The Sol Goldman Pancreatic Cancer Research Center


Advances and Discoveries Made at Johns Hopkins


Early Results Using Therapeutic Pancreatic Cancer Vaccine Show Promise
Researchers in the Sol Goldman Pancreatic Cancer Research Center in the Johns Hopkins Kimmel Cancer Center are encouraged by early results of a treatment vaccine for pancreatic cancer. At about two years into a study of 60 patients, the researchers report that 88 percent survived one year and 76 percent are alive after two years.

"Even though our results are preliminary, the survival rates are an improvement over most published results of pancreatic cancer treatment studies," says Daniel Laheru, assistant professor at the Johns Hopkins Kimmel Cancer Center. Laheru is expected to present his findings in a press briefing at a joint meeting of the American Association for Cancer Research/National Cancer Institute/European Organization for Research and Treatment of Cancer in Philadelphia on November 15.

Until recently, most studies have shown pancreatic cancer survival rates at about 63 percent one year after diagnosis and 42 percent at two years. The long-term outlook is more grim - only 15 to 20 percent of patients with local disease are alive at five years. "Since there is no universal standard for treating pancreatic cancer, it is difficult to make direct comparisons between all the studies," says Laheru.

In the current study, his team combined an immune-boosting vaccine with surgery and conventional postoperative chemotherapy and radiation. The vaccine, originally developed at Johns Hopkins, uses irradiated pancreatic cancer cells incapable of growing, but genetically altered to secrete a molecule called GM-CSF. The molecule acts as a lure to attract immune system cells to the site of the tumor vaccine where they encounter antigens on the surface of the irradiated cells. Then, these newly armed immune cells patrol the rest of the patient's body to destroy remaining circulating pancreatic cancer cells with the same antigen profile.

Patients get one vaccine injection eight to ten weeks after surgery, then four booster shots after chemotherapy and radiation. Laheru and his team completed enrolling patients in the study this past January. The average follow-up time is 32 months.

Jaffee and Laheru hope to begin multi-institutional studies in about a year. They are working with Hopkins pathologists from the Sol Goldman Pancreatic Cancer Research Center to analyze proteins from pancreatic cancer cells that may help them refine the vaccine's targets.

Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, November 2005. (Abstract #2229, A Safety and Efficacy Trial of Lethally Irradiated Allogeneic Pancreatic Tumor Cells Transfected with the GM-CSF Gene in Combination with Adjuvant Chemoradiotherapy for the Treatment of Adenocarcinoma of the Pancreas).

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Reaction of the Normal Pancreas to an Adjacent Pancreatic Cancer Provides Clues about Tissue Invasion and Detection.
Two papers from the Hopkins group help define the genes that are expressed (made) in the tissues adjacent to pancreatic cancer. In the first paper by Ricci and colleagues, the technique of in situ hybridization was used to determine the genes that are turned on in the body's response (called a stromal reaction) to an infiltrating cancer (analogous to the body trying to heal a wound). Importantly, Dr. Ricci found that the genes that are made in this stromal response to an invasive pancreatic cancer are related to how aggressively the tumor invades the surrounding pancreas, and not to the underlying biology of the tumor. Understanding how pancreatic cancers invade the normal pancreas and spread to other organs is a critical step to understanding how to interfere with this process. In the second paper by Fukushima and colleagues, gene expression profiling was used to better understand the gene expression patterns of pancreatic tissue adjacent to infiltrating pancreatic cancers as compared to pancreatic tissue adjacent to chronic pancreatitis. Dr. Fukushima found 20 different genes were overexpressed in pancreatic tissue adjacent to an invasive cancer compared to normal pancreatic tissue adjacent to chronic pancreatitis. These results demonstrate that some of the molecular alterations in normal pancreatic tissues that occur in response to adjacent infiltrating pancreatic ductal adenocarcinoma can provide a rich source of markers for detecting pancreatic cancer.

Cancer Biol Ther. 4:302-7, 2005
Mod Pathol. 18; 779-87, 2005

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New Potential Target for Therapy:
Dr. Anirban Maitra and colleagues at Johns Hopkins have identified a genetic change in pancreatic cancers that has potential therapeutic implications. MTAP is a gene on chromosome 9 and novel chemotherapeutic strategies exploiting the selective loss of MTAP function in cancers have been proposed. The MTAP gene is adjacent to the p16 gene and MTAP and p16 are frequently deleted from the DNA of pancreatic cancers. Dr. Maitra has found these deletions of the MTAP and p16 genes in 30% of pancreatic cancers, suggesting that selected patients with pancreatic cancer may benefit from therapies targeting this loss. Studies are now underway in animal models to test this potential new treatment approach.

Cancer Biol Ther. 15:83-6, 2005

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Precursor Lesions of Pancreatic Cancer
Catching the Horse before It has Fled the barn

Three articles by Johns Hopkins scientists have expanded our knowledge of the precursor lesions which are thought to develop into invasive pancreatic cancers. Understanding the biology of these precursor lesions is of critical importance if we are to detect, and potentially treat, pancreatic cancer before it spreads. In the first article, Anirban Maitra and collegues comprehensively reviewed the various subtypes of precursor lesions that are known to progress to invasive pancreatic cancer. While Pancreatic Intraepithelial Neoplasia or "PanIN" is the prototype precursor lesion associated with the "usual" cancers (ductal adenocarcinomas), other larger precursor subtypes such as intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are being increasingly recognized with better imaging and screening techniques. The pancreatic cancers that arise in the context of these latter precursor lesions, particularly IPMNs, can have a different biology and outcome than the usual PanIN-associated invasive cancers. Therefore, it is important that pathologists who examine surgically removed pancreata are familiar with the histology of the various non-invasive precursors to invasive pancreatic cancers.

The second and third articles identify potential therapeutic targets in PanINs, the most common precursor lesion of pancreatic cancer. Inactivation of function of a critical gene that controls the cell cycle - p16 (CDKN2A) - is extremely frequent in invasive pancreatic cancers. In about a third of these cases, loss of p16 function occurs via deletion of both p16 gene copies (called "homozygous deletion" in genetic terminology) and is large enough to include a neighboring gene known as MTAP in the deletions. Complete loss of MTAP function can be exploited for therapy using drugs that selectively affects MTAP-negative pancreatic cancer cells without damage to normal tissues. Now, Dr. Hustinx and collegues have shown that even subsets of non-invasive precursor lesions (PanINs) harbor deletions of both copies of the MTAP gene. This is the first demonstration of a homozygous deletion in a PanIN lesion, and the authors have described a simple assay that will enable determining MTAP gene status in limited tissue materials, such as biopsy specimens. Why is this important? Compounds that selectively target MTAP-negative pancreatic cancers are already in clinical trials; if successful, one can envision extrapolating these trials to treat the precursors to invasive cancer before a cancer develops. The challenge will be in identifying patients with non-invasive, MTAP-negative precursor lesions who might potentially benefit from this therapy. With advances in molecular imaging and biopsy techniques, scientists are hopeful that this strategy will be actualized in the future.

In the third article, Dr. Prasad and colleagues performed the first large scale gene expression profiling of PanIN lesions using "gene chips". Johns Hopkins scientists were one of the first to comprehensively determine the gene expression profile of invasive pancreatic cancer, and the group at Hopkins has now extended this knowledge to precursor lesions as well. In order to isolate these tiny ductal lesions from surrounding normal tissues, the scientists used a technique called "laser capture microdissection". They found 49 genes that were expressed differentially compared to normal ductal epithelium. Of note, they found many of the overexpressed genes in PanINs are normally turned on by activation of the sonic hedgehog pathway during development, thereby confirming that abnormal activation of this pathway plays a role in both early and advanced pancreatic cancers. Hopkins scientists had previously demonstrated that the sonic hedgehog pathway is a powerful therapeutic target in invasive pancreatic cancers, and this current work provides rationale for investigating this line of therapy in the prevention of pancreatic cancers as well.

Why is this important to me? The studies of the MTAP gene are important because compounds that selectively target MTAP-negative pancreatic cancers are already in clinical trials; if successful, one can envision extrapolating these trials to treat the precursors to invasive cancer before a cancer develops. The challenge will be in identifying patients with non-invasive, MTAP-negative precursor lesions who might potentially benefit from this therapy. With advances in molecular imaging and biopsy techniques, scientists are hopeful that this strategy will be actualized in the future.

Adv Anat Pathol. 2005 Mar;12(2):81-91. PMID: 15731576
Mod Pathol. 2005 Jul;18(7):959-63. PMID: 15832197
Cancer Res. 2005 Mar 1;65(5):1619-26. PMID: 15753353

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