Telomerase inhibition may suggest new treatment for prostate cancer

In a recent paper (Int J Cancer, Nov. 11, 2009), Jerry W. Shay, PhD and colleagues reported results from a series of experiments showing that prostate cancer stem cells, which are considered to be tumor-initiating cells and responsible for relapsing disease, have short telomeres and are not quiescent. Instead, these prostate cancer stem cells exhibit robust telomerase activity that can be inhibited by imetelstat sodium (GRN163L), an investigational telomerase antagonist that is undergoing early-phase clinical testing for various other types of cancer.

"Our findings disprove current concepts that cancer stem cells are similar to normal stem cells in being quiescent and having long telomeres," said Dr. Shay, professor of cell biology at UT Southwestern. "Instead, it appears the prostate cancer stem cells resemble the main population of tumor cells with respect to these features. This is good news because it suggests that treatment with a telomerase inhibitor would be effective in specifically targeting both the bulk of the tumor cells and the rare subset of cancer stem cells that may be escaping conventional chemotherapy and do so with reduced risk of adversely affecting normal stem cells."

In their research, Dr. Shay and colleagues isolated the putative prostate cancer stem cells from three different prostate cancer cell lines (DU145, C4-2, and LNCaP) using three different techniques. Their methods for identification were based on features that have been previously reported in the literature as being characteristics of prostate cancer stem cells: presence of various cell surface markers (CD44, integrin α₂β₁, and CD133), Hoechst 33342 dye exclusion, and holoclone formation. Results from testing of the cells isolated by each of these methods were consistent in showing that the cells had short telomeres and high levels of telomerase activity that was inhibited by imetelstat.

"One caveat to our research is that we are relying on the accuracy of these previously described features for identifying prostate cancer stem cells," Dr. Shay told Urology Times.

Significant telomerase activity has been identified as one of the hallmark features of cancer cells. By acting to maintain telomere length, telomerase enables the continued division of cancer cells. Telomeres, which are specialized nucleoprotein complexes found as protective caps at the ends of linear chromosomes, normally shorten with each cell division. Once the telomeres shorten to a certain minimum length, a cell can no longer divide.

Interest in telomerase as an oncologic therapeutic target is a relatively new field, but one that Dr. Shay believes holds great promise and should be a focus for more intensive research.

Further studies forthcoming

Clinical trials investigating imetelstat in the treatment of nonsmall cell lung cancer, chronic lymphocytic leukemia, breast cancer, and multiple myeloma are currently ongoing or will start soon. The evidence that prostate cancer stem cells are sensitive to imetelstat suggests studies investigating this agent as adjuvant therapy in advanced prostate cancer are warranted, said Dr. Shay.

"Targeting telomerase simultaneously with standard chemotherapy should be additive if not synergistic, and in theory, by eliminating the population of tumor-initiating cells, should result in more durable responses," he said.

In collaboration with Kenneth Koeneman, MD, of the Center for Prostate Cancer at the University of Minnesota, Minneapolis, Dr. Shay has also achieved promising results combining imetelstat with docetaxel (Taxotere) in an animal model of metastatic prostate cancer (Prostate, Dec. 30, 2009).

Telomerase-based immunotherapy of prostate cancer introducing the RNA encoding the catalytic reverse transcriptase protein component of human telomerase into autologous dendritic cells has been studied in a cohort of men with evidence of biochemical recurrence after primary treatment, and this approach was shown to achieve stabilization of PSA.

"There are multiple challenges accompanying immunotherapy approaches to cancer treatment. Imetelstat is a small molecule that directly targets telomerase, and I believe it holds great promise for having added value in clinical care," Dr. Shay said.

Geron Corp. provided imetelstat for the research.