Aging, inflammation and cancer

Aging and inflammation: etiological culprits of cancer by Aamir Ahmad and 5 co-authors, including Fazlul H Sarkar, Curr Aging Sci 2009(Dec); 2(3): 174-86 [PubMed Citation][Full text in PMC]. Excerpt from the full text:

In the context of cancer, like normal tissues, various cancerous tissues also harbor a minor population of cells with enormous self-renewal and tumor-initiating capacity. Such cells are referred to as tumor-initiating cells or cancer stem cells, which offer an attractive target for cancer therapy [136] provided that normal stem cells are spared from the side effects of therapy. A number of molecular events that mark stem cell aging also occur in tumors in the elderly [134] and, as such, play important roles in the processes of cancer and aging, suggesting that these two processes are intertwined.

Comment: The full text of this article is available via PubMed Central (PMC). However, if accessed at the website of Current Aging Science (a journal of Bentham Science Publishers), the full text can only be purchased, and prior registration is required.For some background information about this publisher, see an entry in the French version of Wikipedia [Google translation into English]. (This entry is currently not available in the English version of Wikipedia).

CSC news roundup 2009-12-24

• An adult tissue-specific stem cell molecular phenotype is activated in epithelial cancer stem cells and correlated to patient outcome by Thomas Hussenet and 4 co-authors, including Stanislas du Manoir, Cell Cycle 2010(Jan 23); 9(2) [Epub ahead of print][PubMed Citation][Connotea bookmark].


• Differential Destruction of Stem Cells: Implications for Targeted Cancer Stem Cell Therapy by Mary E Sehl and 3 co-authors, including Kenneth L Lange, Cancer Res 2009(Dec 15); 69(24): 9481-9 [PubMed Citation][Connotea bookmark][ResearchGATE entry].


• EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance by Mario-Luca Suvà and 12 co-authors, including Ivan Stamenkovic, Cancer Res 2009(Dec 15); 69(24): 9211-8 [PubMed Citation][Connotea bookmark].


• Hypoxia-Regulated Delta-like 1 Homologue Enhances Cancer Cell Stemness and Tumorigenicity by Yuri Kim and 3 co-authors, including Zhong Yun, Cancer Res 2009(Dec 15); 69(24): 9271-80 [PubMed Citation][Connotea bookmark].


• Cancer Stem Cells and Aneuploid Populations within Developing Tumors Are the Major Determinants of Tumor Dormancy by Anjali P Kusumbe and Sharmila A Bapat, Cancer Res 2009(Dec 15); 69(24): 9245-53 [PubMed Citation][ResearchGATE entry].


• Stem-like cancer cells are inducible by increasing genomic instability in cancer cells by Yi Liang and 9 co-authors, including Yi-Xin Zeng, J Biol Chem 2009(Dec 9) [Epub ahead of print][PubMed Citation][Early version of full text].


• Gene set enrichment analysis provides insight into novel signalling pathways in breast cancer stem cells by Michiko Murohashi and 9 co-authors, including Noriko Gotoh, Br J Cancer 2009(Dec 8) [Epub ahead of print][PubMed Citation][ResearchGATE entry].


• Brain Tumor Cells Made More Responsive to Radiation, ScienceDaily, December 3, 2009 [Stem Cells 2009(Nov 17)]][PubMed Citation].


• SOM scientists explore spice as complementary treatment option for colorectal cancer, Prognosis E-news, Wayne State University School of Medicine, November 24, 2009 [Transl Oncol 2009(Dec);2(4):321-8][PubMed Citation].


• Is ALDH1 a good method for definition of breast cancer stem cells? by Veronique Neumeister and David Rimm, Breast Cancer Res Treat 2009(Nov 28) [Epub ahead of print][PubMed Citation][Connotea bookmark].


• Single-Cell STAT5 Signal Transduction Profiling in Normal and Leukemic Stem and Progenitor Cell Populations Reveals Highly Distinct Cytokine Responses by Lina Han and 5 co-authors, including Jan Jacob Schuringa, PLoS ONE 2009(Nov 24); 4(11): e7989 [PubMed Citation][Full text in PMC][Connotea bookmark].


• Recurrent hepatocellular carcinoma cells with stem cell-like properties: possible targets for immunotherapy by Xiaolan Xu‌ and 8 co-authors, including Zhiqian Zhang‌, Cytotherapy 2009(Nov 24) [Epub ahead of print][PubMed Citation][Connotea bookmark].

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)

SC-derived gene expression profiles predict poor outcome for AML patients

Leukemic and Normal Stem Cell Transcriptional Signatures Determined by Functional Assays Are Predictive of the Overall Survival of AML Patients by Kolja Eppert and 11 co-authors, including John E Dick, Abstract #389, 51st ASH Annual Meeting, December 7, 2009. Final sentence:

Together these data support the hypothesis that the biological determinants that underlie stemness in both normal and leukemic cells are predictors of poor outcome, and are potential targets for novel therapy.

Differences that separate normal vs cancer SC molecular circuitry

Pluripotent Transcription Factors Possess Distinct Roles in Normal versus Transformed Human Stem Cells by Junfeng Ji, Tamra E Werbowetski-Ogilvie, Bonan Zhong, Seok-Ho Hong and Mickie Bhatia, PLoS ONE 2009(Nov 30); 4(11): e8065 [FriendFeed entry][Full text is publicly accessible (via Libre OA)]. PubMed Abstract:

BACKGROUND: Cancer and normal stem cells (SCs) share proliferative properties of self-renewal and expression of key transcription factors (TFs). Despite similar TF identities, the functional role of specific TFs responsible for retaining SC state has yet to be examined in cancer. METHODOLOGY/PRINCIPAL FINDINGS: Here, we compare the role of Oct4 and Nanog, two-core pluripotent TFs, in transformed (t-hPSCs), and normal human pluripotent stem cells (hPSCs). Unlike normal SCs, self-renewal and survival of t-hPSCs were found to be independent of Oct4. In contrast, t-hPSCs exhibit hypersensitivity to reduction in Nanog and demonstrate complete loss of self-renewal coupled with apoptosis. Dual and sequential knockdown of Oct4 and Nanog revealed that sensitivity of t-hPSCs to Nanog was Oct4 dependent. CONCLUSIONS/SIGNIFICANCE: Our study indicates a bifurcation for the role of two-core SC and cancer related TFs in self-renewal and survival processes. We suggest that the divergent roles of these TFs establish a paradigm to develop novel therapeutics towards selective destruction of aggressive tumors harboring cancer stem cells (CSCs) with similar molecular signatures.

Twist modulates breast CSC

Potential new 'twist' in breast cancer detection, EurekAlert, December 4, 2009 [FriendFeed entry]. First paragraph:

Working with mice, scientists at Johns Hopkins publishing in the December issue of Neoplasia have shown that a protein made by a gene called "Twist" may be the proverbial red flag that can accurately distinguish stem cells that drive aggressive, metastatic breast cancer from other breast cancer cells.

Based on: Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression by Farhad Vesuna, Ala Lisok, Brian Kimble and Venu Raman, Neoplasia 2009(Dec); 11(12): 1318-28 [Abstract][OA full text PDF][DOAJ entry for Neoplasia].

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.

CSC news roundup 2009-11-26

• Distinct population of highly malignant cells in a head and neck squamous cell carcinoma cell line established by xenograft model, 7thSpace Interactive, November 16, 2009 [J Biomed Sci 2009(Nov 16);16(1):100 (OA)][PubMed Citation][FriendFeed entry].


• Tumor-initiating Cells Detected in Pten Null Prostate Cancer Model, PhysOrg.com, November 12, 2009 [Cancer Res 2009(Nov 15); 69(22):8555-62][PubMed Citation][FriendFeed entry].


• Mouse Models for Cancer Stem Cell Research by Le Cheng and 4 co-authors, including Alexander Y Nikitin, Toxicol Pathol 2009(Nov 17) [Epub ahead of print][PubMed Citation].


• Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment by Erika Resetkova and 6 co-authors, including Sunil Badve, Breast Cancer Res Treat 2009(Nov 13) [Epub ahead of print][PubMed Citation][Connotea bookmark].


• Recognition and Killing of Brain Tumor Stem-Like Initiating Cells by CD8+ Cytolytic T Cells by Christine E Brown and 10 co-authors, including Michael C Jensen, Cancer Res 2009(Nov 10) [Epub ahead of print][PubMed Citation][Connotea bookmark].


• Notch Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts by Xing Fan and 14 co-authors, including Charles G Eberhart, Stem Cells 2009(Nov 10) [Epub ahead of print][PubMed Citation][Connotea bookmark].


• Targeting breast stem cells with the cancer preventive compounds curcumin and piperine by Madhuri Kakarala and 8 co-authors, including Max S Wicha, Breast Cancer Res Treat 2009(Nov 7) [Epub ahead of print][PubMed Citation].


• Identification of single chain antibodies to breast cancer stem cells using phage display by Deniz Gur and 5 co-authors, including Max S Wicha and David N Krag, Biotechnology Prog 2009(Nov 6) [Epub ahead of print][PubMed Citation].


• Methodologies in assaying prostate cancer stem cells by Hangwen Li and 7 co-authors, including Dean G Tang, Methods Mol Biol 2009; 568: 85-138 [PubMed Citation].


• Pituitary adenoma stem cells by Patrizia Tunici and John S Yu, Methods Mol Biol 2009; 568: 195-201 [PubMed Citation].


• Targeting breast cancer stem cells by Max S Wicha, The Breast 2009(Oct); 18(Suppl 3): S56-8.

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 of AML-leukemic SC with monoclonal antibodies

Targeting of AML-leukemic stem cells with monoclonal antibodies by Erwin M Lee‌ and Richard B Lock, Future Oncol 2009(Nov); 5(9): 1327-30 [PubMed Citation][FriendFeed entry][Full text PDF]. Final sentence of the full text of this Editorial:

An AML patient surface immunophenotype is relatively cost-effective to characterize, raising the prospect of individualized therapy based on a selection of available MAbs. Most certainly, we are entering a new and exciting era in the struggle to improve outcome in adult AML.

CSC news roundup 2009-11-10

• The cancer stem cell microenvironment and anti-cancer therapy by Veerander P S Ghotra, Jordi C Puigvert and Erik H J Danen. Review in Int J Radiat Biol 2009(Nov); 85(11): 955-62 [PubMed Citation].


• Cancer Stem Cells : A Reality, A Myth, A Fuzzy Concept or A Misnomer? An Analysis by Carine Maenhaut, Jacques E Dumont, Pierre Roger and Wilma C G van Staveren. Review in Carcinogenesis 2009(Oct 25) [Epub ahead of print][PubMed Citation].


• Colorectal cancer stem cells by Paul Salama and Cameron Platell, Review in ANZ J Surg 2009(Oct); 79(10): 697-702 [PubMed Citation][FriendFeed entry].


• Identification and targeting of cancer stem cells by Tobias Schatton, Natasha Y Frank and Markus H Frank. Review in Bioessays 2009(Oct); 31(10): 1038-49 [PubMed Citation].


• Cancer stem cells: Symmetry is key by Mhairi Skinner, Nature Reviews Cancer 2009; 9: 768-9. A commentary about [Cell 2009 Sep 18;138(6):1083-95][FriendFeed entry].


• On cancer stem cells (for the lay public) [All Things Stem Cell 2009(Oct 31)] by Teisha Rowland [FriendFeed entry].


• Immunoselection of breast and ovarian cancer cells with trastuzumab and natural killer cells. [Cancer Res 2009(Oct 15);69(20):8058-66][PubMed Citation][FriendFeed entry].


• CD133 Expression Defines a Tumor Initiating Cell Population in Primary Human Ovarian Cancer by Michael D Curley and 10 co-authors, including Bo R Rueda and Rosemary Foster. Stem Cells 2009(Oct 8) [Epub ahead of print][PubMed Citation].

Heterogeneity in the AML stem cell pool

Heterogeneity in the AML stem cell pool by Laura E Hays, Blood 2009(Nov 5); 114(19): 3976-7 [PubMed Citation][FriendFeed entry]. Excerpt:

To examine AML and stem cell diversity, Heuser and colleagues develop a novel murine model that closely mimics aggressive human AML and demonstrate an essential role of Stat5 in leukemic stem cell renewal.

Comment on: Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal by Michael Heuser and 14 co-authors, including Gerald Krystal and R Keith Humphries, Blood 2009(Nov 5); 114(19): 3983-93 [Epub 2009(Aug 10)][PubMed Citation].

Featured Article in Cell Stem Cell (Nov 09)

Featured article in the November 6, 2009 issue of Cell Stem Cell (access to the Featured Article is free for all readers):

Malignant glioma remains challenging to treat, despite the use of aggressive surgery, radiotherapy, and chemotherapy. Although the concept of cancer stem cells reveals a new framework of cancer therapeutic strategies against malignant glioma, it remains unclear how glioma stem cells could be eradicated. In this issue, Miyazono and colleagues demonstrate that autocrine TGF-β signaling helps maintain glioma-initiating cells and find that chemical inhibition blocks the TGF-β-Sox4-Sox2 signaling axis, resulting in glioma cell differentiation in culture and loss of in vivo tumor-forming capacity. Therefore, clinical disruption of this pathway may represent a therapeutic paradigm against gliomas.

Autocrine TGF-β Signaling Maintains Tumorigenicity of Glioma-Initiating Cells through Sry-Related HMG-Box Factors by Hiroaki Ikushima and 5 co-authors, including Kohei Miyazono, Cell Stem Cell 2009(Nov 6); 5(5): 504-14). [Full text].

CSC news roundup: 2009-11-02

• Compositions and Methods for Determining Cancer Stem Cell Self-Renewal Potential, University of California, San Diego Technology Transfer Office, November 2, 2009. [SD2009-192][Tech ID: 19976].


• ImmunoCellular's Promising Brain Cancer Vaccine, Mike Havrilla, Seeking Alpha, October 28, 2009. [Reuters News Release].


• MicroRNA Regulation of Cancer Stem Cells and Therapeutic Implications, Jeffrey T DeSano and Liang Xu, AAPS J 2009(Oct 20). [PubMed Citation].


• Sphere and/or xenograft formation may be useful to survey colitic patients at risk of developing cancer? [Cancer Res 2009 (Oct 15);69(20):8208-15][PubMed Citation][News Release].


• Recent studies regarding stem cell origin of various solid tumors are discussed briefly in this review. [Onkologie 2009 (Oct);32(10):605-9][PubMed Citation].


• Squelching glioblastoma stem cells by targeting REST for proteasomal degradation by Peisu Zhang and 4 co-authors, including Jeremy N Rich and Mark P Mattson, Trends Neurosci 2009(Nov);32(11):559-65 [Epub 2009(Sep 11)][PubMed Citation].


• Methylation dosage effect controls stem cell function in leukemia. [Nat Genet 2009 (Nov);41(11):1207-15][PubMed Citation][News Release].

Disease Team awards announced

Novel funding mechanism speeds the path of research, News Release, California Institute for Regenerative Medicine (CIRM), October 28, 2009. Excerpt:

The California Institute for Regenerative Medicine, the state stem cell agency, and two international partners awarded more than $250 million to 14 multidisciplinary teams of researchers in California, the UK and Canada to develop stem cell-based therapies for 11 diseases. The Disease Team Research Awards include approximately $8 million from the Medical Research Council, UK, and approximately $35 million from the Cancer Stem Cell Consortium, Canada, to fund the international portions of the collaborations.

See also:

• Two Research Teams Funded through the Innovative Partnership Program Between Canada and California to Advance Cancer Stem Cell Research, News Release, Cancer Stem Cell Consortium (CSCC), October 28, 2009. Excerpts:
  

  The Cancer Stem Cell Consortium (CSCC) is pleased to announce that two multi-disciplinary research teams co-led by Canadian and Californian scientists have been awarded funding through a Collaborative Partnership Program with The California Institute for Regenerative Medicine (CIRM). The program supports research that will result in a cancer stem cell based therapy with the specific aim of improving cancer treatment.

  .....

  The first project is led by Dr. John Dick, University Health Network and Dr. Dennis Carson, University of California, San Diego. Their research will focus on the development of novel drugs to treat leukemia, which will address a compelling medical need as half of adults diagnosed with leukemia die of the disease. Substantial evidence supports the concept that recurrence and persistence of many leukemias stem from the relative resistance of leukemic stem cells (LSCs) to treatments currently in use, so the development of drugs that preferentially target LSCs may be particularly valuable in attacking both lymphoid and myeloid malignancies.

  The goal of the second project is to utilize a pipeline strategy to develop novel drugs targeting cancer-initiating cells in solid tumor cancers. This project is led by Dr. Tak Mak, University Health Network and Dr. Dennis Slamon, UCLA. The reviewers of this application determined that the proposed drugs would provide a significant clinical benefit to cancer patients and recognized the unique capabilities of the assembled team to successfully identify and develop new drugs.

  
  
• New Canadian-Californian investment in stem cell research aims to improve cancer treatments by Michael Rudnicki, Stem Cell Network Blog, October 28, 2009. First paragraph:
  

  I am excited to learn of today’s announcement that two large-scale projects to tackle stem cell therapies for cancer are to be funded by the California Institute for Regenerative Medicine (CIRM) and the Cancer Stem Cell Consortium (CSCC). This is most welcome news, not only because it demonstrates a continued investment in stem cell science but because both projects have a critical Canadian component – both projects will be co-led by Canadian investigators.

Comment: Instead of the eleven likely winners of Disease Team awards, 14 awards were announced. See the list of "Approved Disease Team projects" that's included in CIRM's news release. This list can be compared with the listing of all applications reviewed under RFA 09-01, posted previously by CIRM. The 3 additional awards (to bring the total to 14) were to application numbers DR1-01480, DR1-01485 and DR1-01421.

Disclosure: I'm a member of the Board of the CSCC, but also a staff member (emeritus) at the University Health Network. So, I was in conflict of interest, and was absent during all of the discussions, by the CSCC Board, about which Canadian applications should be considered for the Disease Team awards.

CSC targeted to prevent relapse

Cancer stem cells targeted to prevent relapse by Vivek Sinanan, The Johns Hopkins News-Letter, October 26, 2009. In part, the news item appears to be based on this editorial: Controversies in cancer stem cells by Richard J Jones, J Mol Med 2009(Oct 23) [Epub ahead of print][PubMed Citation][Full text]. In turn, the editorial cites these articles, which will be published in J Mol Med 2009; 87(11):

• Cancer stem cells: controversies in multiple myeloma, Sarah K Brennan, William Matsui, J Mol Med 2009(Sep 17) [Epub ahead of print][PubMed Citation].


• Brain cancer stem cells, Sara GM Piccirillo and 4 co-authors, including Khalid Shah, J Mol Med 2009(Sep 29) [Epub ahead of print][PubMed Citation].


• Colon cancer stem cells, Lucia Ricci-Vitiani and 4 co-authors, including Ruggero De Maria, J Mol Med 2009(Sep 2) [Epub ahead of print][PubMed Citation].


• Cancer stem cells-clinical relevance, Richard J Jones, J Mol Med 2009(Oct 10) [Epub ahead of print][PubMed Citation].

Eleven likely winners of Disease Team awards

Results will soon be announced for the Disease Team Research Awards Competition of the California Institute for Regenerative Medicine (CIRM). These awards will support multi-disciplinary teams of scientists in pursuit of therapies for specific diseases. See: The Lucky 11 and $167 Million in Stem Cell Research Cash, David Jensen, California Stem Cell Report, October 23, 2009. First two paragraphs:

The California stem cell agency has pinpointed 11 likely winners of grants and loans up to $20 million each in the agency's ambitious disease team round, which was once projected at $210 million.

The awards are scheduled to be formally approved next week by the CIRM board of directors at a two-day meeting in Los Angeles at the Luxe Hotel. CIRM's Grants Working Group decided earlier that 11 proposals merited funding. The CIRM board almost never rejects a recommendation for funding by its reviewers.

Comment: Participation in the Disease Team Research Awards program is the first initiative launched by the Cancer Stem Cell Consortium (CSCC), in collaboration with CIRM. This is an international collaboration to advance cancer stem cell research, involving both Canadian and Californian scientists. See this previous post: CIRM/CSCC Joint Announcement: Disease Teams Awards, October 23, 2008.

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.

Aspirin may affect survival of CSC?

Aspirin protection for Lynch syndrome, PhysOrg.com, September 28, 2009. Excerpt:

Professor John Burn, from the Institute of Human Genetics at Newcastle University told the congress ECCO 15 - ESMO 34 held in Berlin on September 21 2009, that he believed that he and his colleagues may have uncovered a simple way of controlling cancer stem cells, which are essential to the formation of malignant tumours.

The clinical trial, which involved 1071 carriers of the Lynch syndrome mutation in 42 centres worldwide, randomised participants to a daily dose of 600mg aspirin and/or 30g Novelose, a resistant starch that escapes digestion in the small intestine.

See also a video (00:11:18) of Prof John Burn, who "talks to ecancer editor Prof Gordon McVie about the results of his trial" (posted September 23, 2009).

And, Aspirin protects against colorectal cancer, says international clinical trial, News Release, ECCO 15 – ESMO 34, September 21, 2009. Excerpt:

The mechanism by which aspirin protects against cancer has yet to be elucidated, but the scientists believe that cancer stem cells are involved.

Also, Aspirin taking on colon cancer, Mark Gertskis, Pharmacy News, September 28, 2009.

Comment: A heads-up: Daily dose of aspirin not safe for everyone, Jodi Mailander Farrell, MiamiHerald.com, September 29, 2009.

CSC news roundup: 2009-10-06

• Tumour-initiating cells: challenges and opportunities for anticancer drug discovery by Bin-Bing S Zhou and 5 co-authors, including Peter B Dirks, Nat Rev Drug Discov 2009(Oct); 8(10): 806-23 (Review) [PubMed Citation].


• The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype by John M Heddleston and 4 co-authors, including Jeremy N Rich, Cell Cycle 2009(Oct 3); 8(20) [Epub ahead of print][PubMed Citation].


• Identification of a myeloid committed progenitor as the cancer initiating cell in acute promyelocytic leukemia by Florence C Guibal and 11 co-authors, including Daniel G Tenen, Blood 2009(Oct 1) [Epub ahead of print][PubMed Citation].


• Targeting leukaemia at the roots by Alison Ross, Science Update blog, Cancer Research UK, September 28, 2009.


• "Tax-ing" the cancer stem cell by Gerold Feuer, Blood 2009(Sep 24); 114(13): 2568-9 [PubMed Citation].


• Cancer stem cell research gains traction, tackles new targets by Katherine Harmon, Scientific American, September 23, 2009 [FriendFeed entry].


• A progenitor cell origin of myeloid malignancies by Hiroshi Haeno, Ross L Levine, D Gary Gilliland and Franziska Michor, Proc Natl Acad Sci USA 2009(Sep 29); 106(39): 16616-21 [Epub 2009(Sep 21)][PubMed Citation].


• Vitro's Cancer Stem Cell Therapy Complements New Hedge Hog Drugs, News Release, September 10, 2009 [Vitro Biopharma].


• Cancer stem cells in breast cancer and metastasis by Jessica C Lawson, Gregory L Blatch and Adrienne L Edkins, Breast Cancer Res Treat 2009(Sep 4) [Epub ahead of print] (Review). [PubMed Citation].


• Cancer stem cell genomics: the quest for early markers of malignant progression by Oswaldo K Okamoto, Expert Rev Mol Diagn 2009(Sep); 9(6): 545-54 (Review). [PubMed Citation].

A contrarian view of 'stemness'

The 'stem cell' concept: is it holding us back? by Arthur D Lander, J Biol 2009(Sep 21); 8(8):70 [Epub ahead of print][Related FriendFeed entry][PubMed Citation][Full text is publicly accessible (via Libre OA)]. Abstract:

Developmental biology, regenerative medicine and cancer biology are increasingly occupied with the molecular characterization of stem cells. Yet recent work adds to a growing body of literature suggesting that 'stemness' cannot be reduced to the molecular features of cell types, and is instead an emergent property of cell lineages under feedback control.

Brief excerpt from the full text: "Like gene or phlogiston, the term 'stem cell' is a scientific concept. Stem cells are very much in the news, thanks to a dramatic upsurge in interest in their therapeutic potential".

Another excerpt from the full text:

For example, in the case of cancers that are stem cell driven, it is not clear that we actually have grounds to assume that the specific chemotherapeutic targeting of cancer stem cells will necessarily stop tumors in their tracks. Indeed, if feedback and lineage progression continue to take place in cancerous tissues, we might observe that, under different conditions - different stages of tumorigensis, different parts of a tumor, different amounts of tumor cells - that different cell types will assume the role of 'cancer stem cell'. The therapeutic implications of this possibility are clearly substantial.

An interview with Arthur Lander is at: Q&A: Is stem cell research misguided? by Bob Grant,TheScientist.com, September 29, 2009 [FriendFeed entry].

Comment: The major contrarian perspective in this opinion piece is the comparison of the stem cell concept with the phlogiston concept. This comparison is discussed further in the Q & A interview. The Comments section of Dr. Lander's article includes an answer to a question that I asked: What about purified stem cells? As part of a discussion on FriendFeed, I also asked: Is the debate about 'stemness' becoming another version of the nature-nurture debate? So far, no response to this question.

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.

Two publications about colorectal cancer

The Key to Stopping Colon Cancer? Med Tech Sentinel, August 30, 2009. Excerpt:

Scientists in Switzerland may have found a way to inhibit the growth of colon cancer in humans, says a new study published in EMBO Molecular Medicine. Researchers in Geneva discovered that by blocking a particular biological pathway, they could prevent the growth of tumors, metastatic lesions, and cancer stem cells. The Hedgehog-GL1 (HH-GL1) pathway appears to be crucial in the progression of colon cancer to an incurable, late stage. Cells use HH-GL1 to communicate with each other to determine position, growth and survival.

See also: 'Hedgehog' pathway may hold key to anti-cancer therapy, EurekAlert, August 26, 2009.

These news reports are about the publication: Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion by Frédéric Varnat and 6 co-authors, including Ariel Ruiz i Altaba, EMBO Molecular Medicine 2009(Aug 27) [Epub ahead of print][Abstract][Full text].

Another excerpt from The Key to Stopping Colon Cancer? (Med Tech Sentinel, August 30, 2009):

Earlier this month, scientists in North Carolina found another genetic target that may be useful in treating colorectal cancer. The pseudokinase ERBB3 is closely related to epidermal growth factor receptor (EGFR), which is already a target of several drugs used to treat colorectal cancer. Scientists found that genetically blocking ERBB3 was effective at preventing the disease in mice with colon cancer. In human colon cancer cells, removing ERBB3 caused a dramatic increase in cell death.

About the publication: Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium by Daekee Lee and 8 co-authors, including David W Threadgill, J Clin Invest 2009(Aug 17) [Epub ahead of print][PubMed Citation][Full text].