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.

Phase I clinical trial of ICT-107

Immune response correlation with progression-free survival in glioblastoma following dendritic cell immunotherapy (ICT-107) by Surasak Phuphanich and 9 co-authors, including Manish Singh, Keith Black and John Wu, J Clin Oncol 28:7s, 2010 (suppl; abstr 2097). To be presented at the 2010 ASCO Annual Meeting, June 06, 2010.

Related news releases:

ImmunoCellular Therapeutics Ltd. (IMUC) to Present Cancer Vaccine Candidate, International Business Times, June 02, 2010. Excerpt:

Data from the company’s recent clinical trial of ICT-107, the company’s dendritic cell-based cancer vaccine candidate, will be presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) June 4-8 in Chicago.

See also: Immunocellular brain cancer vaccine shows promise, Reuters, June 02, 2010. Excerpt:

"We are targeting specific antigens that are on cancer stem cells ... the only population of cells that can really propagate a tumor," said Dr. John Yu, director of surgical neuro-oncology at Cedars-Sinai Medical Center in Los Angeles and ImmunoCellular's chief scientific officer.

Another related news release: Immunocellular Therapeutics Enters into Research Agreement with University of Pennsylvania to Support Phase II Clinical Trial of ICT-107, Business Wire, April 21, 2010.

Generic drug a potential treatment for glioblastoma?

DCA research on brain cancer, EurekAlert, May 12, 2010. [FriendFeed entry]. Excerpt: "... the orphan generic drug Dichloroacetate (DCA) may hold promise as potential therapy for ... a form of brain cancer called glioblastoma". Another excerpt:

By extracting glioblastomas from 49 patients over a period of 2 years and studying them within minutes of removal in the operating room, the team showed that tumors respond to DCA by changing their metabolism. Then, the team treated 5 patients with advanced glioblastoma and secured tumor tissues before and after the DCA therapy. By comparing the two, the team showed that DCA works in these tumors exactly as was predicted by test tube experiments. This is very important because often the results in non-human models tested in the lab do not agree with the results in patients. In addition, the team showed that DCA has anti-cancer effects by altering the metabolism of glioblastoma cancer stem cells, the cells thought responsible for the recurrences of cancer.

And,

No conclusions can be made on whether the drug is safe or effective in patients with this form of brain cancer, due to the limited number of patients tested by the study's leads Drs Michelakis and Petruk. Researchers emphasize that use of DCA by patients or physicians, supplied from for-profit sources or without close clinical observation by experienced medical teams in the setting of research trials, is not only inappropriate but may also be dangerous. ...

See also: Generic drug may be potential treatment for deadly brain cancer: U of A medical study by Noreen Remtulla and Julia Necheff, ExpressNews, University of Alberta, May 12, 2010.

And: Potential brain-cancer drug shows promise, CBC News, May 12, 2010. [CBC video].

And: Cancer drug trial raises hopes by Elise Stolte, Edmonton Journal, May 13, 2010.

These news reports are about the publication: Metabolic Modulation of Glioblastoma with Dichloroacetate by Evangelos D Michelakis and 12 co-authors, including Kenneth C Petruk, Sci Transl Med 2010(May 12); 2(31): 31ra34.

See also an editorial: Targeting Cell Metabolism in Cancer Patients by Matthew G Vander Heiden, Sci Transl Med 2010(May 12); 2(31) :31ed1. From the TOC: "Dichloroacetate can safely modify glucose metabolism in aggressive brain tumors when administered to patients". Last sentence of the editorial: "Time will tell whether this strategy constitutes an effective cancer therapy".

Comments: After an initial research publication in January 2007 [PubMed citation], DCA attracted much attention. See, for example, the Wikipedia entry for Dichloroacetic acid. And, Cancer society warns of untested drug, CBC News, March 22, 2007.

The Official University of Alberta DCA Website provides FAQs about DCA. It includes, in the News & Updates section, DCA Research Team publishes results of Clinical Trials (dated May 12, 2010) and an earlier Letter from Dr. Evangelos Michelakis (dated October 2008).

CSC suppress immune response against brain tumor

Cancer stem cells suppress immune response against brain tumor, News Release, The University of Texas M. D. Anderson Cancer Center, January 15, 2010.

About two publications, one in Clin Cancer Res 2010(Jan 15);16(2):461-73 and the other in Mol Cancer Ther 2010(Jan);9(1):67-78.

See also: Cancer stem cells suppress immune response against brain tumor, Science Blog, January 15, 2010, and, Mechanism that helps brain cancer evade immune system attack discovered, Science News, January 16, 2010.

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].

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.

Mitogen independence of glioblastoma SCs

Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous Mitogens by John J P Kelly and 11 co-authors, including Gregory Cairncross, Ian F Parney and Samuel Weiss, Stem Cells 2009(Aug 1); 27(8): 1722-33. [Epub 2009(Apr 23)][ResearchGATE Citation][PubMed Citation].

CSC, brain cancer and the STAT3 gene

STAT3 Gene Regulates Cancer Stem Cells in Brain Cancer, News Release, Tufts University, August 10, 2009. First paragraph:

In a study published online in advance of print in Stem Cells, Tufts researchers report that the STAT3 gene regulates cancer stem cells in brain cancer. Cancer stem cells have many characteristics of stem cells and are thought to be the cells that drive tumor formation. The researchers report that STAT3 could become a target for cancer therapy, specifically in Glioblastoma multiforme (GBM), a type of malignant and aggressive brain tumor.

See also: [Newswise][Insciences][EurekAlert][Medical News Today].

These News Releases are about this article: STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells by Maureen M Sherry and 4 co-authors, including Brent H Cochran, Stem Cells 2009(Aug 5) [Epub ahead of print]. [PubMed Citation].

More on immune based therapies for the treatment of cancers

ImmunoCellular Therapeutics Retains Services of Torrey Pines Institute for Molecular Studies and Renowned Immunologist to Evaluate Lead Product Candidate, Business Wire, July 14, 2009. Excerpts:

ImmunoCellular Therapeutics, Ltd. (OTCBB: IMUC), a clinical-stage biotechnology company that is developing immune based therapies for the treatment of brain and other cancers, announced today that it has retained the services of the Torrey Pines Institute for Molecular Studies in San Diego, CA, to evaluate the immunogenicity of peptides to target cancer stem cells (CSC’s) relating to the Company’s lead product candidate ICT-121. The evaluation will be conducted by Dr. Clemencia Pinilla, a specialist in immune response mechanisms and their role in the prevention and cause of human disease with over 100 publications and multiple patents to her credit.

.....

ICT-121 is IMUC’s cancer stem cell (CSC) vaccine product candidate that consists of a peptide to stimulate a cytotoxic T-lymphocyte (CTL) response to CD133, which is generally overexpressed on the CSCs.

Relevant links: Profile of Clemencia Pinilla, of the Torrey Pines Institute for Molecular Studies in San Diego, California; and, Opinion: A Stem of Hope for Cancer Treatments by Manish Singh (President and CEO of IMUC), Genetic Engineering & Biotechnology News, June 12, 2009. [Previous blog post: Bright future for CSC therapies?, June 14, 2009].

Note that it is important that CSC-targeted vaccination "should not lead to immune reaction to normal cells that may express common antigens". For a recent publication from which this quotation is taken, see: Antigen-Specific T Cell Response from Dendritic Cell Vaccination Using Cancer Stem-like Cell-Associated Antigens by Qijin Xu and 8 co-authors, including John S Yu, Stem Cells 2009(Apr 23) [Epub ahead of print][PubMed Citation]. (John S Yu is Chief Scientific Officer and Chairman of the Board of IMUC, see: Our Team - IMUC).

For some background about immune based therapies for the treatment of cancer, see: Cancer Vaccines by Preeti Gokal Kochar, ProQuest Discovery Guide, January 2006.

See also: Connotea bookmarks matching tag CD133.

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.

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.

Prognostic potential of CSC analysis in glioblastoma

Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme by Roberto Pallini and 10 co-authors, including Ruggero De Maria, Clin Cancer Res 2008(Dec 15); 14(24): 8205-12. PubMed Abstract:

PURPOSE: Cancer stem cells (CSC) are thought to represent the population of tumorigenic cells responsible for tumor development. The stem cell antigen CD133 identifies such a tumorigenic population in a subset of glioblastoma patients. We conducted a prospective study to explore the prognostic potential of CSC analysis in glioblastoma patients. EXPERIMENTAL DESIGN: We investigated the relationship between the in vitro growth potential of glioblastoma CSCs and patient death or disease progression in tumors of 44 consecutive glioblastoma patients treated with complete or partial tumorectomy followed by radiotherapy combined with temozolomide treatment. Moreover, we evaluated by immunohistochemistry and immunofluorescence the prognostic value of the relative presence of CD133(+) and CD133(+)/Ki67(+) cells in patient tumors. RESULTS: In vitro CSC generation and the presence of >/=2% CD133(+) cells in tumor lesions negatively correlated with overall (P = 0.0001 and 0.02, respectively) and progression-free (P = 0.0002 and 0.01, respectively) survival of patients. A very poor overall (P = 0.007) and progression-free (P = 0.001) survival was observed among patients whose tumors contained CD133(+) cells expressing Ki67. Taking into account symptom duration, surgery type, age, O(6)-methylguanine-DNA methyltransferase promoter methylation, and p53 status, generation of CSCs and CD133/Ki67 coexpression emerged as highly significant independent prognostic factors, with an adjusted hazard ratio of 2.92 (95% confidence interval, 1.37-6.2; P = 0.005) and 4.48 (95% confidence interval, 1.68-11.9; P = 0.003), respectively. CONCLUSIONS: The analysis of CSCs may predict the survival of glioblastoma patients. In vitro CSC generation and presence of CD133(+)/Ki67(+) cells are two considerable prognostic factors of disease progression and poor clinical outcome.

See also: Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme by Maurizio Martini and 5 co-authors, including Luigi Maria Larocca, Int J Cancer 2008(Dec 15); 123(12): 2955-60 [Epub 2008(Sep 3)][PubMed Citation].

[The full text of these articles isn't publicly accessible].

Press release from Celprogen Inc.

Celprogen Introduces an in vivo Model for Human Brain Cancer (Human Glioblastoma GBM) for Drug Discovery Applications, Business Wire, November 17, 2008. Excerpt:

Celprogen has established a Drug Discovery program to provide drug efficacy testing services to major Pharmaceutical firms for their potential drugs against Human Glioblastoma. The other in vivo cancer model systems in the pipe line at Celprogen are: breast cancer, prostate cancer, liver cancer, colon cancer, lung cancer and pancreatic cancer that are scheduled to be released as early as the beginning of second quarter 2009. These in vivo cancer model systems are being generated from already established Celprogen’s Cancer Stem Cells.

See also: Celprogen Launches Cancer Stem Cells, Medical News Today, January 25, 2008.

About Celprogen (located in San Pedro, California).

Two articles about brain tumor initiating cells

Hedgehog signaling regulates brain tumor initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas by Qijin Xu, Xiangpeng Yuan, Gentao Liu, Keith L Black, John S Yu, Stem Cells 2008(Sep 11) [Epub ahead of print][PubMed Citation].

SOX2 silencing in glioblastoma tumor initiating cells causes stop of proliferation and loss of tumorigenicity by Rosaria Maria Rita Gangemi and 9 co-authors, including Giorgio Corte, Stem Cells 2008(Oct 23) [Epub ahead of print][PubMed Citation].

Neither of these articles is openly accessible.