Asthma Drug Shows Promise in Pancreatic Cancer

HOUSTON, Dec. 19 -- Cromolyn, an old-line asthma and allergy drug, has shown a marked effect on the progress of pancreatic cancer -- at least in mice.

In several experiments reported in the Dec. 20 issue of the Journal of the National Cancer Institute, Craig Logsdon, Ph.D., of the M.D. Anderson Cancer Center here, and colleagues, found that:

• Cromolyn binds to S100P, a protein that is over-expressed in pancreatic cancer and is associated with tumor growth and invasion.
• S100P itself binds to the receptor for advanced glycation end-products (or RAGE) to initiate downstream signaling that leads to tumor growth. The researchers showed that cromolyn blocks that interaction in vitro.
• In mice with tumors that express S100P, the medication, in combination with the standard chemotherapy for pancreatic cancer, Gemzar (gemcitabine), sharply reduced tumor growth.
• Finally, in tumors that do not express S100P, cromolyn had no effect.

Dr. Logsdon and his colleagues had previously shown that the S100P-RAGE interaction is key to the aggressiveness of pancreatic cancers, which have a five-year survival rate of less than 5% and which kill 95% of patients within six months of diagnosis.

"S100P plays a role in tumor development because it causes cancer cells to grow faster, survive better, and be more invasive," Dr. Logsdon said, and when the protein is disabled, using genetic techniques, cancer growth is slowed. On the other hand, the researchers previously showed, if the RAGE protein is inactivated, the addition of synthetic S100P has no effect on tumor growth.

Because cromolyn had been shown by Japanese researchers to bind to other members of S100 family, Dr. Logsdon and colleagues decided to see whether it would play any role in mice, whose pancreatic tumors had been genetically engineered by express a luminescent reporter gene. Two of the tumor lines they investigated over-expressed S100P, while the third did not.

Twenty mice with each cell line were divided into four groups - controls, those treated with cromolyn alone, those treated with Gemzar alone, and those treated with the combination.

In the two cell lines expressing S100P, Dr. Logsdon and colleagues said, Gemzar singly had significant effects on tumor growth (as measured by weekly bioluminesence imaging) at P=0.013 and P<0.001, respectively, compared to controls. The reduction amounted to about 50% in each case, Dr. Logsdon said.

At the same time, cromolyn alone had a similar but slightly greater effect, he said, reducing tumor growth by about 70%, compared to controls. The differences were again significant at P<0.001 and P=0.009.

However, the combination of the two medications dramatically increased the effect. Compared to controls, the combination reduced tumor burden by 89% in one cell line and 82% in the other, the researchers found.

In contrast, although Gemzar slowed tumor progression in the mice whose cancers did not express S100P, cromolyn had no effect, either alone or in combination with Gemzar.

"Cromolyn seems to reduce survival mechanisms in pancreatic cancer cells enough that when gemcitabine is added, the chemotherapy is more effective," Dr. Logsdon said. "This is good, because chemotherapy normally has very little effect in patients."

Indeed, there is no effective therapy for pancreatic cancer except early resection, which is only possible in a small minority of patients, he said, so that the finding opens the possibility of better therapies - a possibility that he and colleagues are planning to test in a clinical trial.

"For me this is pretty thrilling," he said. "In a relatively short time, we have gone all the way from discovering a molecule to preparations for a clinical trial."