Sunday, June 28, 2009

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.

Thursday, June 25, 2009

A review of the CSC paradigm

Controversial Cancer Stem Cells Offer New Direction For Treatment, ScienceDaily, June 25, 2009. [FriendFeed entry]. First paragraph:
In a review in Science, a University of Rochester Medical Center researcher sorts out the controversy and promise around a dangerous subtype of cancer cells, known as cancer stem cells, which seem capable of resisting many modern treatments.
Based on this review: The Increasing Complexity of the Cancer Stem Cell Paradigm by Jeffrey M Rosen and Craig T Jordan, Science 2009(Jun 26); 324(5935): 1670-3. First paragraph:
The investigation and study of cancer stem cells (CSCs) have received enormous attention over the past 5 to 10 years but remain topics of considerable controversy. Opinions about the validity of the CSC hypothesis, the biological properties of CSCs, and the relevance of CSCs to cancer therapy differ widely. In the following commentary, we discuss the nature of the debate, the parameters by which CSCs can or cannot be defined, and the identification of new potential therapeutic targets elucidated by considering cancer as a problem in stem cell biology.

Chief Scientific Officer leaving CIRM

Chief Scientific Officer Leaving California Institute of Regenerative Medicine by Monya Baker, The Niche, June 25, 2009. Excerpt:
Marie Csete will resign her post from the California Institute of Regenerative Medicine as of Aug 1st, according to the California Stem Cell Report, Consumer Watchdog and the Silicon Valley Business Journal. The resignation comes just before a huge round of grants aiming to push stem cells toward clinical trials is due to be awarded.
From the Silicon Valley Business Journal: State stem cell agency’s science officer to resign by Ron Leuty, June 24, 2009. Excerpt:
Csete has been an important part of CIRM’s effort to not only review and award grants but, highlighted most recently, to monitor grants after awards have been made. CIRM terminated three research grants this month due to lack of progress.
From the California Stem cell Report: Csete Quits CIRM on Eve of Huge Grant Round by David Jensen, June 24, 2009. Excerpt:
Csete's departure comes as the agency is about to embark on its most ambitious and largest round of research grants – a complex, $210 million “disease team” effort aimed at pushing research towards clinical trials.

Wednesday, June 24, 2009

Hypoxic responses in glioma stem cells

Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells by Zhizhong Li and 11 co-authors, including Jeremy N Rich, Cancer Cell 2009(Jun 2); 15(6): 501-13 [FriendFeed entry] PubMed Abstract:
Glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs). Because hypoxia regulates angiogenesis, we examined hypoxic responses in GSCs. We now demonstrate that hypoxia-inducible factor HIF2alpha and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to non-stem tumor cells and normal neural progenitors. In tumor specimens, HIF2alpha colocalizes with cancer stem cell markers. Targeting HIFs in GSCs inhibits self-renewal, proliferation, and survival in vitro, and attenuates tumor initiation potential of GSCs in vivo. Analysis of a molecular database reveals that HIF2A expression correlates with poor glioma patient survival. Our results demonstrate that GSCs differentially respond to hypoxia with distinct HIF induction patterns, and HIF2alpha might represent a promising target for antiglioblastoma therapies.

Monday, June 22, 2009

About CD133 as a marker for CSC

CD133 as a marker for cancer stem cells: progresses and concerns by Yaojiong Wu, Philip Yuguang Wu, Stem Cells Dev 2009(May 2) [Epub ahead of print][ResearchGATE entry][FriendFeed entry] PubMed Abstract:
Increasing evidence supports the cancer stem cell hypothesis, which postulates that cancer stem cells are responsible for tumor initiation, metastasis and resistance to treatments. Therefore, they are the cells to target to cure a cancer. To study the behavior of cancer stem cells, markers for prospective isolation of cancer stem cells are crucial. Recently, CD133 has been used extensively as a marker for the identification of stem cells from normal and cancerous tissues. Several more recent studies, however, indicate that CD133 are expressed in differentiated epithelial cells in various organs, and CD133-negative cancer cells can also initiate tumors. The findings suggest that CD133 is not restricted to somatic stem cells and cancer stem cells. However, in many cases CD133 may be used in combination with other markers or methods to acquire stem cells. In this review, we summarize findings in CD133 expression in various tissues and critically discuss its applications in stem cell isolation.

Saturday, June 20, 2009

CSC and radiotherapy

Cancer stem cells and radiotherapy by Michael Baumann and 4 co-authors, Int J Radiat Biol 2009(May); 85(5): 391-402 [PubMed Citation][Full text is publicly accessible (via Gratis OA)][Found via ResearchGATE, see: publication link].

In this review, the authors question the interpretation of data in a much-cited article by Shideng Bao and 8 co-authors, including Jeremy N Rich, entitled: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response, Nature 2006(Dec 7); 444(7120): 756-60 [Epub 2006 Oct 18][PubMed Citation][Full text PDF is publicly accessible (via Gratis OA)][Another publicly accessible version].

Excerpt from the review by Baumann et al. 2009:
However, interpretation of these data [of Boa et al] is limited by several factors including the fact that enrichment of CD133+ cells after irradiation may possibly reflect differences in proliferative capability rather than differences in radiosensitivity, and that the irradiation dose of 2 Gy might not be sufficient to generate detectable differences in the transplantation assay used (Baumann et al. 2008).
[PubMed Citation for the reference to Baumann et al. 2008].

Another excerpt from Baumann et al. 2009:
In summary, a higher radioresistance of cancer stem cells compared to non-stem cells has not been proven. More experiments, comparing the results of surface-marker based quantitative transplantation assays with and without irradiation after different doses in different tumours, are necessary before firm conclusions on the radioresistance of cancer stem cells can be drawn.
Comment: The intrinsic radiosensitivity of cancer stem cells compared to non-stem cells is, from the perspective of radiation oncology, an important issue that has been investigated for many years. Some of this history is reviewed by Baumann et al. 2009. The issue needs to be resolved.

Wednesday, June 17, 2009

Malignant Pleural Effusions (MPE) as a model

Researchers Develop Model that May Help Identify Lung Cancer Stem Cells, News Release, UCLA Jonsson Comprehensive Cancer Center, June 16, 2009. First paragraph:
Researchers at UCLA’s Jonsson Comprehensive Cancer Center, on a quest to find lung cancer stem cells, have developed a unique model to allow further investigation into the cells that many believe may be at the root of all lung cancers.
See also: Researchers Use Malignant Pleural Effusion as Model for Lung Cancer, Genetic Engineering & Biotechnology News, June 16, 2009.

Based on: The Malignant Pleural Effusion as a Model to Investigate Intratumoral Heterogeneity in Lung Cancer by Saroj K Basak and 7 co-authors, including Raj K Batra, PLoS ONE 2009(Jun 12); 4(6): e5884 [Entry in FriendFeed]. Abstract:
Malignant Pleural Effusions (MPE) may be useful as a model to study hierarchical progression of cancer and/or intratumoral heterogeneity. To strengthen the rationale for developing the MPE-model for these purposes, we set out to find evidence for the presence of cancer stem cells (CSC) in MPE and demonstrate an ability to sustain intratumoral heterogeneity in MPE-primary cultures. Our studies show that candidate lung CSC-expression signatures (PTEN, OCT4, hTERT, Bmi1, EZH2 and SUZ12) are evident in cell pellets isolated from MPE, and MPE-cytopathology also labels candidate-CSC (CD44, cMET, MDR-1, ALDH) subpopulations. Moreover, in primary cultures that use MPE as the source of both tumor cells and the tumor microenvironment (TME), candidate CSC are maintained over time. This allows us to live-sort candidate CSC-fractions from the MPE-tumor mix on the basis of surface markers (CD44, c-MET, uPAR, MDR-1) or differences in xenobiotic metabolism (ALDH). Thus, MPE-primary cultures provide an avenue to extract candidate CSC populations from individual (isogenic) MPE-tumors. This will allow us to test whether these cells can be discriminated in functional bioassays. Tumor heterogeneity in MPE-primary cultures is evidenced by variable immunolabeling, differences in colony-morphology, and differences in proliferation rates of cell subpopulations. Collectively, these data justify the ongoing development of the MPE-model for the investigation of intratumoral heterogeneity, tumor-TME interactions, and phenotypic validation of candidate lung CSC, in addition to providing direction for the pre-clinical development of rational therapeutics.

Tuesday, June 16, 2009

Presentation on miRNA replacement therapy

Mirna Therapeutics Presents Data at Keystone Symposium on MicroRNA and Cancer, Business Wire, June 15, 2009 [Entry in FriendFeed]. Excerpt:
The expression of miR-34 is reduced in a variety of cancers as well as in cancer stem cells, suggesting that miR-Rx34 may have broad applicability as an anti-cancer agent in miRNA replacement strategies.

Monday, June 15, 2009

About promyelocytic leukaemia protein (PML)

Stemming out of a new PML era? A review by Paolo Salomoni, Cell Death Differ 2009(Jun 12) [Epub ahead of print][Entry in FriendFeed] PubMed Abstract:
The promyelocytic leukaemia protein PML is a growth and tumour suppressor inactivated in acute promyelocytic leukaemia (APL). Recent evidence indicates that PML plays a tumour-suppressive role in cancer of multiple histological origins. However, it is only very recently that PML growth-suppressive functions have been implicated in regulating physiological processes and tissue homoeostasis. In particular, it has been shown that PML is one of the key cell-cycle regulators controlling stem cell function in multiple tissues, from the blood to the brain. As a consequence, PML loss has an impact on tissue development and maintenance of stem cell pools. In addition, new data suggest that PML regulates self-renewal in cancer stem cells. Finally, the oncogenic fusion protein PML/RARalpha, contrary to the conventional view, appears to hijack growth-suppressive pathways to promote transformation of haematopoietic stem cells and to maintain the APL stem cell niche. Overall, these findings not only represent a change in paradigm in the field of PML/APL research, but also contribute to the understanding of fundamental mechanisms underlying stem cell function in vivo. The main objective of this review is to critically discuss the very recent literature on the role of PML in stem cells and tumour-initiating cells. Ultimately, it aims to propose new avenues of investigation.Cell Death and Differentiation advance online publication, 12 June 2009; doi:10.1038/cdd.2009.63.

MicroRNAs play roles in glioma stem-like cell behavior?

A review: MicroRNAs and glioblastoma; the stem cell connection by Jakub Godlewski and 4 co-authors, including Sean E Lawler, Cell Death Differ 2009(Jun 12) [Epub ahead of print][Entry in FriendFeed] PubMed Abstract:
Recent data draw close parallels between cancer, including glial brain tumors, and the biology of stem and progenitor cells. At the same time, it has become clear that one of the major roles that microRNAs play is in the regulation of stem cell biology, differentiation, and cell 'identity'. For example, microRNAs have been increasingly implicated in the regulation of neural differentiation. Interestingly, initial studies in the incurable brain tumor glioblastoma multiforme strongly suggest that microRNAs involved in neural development play a role in this disease. This encourages the idea that certain miRs allow continued tumor growth through the suppression of differentiation and the maintenance of the stem cell-like properties of tumor cells. These concepts will be explored in this article.Cell Death and Differentiation advance online publication, 12 June 2009; doi:10.1038/cdd.2009.71.

Sunday, June 14, 2009

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.

Microtubule-associated kinase DCAMKL-1 a novel target for anti-CSC-based strategies?

Scientists discover stem cell protein linked to cancer growth, Kerentech, May 23, 2009. Excerpt:
Researchers have studied stem cell proteins for years, but Houchen and Anant said they not only found a new cancer protein, but discovered how the protein works to turn off a natural tumor suppressor and turn on a cancer-causing gene.
The results of their research will be published in an upcoming issue of the journal Gastroenterology.
See also: Scientists Discover How Cancer Protein Works, News release, OU Cancer Institute. Excerpt:
The latest work involves a new stem cell protein. Houchen and Anant discovered that this protein was responsible for regulating a natural tumor suppressor. It is the first such evidence of a stem cell protein regulating a tumor suppressor. When the protein, which is found in cancer, was increased, it caused the tumor suppressor to go down and the tumor grew in research models. When the protein was reduced or "knocked down," the level of tumor suppressor went up and the tumor stopped growing. Scientists also found that when they stopped the protein, the expression of a cancer-causing gene also went down.
The relevant publication is: Selective Blockade of DCAMKL-1 Results in Tumor Growth Arrest by a Let-7a MicroRNA-Dependent Mechanism by Sripathi M Sureban and 6 co-authors, including Shrikant Anant and Courtney W Houchen, Gastroenterology 2009(May 12) [PubMed Citation].

Another related publication from this group: Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice by Randal May and 5 co-authors, Stem Cells 2008(Mar); 26(3): 630-7 [Epub 2007 Nov 29]. [PubMed Citation][Full text is publicly accessible (via Gratis OA)].

Wednesday, June 10, 2009

Combined treatment to eliminate CSC in pancreatic cancer

Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer by Maria-Theresa Mueller and 13 co-authors, including Christopher Heeschen, Gastroenterology 2009(Jun 4). PubMed Abstract:
BACKGROUND & AIMS:: Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSC), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mTOR, respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities. METHODS:: We used in vitro and in vivo models of pancreatic cancer to examine the effects of a sonic hedgehog inhibition (cyclopamine / CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population. RESULTS:: Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSC to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival. CONCLUSIONS:: The combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSC. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.
[Thanks to Alexey Bersenev].

Monday, June 8, 2009

Specific target gene found using CML mouse model

Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia by Yaoyu Chen, Yiguo Hu, Haojian Zhang, Cong Peng, Shaoguang Li, Nature Genetics 2009(June 7).

For a news release about this article, see: A lethal cancer knocked down by one-two drug punch, Genetic Engineering & Biotechnology News, June 7, 2009. Excerpts:
The researchers found that CML did not develop in mice without Alox5 because of impaired function of leukemia stem cells. Also, Alox5 deficiency did not affect normal stem cell function, providing the first clear differentiation between normal and cancer stem cells.
[Shaoguang] Li also treated mice with CML with Zileuton, an asthma medication that inhibits the Alox5 inflammation pathway, as well imatinib, commonly known as Gleevec, the most effective current leukemia medication. Imatinib effectively treated CML, but Zileuton was more effective. The two drugs combined provided an even better therapeutic effect.

[Thanks to Alexey Bersenov].

Saturday, June 6, 2009

Updates sent to Twitter, May 31-June 6

Updates about CSC sent to Twitter during May 31-June 6:

About a Phase I clinical trial of ICT-107, a dendritic cell-based vaccine for glioblastoma (ASCO Abst#2032) [June 5]:

Glioma Stem Cells: Better Flat Than Round: - about Cell Stem Cell 2009(June 5;4(6):568-80 [June 4]:

[See also: Cancer stem cell studies could open the door to personalized, targeted treatments for brain cancers, News release, The Hospital for Sick Children, June 4, 2009].

Most Common Brain Cancer May Originate In Neural Stem Cells: - based on (PubMed citation) [June 2]:
[PubMed Citation].

Targeting breast cancer stem cells in mice: - based on (OA full text) [June 2]:
[Full text is publicly accessible (via Libre OA)].

Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells, Cancer Cell 2009(Jun 2) [June 1]:
[PubMed Citation].