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Bridging the Gap Between Pancreatic Cancer Research & Clinical Care

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000527167.75334.e3
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Julia Carnevale, MD, Clinical Instructor in GI Oncology, University of California San Francisco (UCSF), had her feet planted on two continents during her formative years. Though she originally hails from San Diego, her time was divided between that sun-drenched California city and the historic magnificence of Rome, Italy, where she resided half the year. Her parents, both pursuing scientific careers—cognitive neuroscience and physics—had met and fallen in love in Rome, and determined to make “the eternal city” part of their lives.

“They worked with universities that allowed them to travel between California and Italy,” said Carnevale, recalling that as a globe-trotting youth she, too, gravitated toward science. “I remember sitting in a biology class in my sophomore year of high school and being taught about telomerase, an important enzyme that helps immortalize stem cells and cancer cells. I can remember being on the edge of my seat. I felt so excited and couldn't believe such a thing even existed.”

Carnevale's youthful assumption was that everyone in her class would be similarly enthralled. “Then I looked around and realized that wasn't true. Some classmates were yawning, waiting for class to be over,” she recalled. “It was just an average class for everyone else. And there I was, my heart was racing because I was so thrilled. That's when it actually dawned on me that we all must find our own path, and it's these early encounters and realizations that get us there. My passion was for biology.”

That passion became all the more personal during Carnevale's college years at Stanford University when her mother was diagnosed with, and later succumbed to, pancreatic cancer—expected to become the second-leading cause of cancer deaths in the U.S. by 2020. It's a fact that Carnevale called quite simply “scary, particularly because it is generally incurable. It is such a vicious disease, and yet, while many other cancers are doing better in terms of effective treatment options, pancreatic cancer is not keeping the pace and remains one of the most lethal diseases.”

It was her mother's illness that caused Carnevale to gravitate to the integration of science and medicine, and realize how they inform each other and how they necessitate each other, she noted. Carnevale subsequently went east to attend Harvard Medical School in Boston. During a Howard Hughes Research Training year, she honed her interests and decided to pursue molecular medicine for her residency and an eventual fellowship that took her to UCSF.

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Following a Dual Pathway

Today, Carnevale is based in San Francisco, and enjoys a happily married life and the new experience of motherhood to baby daughter, Ellie. She has recently moved into independent practice while continuing extensive research efforts at UCSF.

“Clinical and research were never an ‘either/or’ situation for me,” reflected Carnevale. “I always felt they needed each other. For an individual to embrace both, it can be a struggle sometimes because these paths are fairly polarized; it is not an easy road. But those of us who believe these two things are not exclusive and are important to each other persist to find the right path. Certainly I have, as they are both really necessary in my life.”

Asked why she was attracted to molecular research in particular, Carnevale said it began with the sheer scientific interest and how fascinating it all is. But now there is more to it. “I like the fact that I can bring hope to patients. I like that I can say, ‘The status quo isn't good enough’ and then be able to say, literally, ‘We are working on it,’ makes all the difference. I can actually look patients in the eye and say. ‘We are trying to do better and ‘it’ may be just around the corner.’ And truthfully, I have already seen ‘it’ be around the corner. In the case of melanoma, for example, during my relatively short training period at UCSF, I saw it go from a death sentence to something that we think can even be cured. There is room for hope, especially in the kinds of cancers I see. And to think it is actually believable that we can capture ‘it’ in our lifetime is thrilling.”

Pertinent to her marriage of research and clinical providership, Carnevale said her research efforts “... come together around the idea that we can take clinical questions/problems and use unbiased screening platforms to mold new screens to those very clinical questions to answer them. A lot involves technology—specifically CRISPR. I have been working with existing and developing novel CRISPR screens to try to answer problems I see in clinic.”

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Targetable Subsets

One of Carnevale's main projects revolves around pancreatic cancer, which historically has not had molecular subsets that could be addressed with very precise therapies. She explained that pancreatic cancers have very dominant mutation patterns—classic genes that cannot be targeted. It has been a source of frustration for researchers. But today, a subset of pancreatic cancer characterized by its deficiency in certain types of DNA damage repair is becoming more recognized.

“One of the classic examples is BRCA mutant pancreatic cancer,” detailed Carnevale. “A lot of the pancreatic cancers have the same properties of BRCA mutant pancreatic cancer, and yet we don't necessarily find the BRCA mutation in these tumors. However, they are deficient in homologous recombination repair; there's a specific type of DNA damage that they are unable to repair. That is an interesting and exciting finding because pancreatic cancer has had a long and difficult history of harboring nothing really actionable. There had been no known subsets that we could really go after with specific personalized therapy,” Carnevale told Oncology Times. “So it was exciting when the discovery was made that there are targetable subsets in pancreatic cancer—more than we had thought—that may have therapeutic vulnerabilities due to DNA damage repair defects.”

These were found through bigger sequencing efforts that go deep and look for the “scar” of BRCA mutations. “We can look across the DNA and see that this tumor is full of these rearrangements and these deletions that indicate they must have homologous recombination repair deficiencies even though in some we don't see BRCA mutation,” Carnevale explained. “There must be other genes or phenomena causing this. Nonetheless, these tumors cluster into the same genetic group due to this phenotype, this scar, this DNA damage repair deficit. That is tremendously exciting because they may be targetable with therapies [like] PARP inhibitors that go after tumors with BRCA mutations, or a combination of PARP inhibitors plus some other drug, or they may actually be vulnerable to drugs other than PARP inhibitors.”

Carnevale devotes a great deal of time to using new types of CRISPR screens in hopes of eventually developing new therapies that can be used specifically for these pancreatic cancers with this kind of DNA repair defects. “I use an unbiased new screening approach to try to identify new therapeutic approaches,” she explained. “It is a lot of work to get the screens done; I've done two now and am at the stage where I am converging on what we call ‘hits’—genes that may be potential therapeutic targets.” She further explained that once armed with the candidate list, she must explore a panel of cell lines, usually with genetic inhibition and drug inhibition, to show that these hits validated reproducibly. “Often this includes using mouse models to show that targeting a gene will lead to fewer tumors in mice. So clearly there's a long road after the screens are developed to show that these are therapeutic targets in this cancer type.”

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Research With ‘Power Tools’

Another important project for Carnevale also involves the use of CRISPR technology. “Many gastrointestinal cancers have not had huge success with new immunotherapies, so I am also working on screens to see if we can identify ways for the immune cells to get around suppressive forces in the tumor,” she explained. “I've been excited to work on the cutting edge of harnessing these CRISPR technologies to build new screening approaches, while trying to answer two clinical questions: Can we build better therapies for these pancreatic cancers with DNA repair deficits, and can we find ways to get around the suppressive forces in tumors? By saying we don't know the answer, can we use new technologies to cast a wide net in a biological space and let the screen point to the biology and what might be a previously unrecognized target that could help advance treatments for cancers?”

Carnevale explained there are a lot of different tweaks and iterations on CRISPR that have allowed for a new array of ways to screen and adapt questions that hadn't been addressed before. “CRISPR is basically a very specific molecule that will go to any gene that we tell it to. We can tell it to go to every gene in the genome, or to these specific 10,000 genes, or whatever we like. We can also adorn it with a lot of different functionalities so that, when it gets to where we send it, it can do different things. We can say, ‘OK, CRISPR, go to this gene and cut it out so we can see what happens to this cell when it loses that gene.’ Or we can say, ‘OK CRISPR, go and stop that gene from being expressed,’ or ‘Go and increase its expression,’ and we can see what happens to the cell.”

Even when there is not a specific gene selected for interrogation, “Now we can say, I don't know which genes are important yet, but I want to know. I want to do a pooled screen so each cell is assigned to target a specific gene,” Carnevale continued. “And now we have a library of cells, with each differently affected. Once we have a huge library of differentially edited cells, we can design a screen to ask which genes are important to that tumor.

“We can very specifically and precisely do all of that now; we haven't had that kind of tool before,” she said. “It is really a new power tool that opens up new possibilities. And now we are asking new questions about the immune system, with new screens that are coming out. We didn't even know to go there before. It is an exciting time and the possibilities are endless.”

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Up Close & Personal

Away from the lab and the clinic, Carnevale most enjoys spending time with her daughter and her husband, who is not only her long-distance running partner but also her fail-safe allowing her work/life balance to continue seamlessly. “My husband is amazing, completely supportive,” she said. “When I have to work late, he doesn't bat an eye. He takes care of our baby and we make it work. Having him as a partner has been key to going at this pace, keeping all the balls in the air.”

If those research “balls” eventually hit their targets, what would professional success look like for Carnevale? She paused for barely a moment then answered, “Of course I would like to have my own lab one day, lead clinical trials, and publish my work. But the true dream would be to put something in the clinic that has biologic activity and can lengthen the life of patients and keep cancer at bay. Unfortunately, there is a low bar in the field of pancreatic cancer due to its high death rate. But anything that can improve the outcome, no matter the increment, is important. Today, we are seeing patients with a difficult disease and we don't have a huge array of treatment options. If we can find anything to control the disease for a longer period of time, it would be a decisive win.”

Carnevale's mother died at the age of 54, without such an advantage of prolonged time. And while Carnevale admitted that working in the pancreatic cancer space can be frustrating at times, it remains a very personal and clear path for her. “Seeing my mother sick and seeing the disease up close had a strong impact on me. This is what I want to do.”

Valerie Neff Newitt is a contributing writer.

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