Pancreatic Cancer

 In 2008, an estimated 37,680 individuals will be diagnosed with pancreatic cancer, and approximately 34,290 people will die of this disease in the same year. Pancreatic cancer has the lowest survival rate of all types of malignancies, with the one-year relative survival rate less than 24% and the fi ve-year survival rate of only about 5%.

There are two main reasons that account for the extremely low survival rate of this disease. First, pancreatic cancer patients seldom exhibit disease-specific symptoms until later stages, and in 80-90% of patients the tumor is already at an advanced stage upon diagnosis. Second, the treatment options currently available for pancreatic cancer are limited and ineffective. Thus, NFCR has been focusing on projects that improve early detection and treatment of pancreatic cancer.

Research

NFCR scientists are exploring new approaches for early diagnosis and improved treatment of
pancreatic cancer. Their innovative research could lead to enormous clinical benefits for pancreatic cancer patients:

NFCR Center for Targeted Cancer Therapies
Daniel Von Hoff, M.D. and Laurence Hurley, Ph.D.
Translational Genomics Research Institute (TGen), Phoenix, AZ

NFCR Center for Targeted Cancer Th erapies (NCTCT) at TGen, Arizona, is dedicated to discovering novel and effective therapeutics to treat pancreatic cancer. Led by Center Directors Dr. Von Hoff and Dr. Hurley, researchers at NCTCT have been developing new therapies which block the growth of pancreatic cancer cells by interfering with pancreatic cancer-promoting molecules-an approach called targeted cancer therapy.

While traditional chemotherapeutic drugs function through impairing cell division in a general way, targeted therapies specifically kill cancer cells and leave normal cells unharmed, resulting in enhanced cancer-killing power with less side effects. As pancreatic cancer cells often become resistant to chemotherapy and radiation, targeted therapies may offer new treatment options to kill resistant cancer cells.

In the past few years, NCTCT has made enormous progress in developing new targeted therapies for pancreatic cancer. Researchers at the Center first demonstrated that pancreatic cancer cells produce an abnormally large amount of uPA, a protein that promotes tumor progression and invasion. Using uPA as the drug target, they further identified UK122, a compound that very potently inhibits uPA. When cultured pancreatic cancer cells were treated with UK122, their migration and invasion behaviors – characteristics of cancer cells – were significantly suppressed, suggesting that UK122 is an exciting potential drug candidate for targeted therapy.

Moreover, a computer-based chemical compound screening for more uPA inhibitors has been conducted jointly between NCTCT and the NFCR Center for Computational Drug Discovery at Oxford University. The successful collaboration between the two NFCR centers yielded a pool of over 900 compounds which are potential uPA inhibitors. Together with UK122, these new compounds will be further screened and optimized to generate potent drugs to combat pancreatic cancer.

NFCR Fellow Waun Ki Hong, M.D.
M.D. Anderson Medical Center, Houston, TX

Dr. Hong and his team of research are developing new drugs targeting another pancreatic cancer-promoting molecule, the hepatoma-derived growth factor (HDGF). The HDGF protein is overly expressed in a number of human cancers, including pancreatic and lung cancers. In fact, its overexpression in tumors is directly attributable to tumor progression, recurrence, and metastasis. Dr. Hong’s team has successfully developed monoclonal antibodies (mAbs) against HDGF. mAbs are a group of immune proteins that can accurately bind to their targets. When used as anti-cancer drugs, mAbs specifi cally block the function of the targeted cancer-related proteins, generating powerful anti-cancer effects.

Further research conducted by Dr. Hong’s team showed that the anti-HDGF mAbs were very effective in treating lung and pancreatic cancers in tumor models. Their work will soon be extended to clinical trials and may save more patients’ lives in the near future.

NFCR Project Director Jiayuh Lin, Ph.D.
Children’s Research Institute, Columbus, OH

Pancreatic cancer is often resistant to conventional treatments such as chemotherapy and radiation therapy. NFCR Project Director Dr. Jianyuh Lin is now developing new drugs that target pancreatic cancer-specific proteins, which may lead to more eff ective therapies to overcome drug resistance.

Dr. Lin has developed novel compounds that inhibit Stat3 activity in pancreatic cancer cells. Stat3 is frequently observed to be constantly activated in many types of cancer, including pancreatic cancer. Th e persistent “on” mode of Stat3 is critical for cancer cells to survive and also for them to become resistant to chemotherapy. The new compounds developed by Dr. Lin’s team, named LLL-3, LLL-7, and LLL-8, work by preventing two Stat3 molecules from pairing up with each other, a decisive step during Stat3 activation, making them very potent Stat3 inhibitors. Compared to other Stat3 inhibitors, these compounds have many distinct advantages: because they are not proteins, these compounds are not easily metabolized, which keeps them stable and produces long-lasting anti-cancer eff ects. In addition, they are very small, thus can easily enter the cells to find their targets. Preliminary work using these novel compounds on pancreatic cancer cell lines and tumor models has generated very encouraging results – they eff ectively inhibit Stat3 activity, and cause cancer cells to die quickly in the experimental models.

Because inhibition of Stat3 activity will make cancer cells sensitive to chemotherapy, Dr. Lin will combine these novel inhibitors with conventional chemotherapy agents, gemcitabine and oxaliplatin, to treat pancreaticcancer cells. This approach should maximize the therapeutic effects of chemotherapy, lower dosage of those cytotoxic agents, and reduce their harmful eff ects on normal cells. Dr. Lin’s NFCR-supported research will provide ample laboratory evidence that their newly developed Stat3 inhibitors may provide a promising treatment for pancreatic cancer patients, especially those whose cancer has become resistant to chemotherapy.

How You Can Help

These research projects hold great promise for yielding more effective therapies for pancreatic cancer. With more funding, however, they could ramp up their efforts and accelerate progress to save more lives! When you donate to NFCR, your dollars help our scientists accomplish many important research goals aimed at developing better cancer treatment and prevention strategies. Click here to learn more.

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