Researchers Study CSCs as Therapeutic Targets for Mesothelioma

Researchers Study Cancer Stem Cells as Therapeutic Targets for Mesothelioma, Asbestos.com, July 26, 2010. Excerpt:

In a study published in the International Journal of Oncology, Cortes-Dericks and colleagues tested whether cancer stem cells in malignant pleural mesothelioma express resistance to cisplatin and pemetrexed, two chemotherapy drugs commonly used to treat mesothelioma cancer.

This news item is based on the OA publication entitled: Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed by Lourdes Cortes-Dericks, Giovanni L Carboni, Ralph A Schmid and Golnaz Karoubi, Int J Oncol 2010(Aug); 37(2): 437-44. [PubMed citation].

Irradiating brain's stem cell niche

Irradiating brain's stem cell niche doubles survival time for patients with brain cancers by Kim Irwin, News Release, UCLA Newsroom, July 23, 2010. Excerpt:

Patients with deadly glioblastomas who received high doses of radiation that hit a portion of the brain which harbors neural stem cells had double the progression-free survival time as patients who had lower doses or no radiation targeting the area, a study from the radiation oncology department at UCLA's Jonsson Comprehensive Cancer Center has found.

The news release is based on this OA publication: Irradiation of the Potential Cancer Stem Cell Niches in the Adult Brain Improves Progression-free Survival of Patients with Malignant Glioma by Patrick Evers and 6 co-authors, including Frank Pajonk, BMC Cancer 2010(Jul 21); 10(1):384. [Epub ahead of print][FriendFeed entry].

Comment: On the brain as a model system to study the impact of radiation dose given to stem cell niches. Provides clinical evidence, based on an improvement in progression-free survival, to support the hypothesis that higher radiation doses to neural stem cell (NSC) niches improves patient survival by eradicating CSCs.

More about salinomycin

New mission for salinomycin in cancer by Cord Naujokat, SciTopics, July 15, 2010. Excerpt (in the "continue reading" section):

In addition, a very recent study demonstrates that salinomycin overcomes ATP-binding cassette (ABC) transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like cells (3).

Reference #3: Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells, by Dominik Fuchs and 4 co-authors, including Cord Naujokat, Biochem Biophys Res Commun 2010(Apr 16);394(4): 1098-104 [Epub 2010(Mar 27)][PubMed citation].

Comments: Near the end of this article about salinomycin is the comment that "the investigation of its safety, toxicity, pharmacology and anticancer activity in humans will be a challenge." The author then mentions a preliminary study of "a small cohort of patients with metastatic breast cancer or metastatic head and neck cancers". The results of this preliminary study of the toxicity of salinomycin are summarized. They have not yet been published in the peer-reviewed literature, although a manuscript has been submitted [see reference #4 in the article]. The implication of these preliminary results is that there may be a "therapeutic window" for salinomycin, that is, a drug dosage that yields clinically significant benefits in the absence of excessive toxicity.

For a previous commentary on salinomycin, see: Cancer stem cell breakthrough by Kat Arney, Science Update blog, Cancer Research UK, August 14, 2009. Excerpt:

We need to stress that these were laboratory experiments, and there is no evidence yet that salinomycin can treat cancer in humans. Salinomycin is currently used as an antibiotic for chickens and cows, and it can be toxic or even fatal to humans, causing serious muscle and heart problems.

If there is a "therapeutic window" for salinomycin, it could be a small one, and is likely to vary from one tumor to another.

For a previous post to this blog about salinomycin, see: Identification of selective inhibitors of breast CSCs in mice, August 14, 2009.

OncoMed Has 'Wnt' in its Sails

OncoMed Has 'Wnt' in its Sails; Bayer Deal Adds $40M Up Front by Jennifer Boggs, Bioworld, June 18, 2010. Excerpts:

[OncoMed's] latest accomplishment is another early stage deal, this time with Bayer Schering Pharma AG, to develop drugs targeting the Wnt signaling pathway. It's an agreement that brings $40 million up front, with the potential for more than $1 billion in future milestones.

.....

The Wnt pathway is believed to be a key target in halting cancer stem cell activity. But only a few other firms - Avalon Pharmaceuticals Inc. (now part of Clinical Data Inc.) and 2008 start-up Wintherix LLC, for example - have entered that space, largely because Wnt is not an easily druggable target.

News release from Bayer: Bayer Schering Pharma and OncoMed Pharmaceuticals Enter Strategic Alliance to Develop Anti-Cancer Stem Cell Therapeutics, June 17, 2010. Excerpt:

Bayer Schering Pharma AG, Germany, and OncoMed Pharmaceuticals, Inc., today announced a global strategic alliance to discover, develop and commercialize novel anti-cancer stem cell therapeutics targeting the Wnt signaling pathway. Cancer stem cells are a subset of tumor cells believed to play a significant role in the establishment, metastasis and recurrence of cancer and agents targeting the Wnt pathway have the potential to be developed as pan-tumor drugs.

Comment: The Bayer-OncoMed strategic alliance has received attention via the social media. See, for example, the results of this FriendFeed search.

MK-0752 kills lingering breast CSC

Experimental Drug Kills Breast Cancer Stem Cells In Early Trials by Julie Steenhuysen, Reuters, December 11, 2009 [Another link][FriendFeed entry]. First two paragraphs:

An experimental drug was effective at killing breast cancer stem cells -- a kind of master cancer cell that resists chemotherapy, U.S. researchers said on Friday.

Studies in animals and women with advanced breast cancer showed the experimental compound MK-0752, under development by Merck & Co Inc (MRK.N), was able to kill off cancer stem cells that linger in the breast after chemotherapy.

The NCI Drug Dictionary entry for MK-0752:

A synthetic small molecule with potential antineoplastic activity. MK0752 inhibits the Notch signaling pathway, which may result in induction of growth arrest and apoptosis in tumor cells in which the Notch signaling pathway is overactivated. The Notch signaling pathway plays an important role in cell-fate determination, cell survival, and cell proliferation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

More about IMUC

ImmunoCellular (OTC: IMUC.OB) Notches Deal for New Cancer Stem Cell Vaccine Target by Mike Havrilla, BioMedReports, December 2, 2009. First paragraph:

In an option agreement announced today with MD Anderson Medical Center, ImmunoCellular Therapeutics (OTC: IMUC.OB) has acquired the rights to novel peptides that elicit a T-cell immune response against validated cancer stem cell targets known as the Notch and Numb pathways.

The same news item is also available via iStockAnalyst.

See also: ImmunoCellular Therapeutics Enters into Option Agreement with The University of Texas M. D. Anderson Cancer Center for a Novel Cancer Stem Cell Therapy, Business Wire, December 2, 2009.

IMUC letter to shareholders

ImmunoCellular Therapeutics Issues Letter to Shareholders, News Release, ImmunoCellular Therapeutics (IMUC), November 19, 2009. Excerpt:

• Signed key manufacturing agreement. The Company entered into an agreement with Formatech, Inc. for the manufacture of IMUC's cancer stem cell vaccine product candidate, ICT-121, the Company's lead product candidate that targets cancer stem cells and may have applicability to multiple types of cancer, for an upcoming clinical trial. The Phase I clinical trial of ICT-121, will target glioblastoma (brain cancer) and is expected to begin early next year, pending clearance by the FDA. ICT-121 is an "off-the-shelf" product, and this agreement calls for Formatech to prepare the vials of cancer vaccine for the clinical trial under a GMP (Good Manufacturing Practices) environment.

For a previous news release about this agreement, see: ImmunoCellular Therapeutics Signs Manufacturing Agreement with Formatech for Clinical Trial of ICT-121 Immunotherapy, June 24, 2009 [Formatech release][IMUC release].

Targeting cancer stem cells

Griffin Securities Announces Investment Opinion on Targeting Cancer Stem Cells, Yahoo Finance, October 9, 2008. First paragraph:

Griffin Securities (“Griffin”), a research-driven investment banking firm, has released an industry report on the subject of targeting cancer stem cells (CSCs). The stem cell hypothesis offers a rational approach to preventing, diagnosing, and treating malignant growth. Covered in the report are five classes of drugs nearing the Phase II clinical trial that provides human proof-of concept data, a crucial stage of development: Notch signaling, PI3k/akt pathway, immunotherapeutics, molecular chaperons, and hedgehog signaling.

See also: Firms Seek to Prove Cancer Stem Cell Hypothesis by Keith A Markey (scientific director at Griffin Securities), Genetic Engineering & Biotechnology News, Oct 15, 2009 (Vol 29, No 18).

Comments: Information can be found online about some of the drugs mentioned in the article by Keith A Markey. Two examples:

1. Notch signaling: OMP-21M18
   

   A humanized monoclonal antibody directed against the N-terminal epitope of Notch ligand DLL4 (delta-like 4) with potential antineoplastic activity. Anti-DLL4 monoclonal antibody OMP-21M18 binds to the membrane-binding portion of DLL4 and prevents its interaction with Notch-1 and Notch-4 receptors, thereby inhibiting Notch-mediated signaling and gene transcription, which may impede tumor angiogenesis. Activation of Notch receptors by DLL4 stimulates proteolytic cleavage of the Notch intracellular domain (NICD); after cleavage, NICD is translocated into the nucleus and mediates the transcriptional regulation of a variety of genes involved in vascular development. The expression of DLL4 is highly restricted to the vascular endothelium.

   One Phase 1 trial of OMP-21M18 [ClinicalTrials.gov Identifier: NCT00744562].


2. Hedgehog signaling: IPI-926

   An orally bioavailable, cyclopamine-derived inhibitor of the Hedgehog (Hh) pathway with potential antineoplastic activity. Specifically, Hedgehog pathway inhibitor IPI-926 binds to and inhibits the cell membrane-spanning G-protein coupled receptor SMO, which may result in the suppression of Hh pathway signaling and a decrease in tumor cell proliferation and survival. SMO is activated upon binding of Hh ligand to the cell surface receptor Patched (PTCH); inappropriate activation of Hh signaling and uncontrolled cellular proliferation may be associated with SMO mutations. The Hh signaling pathway plays an important role in proliferation of neuronal precursor cells in the developing cerebellum and other tissues.

   One Phase 1 trial of IPI-926 [ClinicalTrials.gov Identifier: NCT00761696].

A search of the Canadian Cancer Trials database indicated no trial sites, for either of these two particular trials, that are located in Canada.

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].

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].

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.