Diabetes drug metformin appears to target breast CSC

Diabetes Drug Metformin Shows Promise as a Breast Cancer Treatment, NCI Cancer Bulletin 2009(Sep 22); 6(18). First two paragraphs:

Low doses of the commonly used diabetes drug metformin may be an effective treatment for breast cancer, primarily because the drug appears to target breast cancer stem cells, Harvard Medical School researchers reported online September 14 in Cancer Research. Cancer stem cells, also called tumor-initiating cells, are thought to be relatively rare cells that can give rise to new tumors and are resistant to standard cancer treatments.

In the study, the combination of metformin and the chemotherapy agent doxorubicin was more effective than either drug alone at eliminating cancer cells and cancer stem cells in cultured cell lines of four genetically distinct breast cancer types, including HER2-positive and triple-negative breast cancers. In a breast cancer mouse model, the drug combination eliminated tumors and prevented regrowth, whereas doxorubicin alone only reduced tumor size and did not prevent regrowth, and metformin alone had little effect.

This bulletin is about the publication: Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission by Heather A Hirsch, Dimitrios Iliopoulos, Philip N Tsichlis and Kevin Struhl, Cancer Res 2009(Sep 14) [Epub ahead of print][PubMed Citation].

Aurothiomalate being studied in a preclinical lung cancer model

Mayo Clinic researchers find lung cancer oncogene holds key to turning off cancer stem cells, News Release, Mayo Clinic, September 8, 2009. First two paragraphs:

Scientists at the Mayo Clinic campus in Florida have found that the lung cancer oncogene PKCiota is necessary for the proliferation of lung cancer stem cells. These stem cells are rare and powerful master cells that manufacture the other cells that make up lung tumors and are resistant to chemotherapy treatment.

Their study, published in the Oct. 1 issue of Cancer Research, also shows that an agent, aurothiomalate, being tested at Mayo Clinic in a phase I clinical trial substantially inhibits growth of these cancer stem cells.

The news release is about this publication: Atypical Protein Kinase C{iota} Is Required for Bronchioalveolar Stem Cell Expansion and Lung Tumorigenesis by Roderick P Regala and 5 co-authors, including Alan P Fields, Cancer Res 2009(Sep 8) [Epub ahead of print][PubMed Citation]. The final paragraph of the full text:

Our present results show that aurothiomalate exhibits potent antiproliferative activity toward the tumor stem cell niche in a relevant preclinical lung cancer model. Future studies will be required to assess whether aurothiomalate has similar antiproliferative effects on human lung cancer stem cells isolated from primary human lung tumors.

Comment: The publication reports results that were obtained using a mouse model. The News Release states that a Phase I clinical trial is under way at the Mayo Clinic, but this trial isn't mentioned in the full text of the publication in Cancer Research. According to MedicineNet.com, aurothiomalate is a "gold-containing chemical (salt) used in treating rheumatoid arthritis".

IP rules for CIRM disease team project delayed

Prop. 71 Minutia Stalls CIRM Again, David Jensen, California Stem Cell Report, September 16, 2009. First two paragraphs:

The board of directors of the California stem cell agency Tuesday failed to achieve a quorum and was forced to put off action on regulations tied to its ambitious, $210 million disease team grant round, the largest ever in CIRM history.

That means it will be at least another two weeks or more before the board can act on the IP rules that it needs for disease team project. The grants are scheduled to be awarded later this year

Comment: To see previous posts in this blog about the Disease Teams Awards, see posts with the tag "Disease Teams".

Researchers find new kind of prostate SC in mice

New Type Of Adult Stem Cells Found In Prostate May Be Involved In Cancer Development, ScienceDaily, September 10, 2009. Excerpts:

The new study may resolve this conundrum because the newly discovered adult stem cells are also luminal cells. "Previous research suggested that prostate cancer originates from basal stem cells, and that during cancer formation these cells differentiate into luminal cells," said Dr. Shen. "Instead, CARNs may represent a luminal origin for prostate cancer" [CARNs stands for "castration-resistant Nkx3.1-expressing cells"].

And indeed, the researchers found that CARNs in mice can give rise to prostate cancers, after the cells lose the activity of PTEN, a gene that is frequently mutated in human prostate cancers.

See also: New Progenitor Cell in Mice Can Cause Prostate Cancer, Michael Smith, Medpage Today, September 9, 2009; Researchers find prostate cancer stem cell, Reuters, September 9, 2009.

These news items are about the publication: A luminal epithelial stem cell that is a cell of origin for prostate cancer by Xi Wang and 9 co-authors, including Michael M Shen, Nature 2009(Sep 9) [Epub ahead of print][PubMed Citation].

Comment: These CSCs were found in mice, and "it is unclear whether CARNs exist in the normal human prostate and if human prostate cancers can originate from these CARNs" (see last paragraph of the Medpage Today article).

Found via: Two Studies Make Promising Advances in Prostate Cancer Research, Denis Cummings, FindingDulcinea, September 10, 2009.

Promising novel lipid molecule for breast cancer?

New stem cell identification technology could cure breast cancer, Reuters, September 11, 2009. [Twitter entry]. Excerpt:

The key behind GENova's biotechnology is tracing cancer cells to their origin, the very stem cells from where the first malignant cell arose. ...

See also: GENova files patent for new breast cancer treatment, Reuters, September 10, 3009. Excerpt:

... The technology behind Tetanolic acid involved identifying specific characteristics of these cancer stem cells and then tailoring a lipid (Tetanolic acid) that can identify these characteristics and then attack the malignant cells whilst leaving healthy cells intact. This tailor-made cancer treatment strategy is far superior to any existing therapies, as it terminates the cancer at the source, with no side effects, and no harm to surrounding healthy tissues.

From the Pipeline section of the website of GENova Biotherapeutics:

Tetanolic acid: Promising novel lipid molecule for breast cancer

Known as an alpha hydroxyoleic acid, tetanolic acid is a form of a lipid which is also found as a main component of olive oil. Alpha hydroxyoleic acids are able to interact with the cell membrane in order to control its composition or structure with affect on the receptors on the membrane. This control mechanism affects the growth and proliferation of cells – and seeing that cancer is characterised as a normal proliferation of cells, these lipids can potentially prevent cancer spread (Ohba et al., 2007 Int. J. Cancer 121 (1)).

Tests have been shown that such analogues of oleic acid are able to prevent the growth and spread of cancers, including breast cancer, in mice. That is why GENova's Tetanolic acid is a candidate for development of an anti-cancer medicament in humans.

The reference is to: Oleamide derivatives suppress the spontaneous metastasis by inhibiting connexin 26 by Yusuke Ohba and 14 co-authors, including Hiroshi Nojima, Int J Cancer 2007(Jul 1); 121(1): 47-54. [PubMed Citation].

For recent background information, see: Form 10-Q for GENOVA BIOTHERAPEUTICS INC., Yahoo Finance, August 14, 2009. Excerpts:

From inception, Kinder Travel Inc. had been a travel agency offering a full range of travel services including corporate travel, vacations, cruise holidays, and group tours. Since Kinder Travel Inc. was incurring continued losses in the travel industry, the Board of Directors decided it was in the best interests of the Corporation to pursue other business opportunities. Through his past contacts in the bio-medical industry, the then President of Kinder Travel Inc. initiated negotiations with Phoinos Oxford Lifesciences Limited, a company incorporated under the laws of the Federation of St. Kitts & Nevis ("Phoinis Oxford"), for the purchase of medical patents for the treatment of prostate and breast cancers. On April 15, 2009, Kinder Travel Inc. entered into an asset purchase agreement dated April 15, 2009 (the "Asset Purchase Agreement") with Phoinos Oxford.

The Company subsequently changed its to "Genova Biotherapeutics Inc." Our shares of common stock now trade on the Over-the-Counter Bulletin Board under the symbol "GVBP.OB".

For details about the sale of medical patents (filed in Denmark and the United Kingdom) by Phoinos Oxford Lifesciences to Kinder Travel, Inc. (renamed GENova Biotherapeutics Inc.), see: Kinder Travel, Inc. Form PRER14C, June 17, 2009.

A recent clarification: GENova issues clarifying press release, Bloomberg.com, September 12, 2009. Excerpt:

GENova owns the rights to a range of drug targets and has filed patent application for all of them. The patents have not yet been approved and are therefore considered 'patents-pending'. It has been brought to GENova's attention that previous releases were not entirely clear on this issue and may have been misconstrued by some investors.

Comment: A PubMed search and a Google Scholar search didn't yield any additional information about tetanolic acid. A Google search for "tetanolic acid for the treatment of breast cancer" did reveal that NextGen Bioscience Inc. acquired tetanolic acid in November of 2007, but that, while still owning tetanolic acid, was in financial difficulties by February of 2008. This company's website is not online at present. I've not been able to find information online about the transfer of ownership if tetanolic acid from NextGen Bioscience Inc. to Phoinos Oxford Lifesciences Ltd., the seller of tetanolic acid to GENova Biotherapeutics (see above).

A recent publication that may also be relevant is: Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid by Victoria Lladó and 7 co-authors, including John E Halver and Xavier Busquets, Proc Natl Acad Sci USA 2009(Aug 18); 106(33): 13754-8 [Epub 2009(Aug 3)]. [PubMed Citation][ Full text].

Bidirectional interconvertibility between CSCs and non-CSCs?

Cancer stem cells: mirage or reality? Piyush B Gupta, Christine L Chaffer and Robert A Weinberg, Nat Med 2009(Sep); 15(9): 1010-1012 [Epub 2009(Sep 4)]. [FriendFeed entry] PubMed Abstract:

The similarities and differences between normal tissue stem cells and cancer stem cells (CSCs) have been the source of much contention, with some recent studies calling into question the very existence of CSCs. An examination of the literature indicates, however, that the CSC model rests on firm experimental foundations and that differences in the observed frequencies of CSCs within tumors reflect the various cancer types and hosts used to assay these cells. Studies of stem cells and the differentiation program termed the epithelial-mesenchymal transition (EMT) point to the possible existence of plasticity between stem cells and their more differentiated derivatives. If present, such plasticity would have major implications for the CSC model and for future therapeutic approaches.

Excerpt from the full text:

Figure 1: Stem-differentiation hierarchy.

[Figure]

Increased plasticity may be present within cancer populations, enabling bidirectional interconvertibility between CSCs and non-CSCs.

Last two sentences of the full text:

However, if non-CSCs can indeed give rise to CSCs, this plasticity would frustrate attempts to cure tumors by eliminating CSCs alone, as therapeutic elimination of CSCs may be followed by their regeneration from residual non-CSCs, allowing tumor regrowth and clinical relapse. We, therefore, suspect that optimal therapeutic regimens will need to incorporate agents that target both CSCs and non-CSCs if truly curative therapies are ever to be achieved.

Comment: This article presents a novel model of the "stem-differentiation hierarchy" involving CSCs and non-CSCs. The model includes the possibility that "a dynamic equilibrium may exist between CSCs and non-CSCs within tumors" that "may be shifted in one direction or another by contextual signals within the tumor microenvironment that influence the probability of interconversion between the CSC and non-CSC compartments ...". It's unfortunate that the article isn't openly accessible. If it were OA (with an appropriate Creative Commons License), a copy of the model depicted in Figure 1 could have been included in this post.

Cancer cell heterogeneity: an essay

Heterogeneity in Cancer: Cancer Stem Cells versus Clonal Evolution by Mark Shackleton, Elsa Quintana, Eric R Fearon and Sean J Morrison, Cell 2009(Sep 4); 138(5): 822-29. [FriendFeed entry][Full text]. Summary:

The identification and characterization of cancer stem cells might lead to more effective treatments for some cancers by focusing therapy on the most malignant cells. To achieve this goal it will be necessary to determine which cancers follow a cancer stem cell model and which do not, to address technical issues related to tumorigenesis assays, and to test the extent to which cancer cell heterogeneity arises from genetic versus epigenetic differences.

Imatinib refractoriness of leukemia-initiating cells

Persistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder by Katherine I Oravecz-Wilson and 11 co-authors, including Sean J Morrison and Theodora S Ross, Cancer Cell 2009(Aug 4); 16(2): 137-48. Last sentence of the PubMed Abstract:

Although imatinib dramatically decreased disease burden, LICs persisted, demonstrating imatinib refractoriness of LICs.

Prom1-expressing cells not essential for gliomagenesis

Glioblastoma Formation from Cell Population Depleted of Prominin1-Expressing Cells, Elites TV, August 29, 2009. [Twitter entry].

This news item provides the abstract of an article (with the same title) by Kenji Nishide, Yuka Nakatani, Hiroshi Kiyonari and Toru Kondo, published in PLoS One 2009(Aug 31); 4(8): e6869. [PubMed Citation][Full text is publicly accessible (via Libre OA)]. Last sentence of the abstract:

Thus, our studies demonstrate that Prom1-expressing cells are dispensable for gliomagenesis in this mouse model.