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Fighting Pancreatic Cancer: Work Done, Work Begun

August 7, 2017 | Lindsay Morgan

Few cancers are as lethal as pancreatic cancer. In 2016, pancreatic cancer became the third leading cause of cancer death in the United States, surpassing even breast cancer. By 2030, it is predicted to be the second leading cause of cancer death, behind only lung cancer.

Pancreatic cancer is deadly for a number of reasons. It is asymptomatic far into disease progression, and often diagnosed late. When it is diagnosed, half of patients already have metastatic disease; about 30% have inoperable disease; and only 15-20% are candidates for curative therapy. Few are cured.

Because of its unique biology, pancreatic tumors are often resistant to typical therapies. Cancer cells in the pancreas attract a tumor microenvironment that is replete with other cell types, including cancer-associated fibroblasts—immune cells that are conditioned to be pro-tumorigenic. Pancreas tumors also have an abundant stroma, which are hypothesized to inhibit immune cells—and drug therapies—from attacking the cancer.

The American Cancer Society estimates that in 2017, about 53,670 people in the United States will be diagnosed with pancreatic cancer and about 43,090 of them will die.

The Perplexing History of Pancreatic Cancer Research

The history of pancreatic cancer research is perhaps best characterized by the striking disparity between the wealth of knowledge about pancreatic cancer biology and genetics, and the—thus far—inability to use that knowledge to impact patients.

lowy-andy-crop.jpegDr. Andy Lowy , UCSD Chief of the Division of Surgical Oncology in the Department of Surgery, and a pancreatic cancer specialist, has studied pancreatic cancer for more than 21 years. He says: "We know more about the genetics of pancreatic cancer than many other cancers. We understand the first, common mutations; there is work outlining the mutational spectrum; we know a lot about the components of the microenvironment; we have a mouse model that looks like the human disease. We have all these tools and information, yet we haven't impacted the disease for patients."

Part of the problem is that the genetic mutations that are common in pancreas cancer are not easily targetable. There's only one commonly mutated oncogene in pancreatic cancer: KRAS. (Oncogenes are a class of genes that, when mutated, have the potential to cause normal cells to become cancerous.) Scientists have been trying to target KRAS for many years, unsuccessfully. Clinical trials of new therapies have largely been disappointing.

Dr. Lowy, together with Dr. David Tuveson, Director of the Cold Spring Harbor Laboratory Cancer Center, developed a genetically engineered mouse of human pancreatic cancer in 2003, which has allowed study of all stages of the disease, from pre-invasive to metastatic. Today, this model is used throughout the world to investigate pancreatic cancer. Dr. Lowy has also led or co-led dozens of other pancreatic cancer studies.

His motives are personal. Dr. Lowy's mother was diagnosed with cancer when she was 35 years old. She was treated and free of disease for almost eight years, but it came back. She died when Lowy was a surgical intern.

An Unlikely Partnership

In 2011, Dr. Lowy got a call from Dr. Dennis Carson, the former director of the UC San Diego Moores Cancer Center. "He said I needed to meet a great new scientist from Duke," says Lowy. "'She's really smart, you should do something with her,' he said."

tannishtha-reya.jpegThe great new scientist was Dr. Tannishtha Reya , who had just joined UCSD's Pharmacology Department. Trained as an immunologist and stem cell biologist, Reya had spent ten years on the faculty at Duke University trying to understand how cancers highjack stem cell programs to become more aggressive and drug resistant. In her research, she and colleagues identified the stem cell gene Musashi (Msi) as a new driver of cancer progression.

Says Reya: "We found that shutting down this signal blocked leukemia growth and led to improved survival. Msi driven programs were needed, not only for sustaining cancer growth but also for the transition of benign disease to a more malignant phase." Prior to Dr. Reya's research, no link had been made between cancer progression and Msi.

Over coffee, Drs. Lowy and Reya wondered if Msi might be a more general paradigm in regulating aggressive cancers, and if they could test its involvement in pancreatic cancer. They decided to try.

Patching together funds from other projects and donors, they initiated preliminary research and found that Msi was highly expressed in pancreatic cancer cells in both mouse models of the disease and in primary patient samples. Their preliminary studies also showed that Msi inhibition functionally blocked the growth of pancreatic cancer cell lines as well as patient-derived xenografts.

This work led to a joint RO1 grant from the National Cancer Institute to understand how Msi may regulate pancreatic cancer growth and metastasis, and a publication in Nature . Using a combination of mouse genetics and patient-derived xenografts, their work showed that Msi expressing cells were critical drivers of tumor growth and drug resistance and identified Msi as a potential new therapeutic target in pancreatic cancer.

Dr. Lowy and Dr. Reya are also part of a Stand Up To Cancer"Dream Team" that brings together renowned experts from the United States and U.K. to study Transcriptional Reprogramming to Control Pancreatic Cancer .

"The team's approach is rooted in the idea that pancreatic cancers are essentially wounds that never heal. Research from members of the Dream Team, and others in the field, have uncovered gene networks in tumors that are similar to those in injured tissues where repair and regenerative mechanisms are essential to restoration of normal function. Unlike the normal system of wound healing that has a shut-off mechanism, in tumors the process remains on, "hijacked" to constantly drive cancer cell growth. The Dream Team believes that the biological machinery involved is controlled through hot spots in a cell's DNA called Super Enhancers (SE), which control not only the cancer cell, but also surrounding non-cancerous cells, upon which the cancer cells rely for support".

The Dream Team aims to develop new approaches to reset malfunctioning SEs—including in pancreatic cancer stem cells expressing Msi—thereby dialing-up the sensitivity to chemotherapy and to anti-cancer immunotherapies ultimately to push pancreatic tumors into lasting remission.

The Stand Up To Cancerwork kicked off at the end of 2015, and runs for three years. "It's a very tight timeline," says Reya, "but it forces you to focus on what's most immediately applicable. There's an urgency in the field because of continued poor outcomes, and a great deal of motivation to change the status quo."

Lowy agrees: " Stand Up To Cancerinsists that your work be translated to patients, so you have to get trials up and going within two years, and they push you for faster results. It's bench to bedside and back."

Reya, whose team is in part responsible for the pre-clinical data used to inform the clinical trials, says that being part of a multidisciplinary team has been eye-opening. "It's easy to be critical of trials, but when you actually see it in real time you understand how challenging it can be. For any one pathway there are multiple drugs, there are many pathways, and you can combine the drugs in many ways. But you can only take a few combinations to trial. So it sharpens your focus on how to prioritize critical signals, and how to develop more predictive preclinical models. It also highlights the need for developing early detection strategies, since any new agents will likely make the greatest difference in early stage disease."

Discovery Meets Application

During her post-doctoral fellowship at Stanford University, Dr. Reya trained with the renowned stem cell biologist Irving Weissman. One afternoon, they were looking at some experimental data, and Weissman suggested that Reya test if her findings could be moved forward towards the clinic. Reya said to Weissman, "Isn't someone else going to do that?" His response was: There is no one else!

"That moment really stuck with me," says Reya. "If you have a discovery that could impact patients, if you don't fight for it, advocate for it, there isn't anyone else who's going come in and do it. There's a wide gap between discovery and application. For many decades, scientists stayed on one side, with clinicians and industry each in their own spaces. There's been an attempt more recently to connect these pieces and pull it all together." Reya thinks this will make a difference on the ground.

Dr. Lowy agrees: "It's a symbiotic relationship. When you have two people with different training and expertise that complement each other, research can be accelerated. I think it's also a lot more fun."

Collaborations like this are not the norm, because they require an investment in time, and the right partners. Says Dr. Reya: "I never thought I'd be working on pancreatic cancer, but Andy's dedication and generosity were invaluable in making it possible. His ability to bring people together to work on this problem is a reflection of his deep commitment to changing the landscape for pancreatic cancer."

Other Pancreatic Cancer Research in the Division of Surgical Oncology

There are a number of other research projects in the Department of Surgery looking at various aspects of pancreas cancer. Dr. Lowy is funded by the National Institutes of Health to conduct research to understand how to activate the immune system against pancreas cancer, specifically through work on a protein called RON, which is thought to condition immune cells in such a way that they allow pancreatic cancer cells to hide from the immune system and grow.

Dr. Rebekah White was recently awarded $75,000 by the Salk Institute Cancer Center to study irreversible electroporation as an In Situ vaccine for pancreatic cancer; and Dr. Michael Bouvet also conducts major investigations on the growth and spread of pancreatic cancer and the treatment of pancreatic cancer and other tumors. He is an investigator on several major National Cancer Institute-funded studies on the treatment, understanding, and monitoring of pancreatic cancer. In his recent medical publications, he reported the causes and factors that influence its growth as well as new techniques for imaging pancreatic cancer.

Much more work is needed—along with more sustained funding. "It's not easy to take a discovery to translation," says Reya. "I think if we want to seriously change long-range outcomes, academic institutions will need a comprehensive strategy to support and incubate early phase translational projects. Covering that space is an unmet need."

Progress, but (Much) More Work to Do

Much progress has been made in pancreatic cancer research, and current studies may eventually bring new hope to patients and reduce mortality. But in the meantime, pancreatic cancer remains a major public health problem.

"People say: how can you do what you do? It's so depressing," says Lowy. "And it's true, in my field, you can't cure most people, although with incremental progress wenow have a significant number of pancreatic cancer survivors. But even for those we can't cure, you can still make a big difference. If somebody gets to see their children reach milestones like my mom got to see me get my MD, or a child gets to be with their parents for a couple more years, you can't replace that."

The quest to fight pancreatic cancer continues to be personal to Dr. Lowy. Debbie Soldano, a nurse practitioner who has worked with Dr. Lowy for more than 20 years, watched her sister die of pancreatic cancer in 2016, when she was only 53 years old.

"We have so much work to do," Lowy says.