New potential target for cancer therapy identified

In continuation of my update on telomerase...

Source: http://www.cell.com/cell-reports/retrieve/pii/S2211124713001186?_returnURL=http://linkinghub.elsevier.com/retrieve/pii/S2211124713001186?showall=true

The enzyme telomerase is overexpressed in almost all cancer cells, and previous research efforts have failed to identify good telomerase inhibitors. The study by Dr. Woodring Wright and UT Southwestern colleagues in the April 4 issue of Cell Reports identifies a new approach for inhibiting telomerase, which is an enzyme that drives uncontrolled division and replication of cancer cells.

Alternative splicing allows genetic information to be assembled in different ways and is almost always controlled by DNA sequences that are immediately adjacent to the parts of a gene that code for protein. "In the case of the telomerase gene, we found that these controlling regions are located very far from the protein coding regions and that they contain unusual DNA sequences," said Dr. Wright, professor of cell biology and internal medicine. "Their unusual DNA structure suggests that humans regulate telomerase in a very different fashion that we may be able to exploit to develop inhibitors of the enzyme."

Most of the splice variants that telomerase makes are inactive, but Dr. Wright's team demonstrated that it was possible to shift the splicing to make even less active telomerase, potentially providing a new approach for cancer therapy....

New potential target for cancer therapy identified

Novel technique reveals dynamics of telomere DNA structure: Chromosome-capping telomeres are a potential target for anti-cancer drugs

In continuation of my update on telomerase

"Most cancer cells use telomerase as one mechanism to maintain uncontrolled growth, so it is an important target for anti-cancer therapeutics," Stone said. "The G-quadruplex structures of telomere DNA inhibit the function of the telomerase enzyme, so we wanted to understand the mechanical stability of this structure."

Researchers used  "magnetic tweezers" system to stretch the DNA molecule, while a fluorescence microscopy technique was used to monitor small-scale structural changes in the DNA. 

"Unlike other DNA structures, the G-quadruplex structure is fairly brittle. It takes very little perturbation to make the whole thing fall apart," Stone said. "We also found that the unfolded state has a highly compacted conformation, which tells us that it still has interactions that favor the folding reaction."

These findings have implications for understanding the molecular mechanisms of telomere-associated proteins and enzymes involved in the unfolding reaction, as well as for rational design of anti-cancer drugs, Stone said. Small molecules that bind to and stabilize telomere DNA G-quadruplexes have shown promise as anti-cancer drugs.

The integration of fluorescence measurements and magnetic tweezers is a powerful method for monitoring DNA structural dynamics, and as biophysical techniques go, it is not hard to implement, Stone said. His lab worked with DNA molecules containing the G-quadruplex sequence from human telomere DNA, attaching one end of the DNA to a glass slide and the other end to a tiny magnetic bead. A magnet held above the sample pulled on the bead, exerting a stretching force on the DNA molecule that varied according to how close the magnet was to the sample.

Ref : http://nar.oxfordjournals.org/content/early/2013/01/08/nar.gks1341

Novel technique reveals dynamics of telomere DNA structure: Chromosome-capping telomeres are a potential target for anti-cancer drugs

Enzyme telomerase activating compound discovered....

In continuation of telomerase and its importance...

Sierra Sciences, in collaboration with TA Sciences, Geron Corporation, PhysioAge, and the Spanish National Cancer Research Center (CNIO), has announced the first compound ever discovered that activates the enzyme telomerase in the human body - a critical prerequisite for technology that could arrest or reverse the aging process in humans. This compound is a natural product derived nutraceutical known as TA-65.

TA-65, exclusively licensed to TA Sciences from Geron Corporation, is a >95% pure single chemical entity isolated from a proprietary extract of the dried root of Astragalus membranaceus and formulated into 5- to 10-mg capsules with inert excipients. Starting doses of 5–10 mg/day were considered safe on the basis of historical usage of extracts. Some subjects increased their dosage after several months on the product to 25–50 mg/day. Cumulative dose consumed during the year was recorded for each subject and used for preliminary dose–response analysis.

Researchers discovered that TA-65 was associated with a statistically significant "age-reversal" effect in the immune system, in that it led to declines in the percentage of senescent cytotoxic T cells and natural killer cells after six to twelve months of use. In addition, further analysis with automated high-throughput confocal microscopy (HT-qFISH) revealed a decline in the percentage of white blood cells with critically short telomeres after twelve to eighteen months of use.

Telomere shortening is thought to be the "clock of aging" contained within the human body. It has been repeatedly demonstrated that a human cell that does not undergo telomere shortening will divide indefinitely and is, by all available measurements, immortal.

Researchers reports that TA-65 can cause telomerase, an enzyme that lengthens telomeres, to become active in human cells.  Telomerase activation by TA-65 was shown to lengthen the shortest telomeres in humans, potentially extending human lifespan and healthspan. Telomerase activation is thought to be a keystone of future regenerative medicine and a necessary condition for clinical immortality. Although TA-65 is probably too weak to completely arrest the aging process, it is the first telomerase activator recognized as safe for human use.

"We are on the cusp of curing aging," said William Andrews, Ph.D., co-author of this study and President and CEO of Sierra Sciences, LLC. "TA-65 is going to go down in history as the first supplement you can take that doesn't merely extend your life a few years by improving your health, but actually affects the underlying mechanisms of aging. Better telomerase inducers will be developed in the coming years, but TA-65 is the first of a whole new family of telomerase-activating therapies that could eventually keep us young and healthy forever."

Telomerase activation has potential medical applications beyond extending human lifespan.  Epidemiological studies have shown that short telomeres in humans are a risk factor for diseases including, among others, atherosclerosis, diabetes, Alzheimer's, and cancer. The present study also reports encouraging news on the effect of TA-65 on the body's immune system. Infectious diseases lead to telomere shortening in the immune system, as immune cells divide to fight infections. Telomerase activation should prevent this telomere shortening and allow the body's immune system to fight a chronic infection indefinitely.

The present study on TA-65 lends support to this hypothesis. In individuals infected with CMV, a virus which prematurely ages the immune system and significantly reduces life expectancy, TA-65 caused an apparent "age reversal" of approximately 5 to 20 years based on one biomarker of immune aging. For the same reason, telomerase activation is a potential treatment for AIDS.

"We tend to see HIV turning into AIDS when the cells of the immune system develop critically short telomeres," said Andrews...

HIV can essentially cause the immune system to die of old age while the majority of the body is still young and therefore the researchers are hopeful that a telomerase activator could theoretically prevent an HIV-positive individual from ever developing AIDS....

Ref : http://www.liebertonline.com/doi/abs/10.1089/rej.2010.1085

Telomeres: Size matters when it comes to DNA

In continuation of my update on Telomerase and Telomerase inhibition....

Telomeres: Size matters when it comes to DNA

Imetelstat (GRN 163L) shows promising results against brain cancer glioblastoma and prostate cancer...

In continuation of my update on Telomerase inhibitors, I find this info really interesting and hence sharing here with. As mentioned in my earlier blog about imetelstat (GRN163L )  has been undergoing Phase I clinical trials designed to examine the safety, tolerability, pharmacokinetics and pharmacodynamics of the drug, alone or in combination, in solid tumors, chronic lymphoproliferative disease, multiple myeloma, lung and breast cancers and the company claims that Phase I objectives for imetelstat  (structure) have been achieved. Now  Dr. Jerry Shay, professor of cell biology of  The University of Texas Southwestern Medical Center at Dallas, claims that the same drug shows promise in fighting the brain cancer glioblastoma and prostate cancer.

Glioblastomas are the most common malignant brain tumors in adults, according to the American Cancer Society. They are difficult to treat with drugs because blood vessels in the brain have tightly constructed walls that allow only a few substances to pass through.

The researcher focused on cells called tumor-initiating cells. Some researchers believe that tumors contain a small subset of initiating cells – or cancer stem cells – that are able to initiate and drive tumors and that are often resistant to radiation therapy and chemotherapy.

In the glioblastoma study, Dr. Shay and his colleagues found that imetelstat blocked the action of telomerase in isolated tumor-initiating cells as well as the bulk of the tumor cells, eventually killing the cells. Combining imetelstat with radiation and a standard chemotherapy drug made imetelstat even more effective. When the researchers implanted human tumor-initiating cells into rodents, they found that imetelstat was able to enter brain tissue and inhibit telomerase activity.

In the prostate cancer study, the researchers isolated tumor-initiating cells from human prostate cancer cells. The cells showed significant telomerase activity. Imetelstat blocked the enzyme’s activity, and telomeres shortened greatly. As per Dr.Shay, since the drug attacks a mechanism that is active in most cancers, it might prove to be widely useful, especially when combined with other therapies.

Hope  Geron people must be really happy for these results  and conclusions.....

Ref : http://www.utsouthwestern.edu/utsw/cda/dept353744/files/570509.html

Telomerase & Telomerase inhibition.......

When I read about the Nobel prize in Medicine, was really excited because the scientists who discovered the enzyme telomerase got the Nobel prize for the year 2009 and the reason for this is simple and obvious....

When I was working with my previous company (Innovasynth Technologies Limited, Khopoli), I had opportunity to learn lots of things (from Dr. Sergei Gryaznov of Geron Corporation) about the drugs with Telomerase inhibition activity. As for as my knowledge goes, there are many companies working on these class of compounds and hope in the days to come there will be many drugs from this class of compounds and antisense drugs.

About Telomerase :

Telomerase, is an enzyme that adds specific DNA sequence repeats to the 3' end of DNA strands in the telomerase regions, which are found at the ends of eukaryotic chromosomes. The telomeres contain condensed DNA material, giving stability to the chromosomes. The enzyme is a reverse transcriptase that carries its own RNA molecule. Though the existence of a compensatory shortening of telomere (telomerase) mechanism, was first predicted by Soviet biologist Alexey Olovnikov (1973), who also suggested the Telomere hypothesis of ageing and the Telomere relations to cancer. Carol Greider and Elizabeth Blackburn in 1985, discovered telomerase together with Jack Szostak. Greider and Blackburn have been awarded the Nobel Prize in Physiology or Medicine. Congrats for this remarkable achievement.


Telomerase inhibitors :

To safeguard against cancer, adult cells keep track of how many times that they have multiplied, and once they have reached a pre-set limit — often around 80 divisions — they die. Telomerase interferes with this record keeping. So if one can find a drug or gene therapy that interferes with telomerase, it could fight the unchecked growth of cancer cells. As per the claim by lead researcher (Mark Muller), 90% all cancer cells are telomerase rich. Geron corporation, is developing modified DNA molecule (for which Innovasynth, has tie up with Geron to provide the intermediate amidites). The oligonucleotides, which target the template region, or active site, of telomerase. Geron's work has focused oligonucleotides (GRN163 and GRN163L,) and as per the claim by the company, both of them have demonstrated highly potent telomerase inhibitory activity at very low concentrations in biochemical assays, various cellular systems and animal studies. Interestingly these compounds are direct enzyme inhibitors, not antisense compounds and smaller than typical antisense compounds or other oligonucleotide drug candidates. Both compounds use a special thiophosphoramidate chemical backbone and the company is hopeful of convincing clinical trial results. All the best...

Ref : 1. http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html
2. http://www.geron.com/products/productinformation/cancerdrug.aspx