood. An artificial receptor, called a chimeric antigen receptor (CAR), is added to the surface of the T cells. The receptor functions as a targeted missile that enables these modified cells, once they are reinfused back to a patient and begin to multiply, to produce chemicals that can destroy cancer cells.
This form of therapy has had success in treating some forms of so-called blood-based cancers like leukemia and lymphoma. But there has been less success with solid tumors, especially the “rock hard” pancreatic cancer tumors, Posey says. “Everything about a pancreatic tumor makes it challenging. There are few targets, the microenvironment is hostile, and the stroma is extraordinarily dense, all of which work together to make it tricky to get T cells in there.” To add to that mix, CAR T cell treatment, if not carefully designed, could target molecules found on the surface of both malignant and healthy cells, and treatment side effects could be severe.
Posey and colleagues are working to change that by honing in on malignant cells. For example, his lab developed specially engineered T-cell therapies focusing on a cellular process called glycosylation in cancer. Glycosylation is a complex process where glycans, which are carbohydrate molecules, attach to proteins. The process plays a critical role in determining protein structure, function, and stability. The researchers engineered immune cells to recognize an antigen called Tn-MUC1, which is found on the surface of tumor cells but practically never on healthy tissue. The group also found that by modifying the signaling domain of a CAR, the anti-tumor response can be enhanced.
Engle Hones in on CA 19-9
Chronic pancreatitis is a miserable, painful disease accounting for about 275,000 hospitalizations each year in the U.S. alone. It is also a known risk factor for the development of pancreatic cancer. To help diagnose chronic pancreatitis, doctors look for a biomarker called CA 19-9, which is often elevated. All research begins with a hypothesis, and Engle wondered if it would be possible to somehow intervene in the process of chronic pancreatitis leading to pancreatic cancer.
With powerful mouse models that she developed, Engle showed that CA 19-9 is more than a biomarker and actually causes chronic pancreatitis. By blocking CA 19-9 the progression from pancreatitis to pancreatic cancer was averted. “Finding ways to intervene. . . to stop pancreatic cancer from developing in those who are at high risk would be incredible,” she says. “Pancreatic cancer is a terrible disease with an incredibly high mortality rate. We are getting better at treating it and extending life, but we need to do so much more. This is an early step in the right direction hopefully.”
Engle has also been instrumental in the development of organoids, which will help track how pancreatic cancer develops and identify potential new biomarkers to better distinguish between pancreatitis and pancreatic cancer.
A Hope-Filled Outlook
Both Posey and Engle have lost family members to pancreatic cancer. It’s those losses that often play a part in influencing and shaping their research. It is also those losses that cement their commitment to improving the outlook for pancreatic cancer patients.
“I would love to see a time in which pancreatic cancer is treated the way breast cancer is treated today,” explains Engle, who lost her father and her uncle to pancreatic cancer. “What I want to see is when a patient is diagnosed, we will have the ability to form a strategy that is best suited to their tumor. We have made fundamental discoveries in understanding the biology of pancreatic cancer, but those discoveries need to be turned into better, more precise treatments.
“My dad and my uncle died 10 years apart and the truth is that not much changed in that decade in terms of treatment for pancreatic cancer. That made me angry; now there are more options. But we still need better ones. I am absolutely sure we will get there.”
Posey echoes the sentiment, He lost his aunt to pancreatic cancer earlier this year. “Pancreatic cancer is devastating, treatments are tough, and quality of life is often degraded,” he says. “My aunt had one round of chemo, and that along with her dialysis was about all she could take. She died 10 months after diagnosis which, unfortunately, happens to too many people.
“My focus is on gene therapy. There is absolutely no reason why we won’t have better treatments and better survival. I would love to see a time, and I think it can happen, where one day we are able to develop a therapeutic vaccine that’s applicable to a broader range of people, a kind of off-the-shelf treatment. I think anything is possible. And I am hopeful about the future, and it’s not misplaced hope. It’s hope based in science.”