In 2011, an estimated 44,030 individuals will be diagnosed with pancreatic cancer, and approximately 37,660 people will lose their battle with this disease. Pancreatic cancer has the lowest survival rate of all types of malignancies; for all stages combined, the one-year relative survival rate is 26% and the five-year survival rate is only about 6%.

There are two main reasons that account for the extremely low survival rates of this disease. First, pancreatic cancer patients seldom exhibit disease-specific symptoms until later stages, so in more than 90% of patients the tumor is already at an advanced stage upon diagnosis. Second, the treatment options currently available for pancreatic cancer are limited and generally ineffective.

With funding from NFCR, four leading scientists are exploring new and improved approaches to preventing and treating pancreatic cancer. Their innovative research could lead to enormous clinical benefits for pancreatic cancer patients and those at risk of developing this aggressive malignancy.

Advancements in Prevention and Treatment of Pancreatic Cancer

Developing a new class of multi-functional cancer-preventing drugs

NFCR scientist Michael Sporn, M.D., known as "the father of chemoprevention", has devoted his scientific career to new anti-cancer drug development for treatment and for chemoprevention-the use of drugs or other substances to prevent or stop cancer development. For those at high risk for pancreatic cancer or other highly aggressive cancers, Dr. Sporn believes that using chemoprevention to reduce their risk in the first place is a sensible approach to helping save their lives.

Dr. Sporn and his team of researchers at Dartmouth Medical School design and synthesize compounds that suppress inflammation, inhibit cancer cell proliferation, and induce cancer cell suicide. Recently, his team published impressive results from studies that demonstrate that two of these compounds, rexinoids and synthetic triterpenoids, delayed the development of an aggressive type of pancreatic cancer in a complex tumor model that mimics human disease. This is one of the first times scientists have been able to demonstrate the feasibility of using chemopreventative drugs to prevent pancreatic cancer or delay its onset. These results are particularly important since one of the triterpenoids, CDDO-ME, has shown very encouraging clinical benefit for patients with pancreatic cancer and other different types of solid tumors enrolled in recently completed Phase II clinical trials. Continued success of rexinoids and triterpenoids in preventing pancreatic cancer in the laboratory will move these compounds closer to becoming an effective tool for prevention for people who are at high risk of developing this devastating disease.

Chinese Herbal Medicines: Beneficial Adjunct to Cancer Chemotherapy

The therapeutic effects of traditional Chinese medicines (TCM) have been documented for centuries but have been regarded by modern medicine as "alternative therapy" because there has been too little scientific proof that it works as claimed. For the last decade, with NFCR support, Dr.Yung-Chi Cheng of Yale University School of Medicine explored the therapeutic properties of PHY906, a Chinese herbal medicine formula of four herbs first described 1,700 years ago. NFCR is pleased that our long-term commitment to Dr. Cheng and his team is paying off. In recently completed Phase I/II clinical trials, PHY906 demonstrated encouraging clinical results when it was used in combination with anticancer drugs for the treatment of pancreatic, colon, and liver cancer. PH906 alleviated the unpleasant gastrointestinal side effects of the chemotherapy. Dr. Cheng's laboratory research demonstrates that PHY906 may also have anti-tumor effects that enhance those of chemotherapy agents. Using cancer cell lines and tumor models, the researchers are now working to determine how PHY906 fights cancer and reduces the side effects of chemotherapy. With continued success, PHY906 could become one of the first FDA-approved oral herbal medicines for anti-cancer treatment. This breakthrough represents a paradigm shift in the way the cancer research community thinks about TCM, opening the door to new approaches to treating cancer using these ancient medicines and potentially giving physicians a new and more effective option for treating many cancer patients.

Developing New Therapies Targeting Pancreatic Cancer

The NFCR Center for Targeted Cancer Therapies is dedicated to discovering novel and more effective therapeutics to treat pancreatic cancer. Led by Directors Daniel Von Hoff, M.D. and Laurence Hurley, Ph.D., researchers at the Center are trying to develop new therapies that block the growth of pancreatic cancer cells by interfering with pancreatic cancer-promoting molecules-an approach called targeted cancer therapy. As pancreatic cancer cells often become resistant to traditional chemotherapy and radiation, targeted therapies may offer new treatment options for killing off resistant cancer cells.

One of the current treatments for pancreatic cancer is combining chemotherapy with the targeted agent, erlotinib (trade name Tarceva^TM)  — the FDA-approved drug for pancreatic cancer treatment that specifically targets a cancer-causing growth-producing molecule. Patients undergoing this treatment regime experience only small benefits and eventually lose the battle with their cancer. For two years, Center researchers have focused on identifying agents that will enhance the treatment efficacy of erlotinib. They have identified a candidate gene and a gene-inhibiting agent that significantly boost the treatment efficacy of erlotinib when used together in pancreatic cancer cell lines and in complex tumor models. This highly fruitful research is about to enter the next phase: Drs. Von Hoff and Hurley are planning a clinical trial to treat pancreatic cancer patients with this gene inhibitor combined with erlotinib. The combination of these two targeted therapies holds promise for further extending the lives of patients fighting this lethal disease.

Computer-aided Design of Novel Drugs

NFCR scientist, William Jorgensen, Ph.D., at Yale University, is a world renowned leader in computer-aided drug design, leading his team to develop, design, and apply the necessary methodology and computer software for use in developing novel targeted drugs. The Jorgensen team starts from a detailed, three-dimensional picture of the target protein and use computational methods to automatically construct potential drug molecules that fit into sites of the target protein and cause the protein to malfunction. The computer-aided design greatly reduces the time and other costs associated with creating efficacious inhibitors. Dr. Jorgensen has successfully applied this methodology to rapidly obtain a novel, potent anti-HIV drug and an anti-inflammatory agent for arthritis.

Armed with their superior methodology, Dr. Jorgensen's team is focused on the development of new targeted agents that inhibit FGFR (Fibroblast Growth Factor Receptor). Abnormal FGFR enzyme activity is implicated in pancreatic cancer as well as breast cancer and other cancers. Preliminary results have narrowed the candidate list down to a "top 23" structurally diverse compounds -- this is after the computer had visualized what might result from inserting over 2 million compounds into the FGFR molecule. The Jorgensen team is using their software program called "BOMB" to generate and optimize these lead compounds. Discovery of inhibitors of the FGFR enzyme through this sophisticated computer-aided design has the potential to bring novel targeted therapies rapidly into the clinic, giving pancreatic patients hope that their cancer can be effectively treated.