A difference between normal and cancer SC biology in the nervous system

Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition by Pedro Castelo-Branco and 12 co-authors, including Uri Tabori, Clin Cancer Res 2011(Jan 1); 17(1): 111-121 [Full text]. Translational Relevance:

Pediatric neural tumors (brain tumors and neuroblastoma) are the leading cause of morbidity and mortality in childhood cancer. This is due to their ability to recur after minimal disease is achieved. Telomerase is active in most malignant pediatric neural tumors. Therefore, telomerase inhibition may offer an effective treatment option for such patients. Because normal stem cells may require telomerase for continuous self-renewal, this therapy may have devastating effects on normal nervous system development and maintenance.

This study reveals that telomerase activation exists only in the tumor-initiating cancer subpopulation and is critical to sustain their survival and self-renewal potential. Importantly, normal neural or neural crest stem cells do not require telomerase for their self-renewal. Furthermore, as opposed to conventional chemoradiation therapies, telomerase inhibition results in irreversible loss of self-renewal capacity of tumor initiating cells in vitro and in vivo.

These observations uncover a difference between normal and cancer stem cell biology in the nervous system and suggest that telomerase inhibition may offer a specific and safe therapeutic approach for these devastating tumors.

For a commentary on this article, see: Anita B Hjelmeland and Jeremy N Rich, Clin Cancer Res 2011(Jan 1); 17(1): 3-5 (unlike the article, the commentary is not publicly accessible). Abstract:

Telomerase is an important mechanism by which cancers escape replicative senescence. In neural tumors, cancer stem cells express telomerase, suggesting that this may explain their preferential tumorigenesis. Oligonucleotide telomerase targeting selectively disrupts cancer stem cell growth through the induction of differentiation, adding to the armamentarium of anticancer stem cell therapies.

Prostate CSCs sensitive to gamma-tocotrienol?

Gamma-Tocotrienol Kills Prostate Cancer Stem Cells, PRNewswire, July 25, 2010. Excerpt:

The scientists found that low doses of gamma-tocotrienol cause apoptosis in the prostate cancer stem cells and suppress their colony formation capability. This results in a lower prostate cancer stem cell population (as defined by the protein markers CD133 and CD44). Further tests in mice models were conducted, where mice implanted with hormonal refractory prostate cancer cells were given gamma-tocotrienol orally. The results showed that gamma- tocotrienol not only reduced tumour size formed, but also decreased the incidence rate of tumour formation by 75%, as compared to the control group of mice, which had 100% tumour formation. These results strongly suggest that gamma-tocotrienol could be developed for prostate cancer prevention and treatment.

The news release by Davos Life Science is based on the publication:

Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population by Sze Ue Luk and 11 co-authors, including Ming-Tat Ling, Int J Cancer 2010(Jul 8) [Epub ahead of print][PubMed citation].

Comment:

See also a relevant patent application: (WO/2010/047663) Use of Tocotrienol Composition for the Prevention of Cancer.
Publication Date: 29.04.2010
Applicants: DAVOS LIFE SCIENCE PTE. LTD. [SG/SG]; 16 Tuas South Street 5 Singapore 637795 (SG) (All Except US).
LING, Ming Tat [CN/AU]; (AU) (US Only).
YAP, Wei Ney [MY/SG]; (SG) (US Only).
WONG, Yong Chuan [MY/CN]; (CN) (US Only).
YAP, Yee Leng, Daniel [MY/SG]; (SG) (US Only).

On CSC and therapeutic sensitivity studies

If cancer stem cells are resistant to current therapies, what’s next? by Paola Marcato‌, Cheryl A Dean‌, Carman A Giacomantonio‌ and Patrick WK Lee‌, Future Oncol 2009(Aug); 5(6): 747-50. [Twitter entry][FriendFeed entry][PubMed Citation]. Excerpts from the final portion of this Editorial:

Thus far, oncolytic viruses as a class of novel cancer therapeutics appear to kill CSCs with the same efficiency as non-CSCs [references]. Therefore, the characteristics that make CSCs resistant to current therapies do not limit the ability of the viral-based therapies to infect and kill these cells. Of further interest is the possibility of engineering oncolytic viruses to specifically kill tumor cells that express CSC markers.

We conclude that with increasing evidence that CSCs are potent initiators of cancer and have an intrinsic resistance to current therapies, scientists and clinicians will need to rethink traditional end points, such as tumor regression, as the major indicator of the efficacy of anticancer therapies, new and old.

Translation of knowledge about CSC into clinical use

Radiation Therapy Oncology Group Translational Research Program Stem Cell Symposium: Incorporating Stem Cell Hypotheses into Clinical Trials. Authors: Wendy A Woodward, Robert G Bristow, Michael F Clarke, Robert P Coppes, Massimo Cristofanilli, Dan G Duda, John R Fike, Dolores Hambardzumyan, Richard P Hill, Craig T Jordan, Luka Milas, Frank Pajonk, Walter J Curran, Adam P Dicker, Yuhchyau Chen. Int J Radiat Oncol Biol Phys 2009(Aug 1); 74(5): 1580-91 [Epub 2009(Jun 17)]. PubMed Abstract:

At a meeting of the Translation Research Program of the Radiation Therapy Oncology Group held in early 2008, attendees focused on updating the current state of knowledge in cancer stem cell research and discussing ways in which this knowledge can be translated into clinical use across all disease sites. This report summarizes the major topics discussed and the future directions that research should take. Major conclusions of the symposium were that the flow cytometry of multiple markers in fresh tissue would remain the standard technique of evaluating cancer-initiating cells and that surrogates need to be developed for both experimental and clinical use.

Grant system good at ruling out bad things?

Grant System Leads Cancer Researchers to Play It Safe, by Gina Kolata, The New York Times, June 27, 2009. [Page 1][Page 2][Page 3][FriendFeed entry].

Excerpts from Page 1:

Yet the fight against cancer is going slower than most had hoped, with only small changes in the death rate in the almost 40 years since it [the "war on cancer" initiated by President Nixon in 1971] began.

One major impediment, scientists agree, is the grant system itself. It has become a sort of jobs program, a way to keep research laboratories going year after year with the understanding that the focus will be on small projects unlikely to take significant steps toward curing cancer.

.....

Even top federal cancer officials say the system needs to be changed.

“We have a system that works over all pretty well, and is very good at ruling out bad things — we don’t fund bad research,” said Dr. Raynard S. Kington, acting director of the National Institutes of Health, which includes the cancer institute. “But given that, we also recognize that the system probably provides disincentives to funding really transformative research.”

Excerpt from Page 2:

“They said I don’t have preliminary results,” she said. “Of course I don’t. I need the grant money to get them.”

Excerpt from Page 3:

Some experienced scientists have found a way to offset the problem somewhat. They do chancy experiments by siphoning money from their grants.

Comment: The focus of the article is on the grant funding system for cancer research in the USA. The author, a well-known science journalist, is pessimistic about the success that the current funding system has had in yielding research outputs that have led to any substantial decrease in cancer mortality rates. However, other than briefly mentioning overall cancer mortality rates, she does not attempt to analyze current approaches to cancer control.

In Canada, age-standardized mortality rates, for all cancers and all age groups, have decreased from 248/100,000 in 1984 to 212/100,000 in 2004 (about 15%) for males. In contrast, the corresponding mortality rates for Canadian females were 152/100,000 in 1984 and 147/100,000 in 2004 (a decrease of only about 3%). A detailed analysis is beyond the scope of this brief commentary, but a major reason is that age-standardized mortality rates for respiratory cancers have been higher in males and have been decreasing, while they have been lower in females, and have been increasing.

It has been estimated that, in the USA, "reductions in lung cancer, resulting from reductions in tobacco smoking over the last half century, account for about 40% of the decrease in overall male cancer death rates" (Tobacco Control 2006; 15: 345-347; doi:10.1136/tc.2006.017749). Strong evidence that tobacco smoking and lung cancer rates are related has been available for more than 50 years, since the research work of Richard Doll and Austin Bradford Hill.

We now know a great deal about success stories and best practices for effective, evidence-based tobacco control programs. (See, for example, Success stories and lessons learnt, Tobacco Free Initiative (TFI), World Health Organization).

So, does research play a crucial role in cancer control? Of course it does.

Can it take a very long time for research outputs to have a substantial impact on cancer control? Unfortunately, it can.

Do we have good ways to identify, in advance, areas of transformative research? Unfortunately, no. It can even take a long time to demonstrate that certain research has, indeed, been transformative.

So, what to do? My answer: investment in research is much like investment of venture capital. Only a very small minority of investments yield a big payoff, but one can predict much more easily which investments are likely do badly than which ones are likely to do well.

Bright future for CSC therapies?

Opinion: A Stem of Hope for Cancer Treatments, Manish Singh, Genetic Engineering & Biotechnology News, June 12, 2009. Excerpts:

Three Attack Strategies
Investigations currently in progress target cancer stem cells using one of three approaches: small molecules, mAbs, or vaccines. Small molecule therapies work by perturbing the signaling pathway of cancer stem cells to put brakes on tumorogenesis. mAbs, on the other hand, are focused on recognizing certain markers that are highly expressed on CSCs but not on normal cells or normal stem cells. Lastly, active immunotherapy utilizes the native immune system to recognize and destroy cancer stem cells while leaving normal cells intact. While a few companies have been started de novo to focus on these programs, a number of existing compounds are also being tested for their effect on cancer stem cells.

.....

Our understanding of stem cells is in its infancy today, but there can be no doubt about their potential to solve some of the most complicated health problems in both regenerative medicine as well as cancer. Regenerative medicine is much more complicated due to several stages of development that the stem cells have to undergo to regenerate tissue. However, it may be easier to find therapeutic application in cancer, where the goal is to capture and destroy these tumor-initiating stem cells. Based on several encouraging clinical and preclinical studies combined with significant interest from large pharma to acquire these early-stage assets even before they enter the clinic, a bright future may be in store for cancer stem cell therapies.

Article in the San Francisco News

Stem-cell stalemate: The push for cures may produce only disappointment - or worse, Peter Jamison, San Francisco News, April 14, 2009. Excerpt from page 5:

And CIRM's 2009 funding priorities speak volumes about the direction of its decision-making. In its first two years of operating — legal challenges kept CIRM from starting its operations until 2007, setting back its sunset date to 2017 — the agency has distributed more than $600 million in grants for basic science and facilities. By contrast, the next round of grants will devote more than $200 million to disease teams; the goal for these teams is to prepare therapies for FDA clinical trials within four years. As little as $20 million will go to basic research.

Found via: The California Stem Cell Story: Safety, Waste and Promises, David Jensen, California Stem Cell Report, April 15, 2009.

On a shift in focus for CIRM

CIRM Close-Hauled, Seeks Bonds to Sustain Headway by Constance Holden, Science 2009(Mar 27); 323(5922): 1660-1 [PubMed Citation]. Excerpt:

A $210 million, 4-year program of "disease team grants," to be awarded this year, is the centerpiece of this thrust [toward support for translational research]. The program will entail perhaps 10 large grants to teams combining academic and industrial researchers working on a specific stem cell product for, say, Parkinson's disease. .....

Found via: Science Magazine on the State of CIRM, David Jensen, California Stem cell Report, March 27, 2009.

CIRM videos on YouTube

There's an Announcement, dated January 20, 2009, on the home page of the California Institute for Regenerative Medicine (CIRM), entitled: CIRMTV: CIRM videos now available on YouTube. The link leads to a Playlist of CIRM Video Stem Cell Basics. One of these, Therapies Based on Cancer Stem Cells (4:33 min), features Catriona Jamieson. It currently has a 5-star rating.

For an example of a news release about the work of her group, dated April 7, 2008, see: From Bench to Bedside in One Year: Stem Cell Research Leads to Potential New Therapy for Rare Blood Disorder by Debra Kain, University of California - San Diego News Center. The first sentence:

A unique partnership between industry and academia has led to human clinical trials of a new drug for a rare class of blood diseases called myeloproliferative disorders (MPD), which are all driven by the same genetic mutation and can evolve into leukemia.

This research was funded in part by a grant from CIRM.

Translational research for medical interventions

Tracking the lag between promise and payoff by Janet D. Stemwedel, Adventures in Ethics and Science, October 2, 2008. This blog post isn't about cancer stem cells, but is of interest because it's focus is on translational research for medical interventions. Excerpts:

One of the reasons non-scientists see science as at all valuable is that scientific research may result in useful medical treatments. And one of the aspects of science that seems elusive to non-scientists is just how long it can take scientific research to bring those useful medical treatments about.

.....

The time interval between the first report on preparation, isolation, or synthesis (or the earliest patent) and the highly cited articles reporting successful clinical interventions -- between the report of findings with clinical potential and the determination via clinical trials that that promise is realized in a treatment -- is the "translational lag". (There is, of course, another lag that's harder to quantify this way -- that between the initial findings in the research lab and the publication of those findings.)

Contopoulos-Ioannidis et al. found that the median translational lag for the highly cited article[s] in their study was 24 years. That's a long time.

The blog post is based on this article: Life Cycle of Translational Research for Medical Interventions, by Despina G. Contopoulos-Ioannidis, George A. Alexiou, Theodore C. Gouvias, John P. A. Ioannidis, Science 2008(Sep 5); 321(5894): 1298-9 [PubMed Citation]. The article isn't freely accessible, and has no abstract. The brief Summary:

From the initial discovery of a medical intervention to a highly cited article is a long road, and even this is not the end of the journey.

An excerpt from the final section of the full text:

The following are some recommendations for improving the system, based on our analyses:
• Discovery of new substances and interventions remains essential, but proper credit and incentives should be given to accelerate the testing of these applications in high-quality, unbiased clinical research and the replication of claims for effectiveness.
• Multidisciplinary collaboration with focused targets and involving both basic and clinical sciences should be encouraged.
• Proof of effectiveness for new interventions requires large, robust randomized clinical trials.
• Translational efforts for common diseases should focus more on novel agents and new cutting-edge technologies; for these ailments, it is unlikely that genuine major benefits from interventions already known for a long time have gone unnoticed.

Comments: Of the 32 interventions highlighted in this study, only two were cancer-related:

1) Levamisole (with Fluorouracil): Colon cancer

• Date of highly cited study: 1990
• Date of first description of intervention: 1966
• Report of first human use: 1977

2) Tamoxifen: Breast cancer prevention

• Date of highly cited study: 1998
• Date of first description of intervention: 1964
• Report of first human use: 1971

For cancer stem cells, what might be an important first intervention to be described? Proof that the eradication of cancer stem cells from a patient's tumor is therapeutic?

Perhaps a clinical demonstration that cancer stem cells can be used as a prognostic indicator of disease progression wouldn't be regarded as a "therapeutic intervention", but it's a key challenge for those doing research on cancer stem cells. See, for example, a review by Eric Lagasse, Gene Ther 2008(Jan); 15(2): 136-42 [PubMed Abstract]. Excerpt from the full text (not freely accessible):

[Remaining challenges] include the clinical demonstration that cancer stem cells can be used as a prognostic indicator of disease progression and proof that the eradication of cancer stem cells from a patient's tumor is therapeutic.