Inhibitors of Telomerase in treatment of pancreatic adenocarcinoma

Project Leaders: Michel Ouellette, Ph.D., Jerry Shay, Ph.D. (UT Southwestern Medical Center, Dallas, TX), and Jean Grem, M.D.

    Translational Goal: Evaluate the in vivo effects of a telomerase inhibitor, GRN163L alone and in combination with standard chemotherapy, on human metastatic pancreatic cancer cell lines. In a phase I/II trial, pancreatic cancer patients with locally advanced, unresectable, or metastatic disease will receive combined gemcitabine/erlotinib chemotherapy with prolonged exposure to GRN163L, and the safety and effects of GRN163L on survival and progression-free survival will be assessed.

Telomerase is the enzyme responsible for the maintenance of telomeres, structures that protect the ends of chromosomes. In cells that lack telomerase, telomeres shorten each time cells divide and this attrition limits cellular lifespan. Because they lack telomerase, most normal human cells senesce or die after a limited number of cell divisions. During cancer development, this limited lifespan poses an obstacle that the great majority of cancers overcome by mean of telomerase expression. Absent from most normal tissues, telomerase is present in more than 85% of all cases of cancer, including pancreatic adenocarcinomas. This has led to approaches for inhibiting telomerase as a target for cancer therapeutics. Our lead compound, GRN163L, is a lipid-conjugated oligonucleotide that binds the active center of telomerase. This project will conduct pre-clinical studies in mice orthotopically implanted with human pancreatic cancer cells followed by clinical trials in patients with advanced pancreatic cancer. In mice carrying pancreatic tumors, the preclinical experiments will evaluate the effectiveness of GRN163L alone and in combination with conventional chemotherapy. The knowledge gained from these studies will be used to conduct early stage clinical trials in patients with locally advanced, unresectable, or metastatic pancreatic cancer. In a phase I/II trial, patients on standard gemcitabine/erlotinib chemotherapy will be given prolonged exposures to GRN163L to assess the safety and efficacy of GRN163L. The primary endpoints will be telomerase inhibition, survival and progression-free survival. From patients that consent to participate in an ongoing rapid autopsy program, measurements of telomere size in tumors will also be obtained at time of death.

Michel M. Ouellette, Ph.D.
Michel M. Ouellette, Ph.D.
Associate Professor
Eppley Institute
mouellet@unmc.edu

Jean L. Grem, M.D.
Jean L. Grem, M.D.
Professor
UNMC Internal Medicine
Oncology/Hematology

Jerry Shay, Ph.D.
Jerry Shay, Ph.D.
Professor & Chair
UT Southwestern Medical Center
Dallas, Texas