Mouse Study Shows Some Pancreatic Cancers Susceptible to New Drug Treatment

Initial findings suggest that an aggressive form of pancreatic cancer may be susceptible to treatment with drugs that block the activity of the protein encoded by the SPINK1 (serine peptidase inhibitor, Kazal type 1) gene.

The protein encoded by this gene - present in about 10% of pancreatic tumors - is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis.

Investigators at the University of Michigan (Ann Arbor, USA) worked with cultures of different pancreatic cancer cell lines and with mice that had received grafts of human pancreatic cancer cells.

They reported in the March 2, 2011, issue of the journal Science Translational Medicine that recombinant SPINK1 protein (rSPINK1) stimulated cell proliferation of benign RWPE cells as well as of cancerous prostate cells. RWPE cells treated with either rSPINK1 or conditioned medium from 22RV1 prostate cancer cells significantly increased cell invasion and intravasation when compared with untreated cells.

In contrast, knockdown of SPINK1 in 22RV1 cells inhibited cell proliferation, cell invasion, and tumor growth in xenograft assays. Furthermore, 22RV1 cell proliferation, invasion, and intravasation were attenuated by a monoclonal antibody (mAb) to SPINK1.

The investigators found that SPINK1 activity required binding to the epidermal growth factor receptor (EGFR). Therefore, they examined the effect of the EGFR inhibitor cetuximab on pancreatic cancer cell cultures and xenografts. They found that while cetuximab shrank tumors by 40%, the monoclonal antibody against SPINK1 shrank them by 60%. Tumors treated with a combination of the two drugs, reduced the size of tumors by 74%. The inhibitory effect was seen only in tumors that expressed SPINK1, and was not seen in tumors that did not express SPINK1.

"Since SPINK1 can be made on the surface of cells, it attracted our attention as a therapeutic target. Here we show that a "blocking” antibody to SPINK1 could slow the growth of prostate tumors in mice that were positive for the SPINK protein,” said senior author Dr. Arul Chinnaiyan, professor of pathology at the University of Michigan.

SPINK1 can be detected in the urine of prostate cancer patients. "This noninvasive form of screening could be helpful in the molecular categorization of prostate cancer patients and administering therapies in a molecularly guided fashion,” said Dr. Chinnaiyan.

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