Potential for Telomeres, Telomerase as Therapeutic, Prevention Targets

Joint ASCO/AACR session highlights research opportunities for this nonredundant pathway

There is a growing body of research surrounding telomeres — the protective ends of chromosomes that prevent their degradation — and their relationship to cancer development and prevention.

In yesterday’s Special Session “ASCO/American Association for Cancer Research (AACR) Joint Session: Telomeres and Telomerase in Cancer,” researchers discussed the progress of both basic science and clinical efforts with this novel target for cancer therapy.

Immediate Past President George W. Sledge Jr., MD, of the Indiana University Melvin and Bren Simon Cancer Center, co-chaired the session with Elizabeth Blackburn, PhD, of the University of California, San Francisco. Dr. Blackburn was a co-recipient of the 2009 Nobel Prize in Physiology or Medicine for the discovery of telomeres and the enzyme telomerase.

“The general idea about telomeres is that if they erode away, then cells will no longer be able to live,” Dr. Blackburn said.

If telomeres grow too short they can no longer protect the chromosomes; the enzyme telomerase functions to maintain appropriate telomere length by replenishing the DNA at chromosome ends that are continuously being eroded. There has been substantial research showing that such shortened telomeres are associated with a number of diseases, including cancer, cirrhosis, and diabetes.

“Telomerase is highly active in the vast majority — particularly the common epithelial types — of human tumors,” Dr. Blackburn said. It was initially hypothesized, then, that inhibition of telomerase would eventually shorten telomeres over many cell division cycles, leading to cell senescence.

Research indicated, however, that inhibition of the enzyme in cancer cells rapidly inhibited cell growth, much faster than would be expected if the model of cell division was correct. Dr. Blackburn said that instead there appears to be a rapid down-regulation of cell cycle and tumor progression genes, including those involved with glucose metabolism.

Potential Causes of Telomere Shortening Though the mechanisms are still being investigated, evidence that links telomere shortness to cancer development continues to build.

One study in 2010 showed a relationship between telomere shortness and both cancer incidence and mortality among 787 participants.

There is also a growing understanding of what might result in shortened telomeres; several studies have indicated that chronic stress could play a role, and there are even correlations between level of education attained and telomere length. Additionally, exposure to multiple traumatic events during childhood has been shown to correlate with shorter telomeres.

“Also, telomere shortness is clearly related to a couple of significant inflammation markers, particularly IL-6 and TNF-alpha,” Dr. Blackburn said. The causative direction of this correlation and subsequent correlations with disease, however, is still not fully understood.

The shorter telomeres could result from inflammation and stress, and then lead to cancer and other diseases, or the inflammation could cause disease more directly, which then feeds back and causes shorter telomeres.

Steven Artandi, MD, PhD, of Stanford University School of Medicine, discussed some of the underlying biologic mechanisms that appear to connect telomeres, telomerase, and cancer, particularly in the Wnt signaling pathway.

Dr. Artandi described how the introduction of TERT, the protein subunit of telomerase, into normal cells can reconstitute telomerase.

“So just one simple genetic switch can take a mortal human cell and render it immortal,” he said.

Notably, some research has indicated that inhibiting telomerase in cancer cells down to the 10% to 25% range may be adequate to impair that immortal self-renewal process.

Dr. Artandi described how the TERT protein appears to be involved tightly with the important Wnt signaling pathway.

Inherent in those interactions, he said, is the possibility that inhibiting telomerase in certain ways could achieve an acute response in tumor cells rather than a delayed response over many cell divisions.

Trials of Vaccines and Direct Inhibition Kathy D. Miller, MD, of Indiana University Melvin and Bren Simon Cancer Center, spoke about progress in taking some of this basic science research and moving it into clinical settings. Telomerase has a number of factors making it an attractive target in cancer therapy.

“It is, one could argue, the most common tumor-associated gene, and it is also generally nonredundant,” Dr. Miller said. “So, while we might think of multiple oncogenes that might drive proliferation, and inhibiting one might have a transient effect… there are relatively few other ways of maintaining the function and integrity of telomeres, making this nonredundant pathway potentially very fruitful.”

There are some drawbacks to telomerase as a target, as well: there is potential toxicity to normal stem cells as well as to the desired target of cancer stem cells, and though as Dr. Artandi suggested there may be ways around this, there is also a phenotypic lag involved with waiting for cell division to bring down telomere length.

“While basic scientists are quite happy passing their tumor cells until they reach that short length, those of us who deal with patients in the clinic call phenotypic lag disease progression,” Dr. Miller said.

There has been some clinical study of a vaccine model used to target telomerase. The TERT peptide vaccine known as GV1001 showed promise in a phase I/II study of patients with unresectable pancreas cancer, and as a result went on to a phase III trial comparing the vaccine with gemcitabine. The trial was stopped early, however, after an analysis indicated significantly greater overall survival and progression-free survival in the patients being treated with gemcitabine.

Another attempt known as GRNVAC1 tested a telomerase vaccine attained through leukapheresis harvesting and introduction of TERT mRNA in adult patients with acute myelogenous leukemia. A total of 55% of vaccinated patients showed some immune response.

Other clinical options include direct inhibition of telomerase activity, such as with a modified DNA oligonucleotide known as imetelstat.

The compound was able to inhibit telomerase activity in breast cancer cells, and subsequently reduced tumor volume, leading to a series of phase I and II trials in breast and non-small cell lung cancer. Phase II studies are ongoing.

According to Dr. Miller, patient selection is a challenge in this field. Choosing slower growing tumors may present the best opportunities given the phenotypic lag inherent with telomerase-targeting therapies.

“At this point I have to conclude that the opportunities are much bigger than the challenges,” Dr. Miller said, adding that even with the limited clinical data to date, they are still quite encouraging. “And it just strikes me as such an unlikely paradox that something that is a biologic imperative would be therapeutically irrelevant.”