Advances in Pancreatic Cancer

New treatment approaches and drug regimens are improving outcomes in pancreatic cancer, but more research funding and more patients on clinical trials are needed.

Medical advances of the past few years have doubled the one- to two-year overall survival rate for patients with pancreatic cancer, a specialist at The Ohio State University reports.

“This is a substantial advance for patients with a cancer that has historically had such a dismal prognosis,” says Richard M. Goldberg, MD, referring to a malignancy that ranks as the 12th most common cancer but third leading cause of cancer-related death among men and women in the United States, with an overall five-year survival rate of only 7 percent.

Goldberg, a gastrointestinal (GI) oncologist and physician-in-chief at The Ohio State University Comprehensive Cancer Center— James Cancer Hospital and Solove Research Institute (OSUCCC – James), says advances leading to the improved one- to two-year survival rate have come through steady progress in pancreatic cancer research at the OSUCCC – James and elsewhere.

In a 2015 editorial in the Journal of the National Cancer Institute, Goldberg and his collaborator, Tanios Bekaii-Saab, MD, stated that new drug combinations are “shifting the treatment landscape for this disease,” giving physicians and their patients more choices for managing pancreatic adenocarcinoma.

In addition, they noted that recently identified predictive biomarkers might help doctors stratify patients for treatment and choose those most likely to benefit from the variety of regimens showing activity in the disease.

Making a Difference

Darwin ConwellAt Ohio State, the expanding GI Oncology Program offers care to a growing number of patients—the program currently sees nearly 1,300 new patients per year and schedules nearly 20,000 patient visits annually.

“As the third largest cancer hospital in the country, we see a huge volume of patients with cancer who cross the entire spectrum of tumors originating in the GI tract, from the esophagus to the anus,” Goldberg says, noting that Ohio State’s Division of Medical Oncology includes a section for GI oncology with eight physicians and a translational researcher. “Conservatively, 20-30 percent of our GI volume is pancreatic cancer.”

Darwin Conwell, MD, director of the Division of Gastroenterology, Hepatology and Nutrition at Ohio State, has hired several gastroenterology physicians with cancer focus for the GI clinics.

“In addition, we have 11 to 15 surgeons and four radiation oncologists who work with us on patients with GI cancers. We have seen quite an expansion among patients with these diagnoses looking to our specialists for care,” Goldberg says.

In 2015 the university was chosen as one of 10 members of a national Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer. The NCI and the National Institute of Digestive and Diabetes and Kidney Disorders will provide $2.3 million in funding over five years (DK108327), with Conwell as principal investigator.

Left untreated, chronic pancreatitis can cause irreversible fibrosis and destruction of pancreatic tissue, potentially leading to malnutrition, abdominal pain, Type 3c diabetes mellitus (T3cDin) and, over time, to pancreatic cancer. Consortium members will conduct studies on chronic pancreatitis and factors that increase the risk of pancreatic cancer in children and adults with chronic pancreatitis and with T3cDM.

Conwell is principal investigator (PI) for the Ohio State consortium; co-PIs are Philip Hart, MD, and Gregory Lesinski, PhD, MPH.

Also, Ohio State’s multidisciplinary pancreas program, which treats both cancerous and non-cancerous conditions, has been designated as a National Pancreas Foundation (NPF) Center. It is one of 30 hospitals nationwide and the only adult hospital in Ohio to earn this distinction. The program is a collaboration of the Ohio State Wexner Medical Center and the OSUCCC – James.

“This major achievement demonstrates that we are one of the most comprehensive pancreatic disorders clinics in the nation,” Conwell says. “Our center is more robust than the minimal NPF requirements, housing a multidisciplinary pancreatic disorders clinic that includes GI oncology, surgical oncology, radiation oncology and advanced abdominal imaging.”

Clinical Research

Pancreatic cancer researchers at Ohio State are studying immunotherapeutic approaches, molecularly targeted therapies, the use of genomic selection data to define cancer pathways, and strategies for combating cachexia, a muscle-wasting condition common in patients with pancreatic and other GI cancers.

“We provide multiple clinical trials for pancreatic cancer, many of which are ideas initiated by our own faculty members, who then lead national clinical trials efforts. By collaborating with our colleagues in basic science laboratories, we also have studies under way that link treatments to the basic biology of this disease,” Goldberg says. “Clinical trials for every stage of pancreatic cancer and every line of therapy are available at The James, from radiation to immunotherapy to chemotherapy.”

Examples include trials that incorporate PD-1 (programmed cell-death protein 1) inhibitors, which stimulate the immune system to kill tumor cells. “PD-1 inhibitors allow the patient’s own immune system to recognize cancer as a foreign invader, permitting the immune system to destroy tumors,” Goldberg says. “As we learn how to use these tools most effectively, these agents are likely to be an increasingly important part of our future treatment regimens in combination with standard cytotoxic chemotherapies, even for early-stage disease.”

Reducing Treatment Toxicity

Pancreatic cancer is typically diagnosed after it has metastasized, when the five-year survival rate is only 2 percent. New treatments are badly needed. In 2013, findings from a multicenter phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) led to FDA approval of an agent called nab-paclitaxel combined with the standard-of-care drug gemcitabine for metastatic cancer.

But while this regimen improved survival, it also resulted in more toxicities than gemcitabine alone, reducing quality of life. Seeking a safer treatment, OSUCCC – James researchers recently reported the results of a study that showed administering the regimen every other week may reduce the toxic effects while maintaining effectiveness. These findings were presented at the 2015 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium and are under review for publication.

“The modified regimen is easier to administer and results in fewer neurological side effects and less compromise of the patient’s immune system while maintaining positive effects on the overall survival and lengthening the time to progression of tumors in our patients,” Goldberg says. “It also means fewer visits to the infusion center, leading to a reduction in each patient’s medical costs by about $5,500 per month.” He notes that these results are intriguing preliminary findings that will need to be confirmed in a larger randomized trial.

Surgery for Locally Advanced Disease

Carl SchmidtSurgical oncologist and OSUCCC – James researcher Carl Schmidt, MD, is leading a clinical trial (NCT02446093) to determine whether adding a modified herpes virus called GMCI to a neoadjuvant chemotherapy regimen (modified FOLFIRINOX) followed by chemoradiation is safe and benefits patients with borderline resectable and unresectable locally advanced pancreatic adenocarcinoma.

“The protocol is designed to deliver multiple courses of GMCI timed with a series of neoadjuvant debulking therapies to capitalize on the synergy produced by these different treatment modalities,” Schmidt says.

The adenovirus vector delivers a herpes simplex enzyme to the cancer cells that activates a prodrug, which then generates nucleotide analogs that kill the cancer cells. The dead cells release tumor antigens that stimulate a tumor-specific immune response that will help clear micrometastatic disease. “We hope that this regimen will make more patients treatable with surgical resection,” Schmidt says.

Translational Research

Gregory LesinskiIn the December 2015 issue of the Journal of the National Cancer Institute, OSUCCC – James researchers reported a preclinical study showing that an experimental agent developed at Ohio State may stop the muscle-wasting process that patients often develop, which is called cancer cachexia, and that this intervention can restore muscle health.

The agent, AR-42, is a histone deacetylase (HDAC) inhibitor. It blocks the expression of genes that play a key role in skeletal muscle breakdown. The study team—which includes Samuel Kulp, DVM, PhD; Pearlly Yan, PhD; Gregory Lesinski, PhD, MPH; Denis Guttridge, PhD; and Ching-Shih Chen, PhD, whose lab developed the agent—showed that oral AR-42 can preserve body weight and prolong survival while preventing loss of muscle and fat tissue and preserving muscle health.

“These findings show that AR-42 can preserve muscle and every aspect of its functionality, which is an important step in refining methods for stopping cachexia,” Chen says.

“Astoundingly, our researchers found that AR-42, unlike other HDAC inhibitors we tested, reverses the process of cachexia building a pancreas cancer mouse model to further test this and are in the process of designing our next clinical trial with AR-42 in pancreatic cancer. Cachexia is the cause of death in 30-40 percent of pancreatic cancer patients. If we have an agent that reverses cachexia and has anticancer activity, it’s a double win. We believe AR-42 has both properties.”

MEK Inhibition

Over 90 percent of pancreatic cancers express KRAS oncogene mutations that activate the Raf-MEK-MAPK genetic pathway and confer resistance to radiation and chemotherapy. Because MEK inhibitors have shown promising antitumor responses in recent preclinical and clinical studies, OSUCCC – James researchers evaluated a MEK1/2 inhibitor called GSK212 and found that it suppressed major DNA repair pathways in KRAS-driven pancreatic cancer cells, making them more sensitive to radiation.

The team, led by Terence Williams, MD, PhD, assistant professor in the Department of Radiation Oncology, reported the findings in the journal Cell Cycle, concluding that a clinical trial combining MEK1/2 inhibition and radiation in the treatment of pancreatic cancer is warranted.

JAK2 Inhibition

A biorepository of more than 500 tissue samples drawn from patients at different treatment stages enables OSUCCC – James researchers to conduct studies that are shedding light on the biology and immunology of pancreatic cancer.

OSUCCC – James researcher Gregory Lesinski, PhD, MPH, associate professor in the Division of Medical Oncology, recently led a study published in the journal Oncotarget that revealed the promising anticancer effects of a Jak2 inhibitor in mice with pancreatic cancer.

“The Jak/STAT pathway is activated in human pancreatic ductal adenocarcinoma (PDAC) and cooperates with mutant KRAS genes to drive initiation and progression of PDAC in mouse models,” wrote the investigators, led by Lesinski and first author Thomas Mace, PhD, a research scientist at Ohio State. “We hypothesized that the small-molecule Jak2 inhibitor (BMS-911543) would elicit antitumor activity against PDAC and decrease immune suppressive features of the disease.”

Their results “indicate that Jak2 deserves further study in preclinical models of PDAC and has distinct inhibitory effects on STAT5- mediated signaling that could alter immune aspects of this disease.”

More Funding Needed

Richard Goldberg“Federal funding for pancreatic cancer research has increased dramatically from where it was just a few years ago, but the disease still remains a lethal one,” Goldberg says.

The NCI estimated that about $102 million would be spent on pancreatic cancer research in fiscal 2013, but Goldberg would like to see more resources go into research in this area.

“While it sounds like a lot, it’s not close to the resources devoted to research in breast or lung cancer, for example,” he says, especially since the incidence of this disease is expected to rise to about 100,000 cases per year by 2030 due to the aging population (median age at diagnosis is 71) and to a lack of preventive measures and methods for routine screening. A study published in the June 2014 issue of the journal Cancer Research states that PDAC is projected to become the second leading cause of cancer-related deaths in the United States by 2030.

“The low survival rate means we have few long-term survivors who can step forward and advocate for resource investment,” Goldberg says. “Plus, some people think, ‘Why spend money on a disease where efforts to date have led to only incremental improvements in outcomes?’ However, if we don’t incentivize researchers by spending money on this problem, outcomes will remain where they are today.”

Fortunately, he adds, successes with new drug regimens have prompted pharmaceutical
companies to start testing more of their products in pancreatic cancer, which should lead to more clinical trials that may advance the field if enough patients are accrued.

“We need to increase awareness that pancreatic cancer is not necessarily lethal for all patients, and that many of those who get the diagnosis will benefit from being assessed and treated,” he explains. “An estimated 20-30 percent of patients who are diagnosed with this disease never see an oncologist and are never treated.

“So we’re not capturing all of the patients that we should,” he adds. “The more we see, the more can be helped, and survival numbers may improve. More patients need to be on clinical trials. We have those trials available at Ohio State, and we’re willing to share them with the community.”

Pointing out that results from an international study called NAPOLI-1 recently led the FDA to approve yet another regimen for patients with metastatic pancreatic cancer (MM-398 in combination with 5-fluorouracil and leucovoriun following prior treatment with a gemcitabine-based regimen), Goldberg says clinical progress against this disease should be encouraging to all.

“Several years ago, we essentially had one option, gemcitabine,” he says. “But studies such as ACCORD11, MPACT and NAPOLI-1 have given us stronger regimens with newer drug combinations. The treatment landscape is shifting from nihilism and futility to optimism, and we are finally moving the needle against pancreatic cancer.

“Today, we have stronger chemotherapeutic backbones to work with, and I think we are more likely to induce meaningful responses with new combinations of biologic and immunologic agents. This is an exciting time for treatment of pancreatic cancer, a time for optimism.”

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