Companies selectively targeting cancer stem cells

Today, I posted this to Twitter:

3 Innovative Cancer Treatments...But Which Is The Best Bet? seekingalpha.com/a/fjed $GSK $IMUC $VSTM #cancerSC via @seekingalpha — Jim Till (@jimtill) July 17, 2012

The article is about three companies that are working on treatments designed to target cancer stem cells (CSCs). The companies are OncoMed, Verastem and ImmunoCellular Therapeutics. The article is interesting.

Cancer Stem Cell Chronicle

About 3 months ago, as an experiment, I launched the Cancer Stem Cell Chronicle, an online daily newspaper that's based on excerpts from 3 streams of content: 1) Twitter content tagged #cancerSC, 2) Twitter content that includes the keywords "cancer stem", and, 3) content derived from a PubMed RSS feed for the search term "cancer stem".

The experiment looks promising. The CSC Chronicle is beginning to provide a convenient way to monitor recent research news about cancer stem cells. Archives are available. The section headings in the CSC Chronicle aren't very meaningful, and should be ignored.

The CSC Chronicle is hosted by Paper.li.

Therapeutic implications of colon CSCs

Therapeutic implications of colon cancer stem cells by Eros Fabrizi and 3 co-authors, including Lucia Ricci-Vitiani, World J Gastroenterol 2010(Aug 21); 16(31): 3871-7. OA review. [FriendFeed entry][PubMed citation]. Abstract:

Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.

Disagreement about melanoma CSCs

The Evolving Science of Cancer Stem Cells by Carmen Phillips, NCI Cancer Bulletin 2010(Jul 27); 7(15). Excerpt:

Researchers from Stanford University earlier this month reported in Nature that they had found a marker, CD271, that identified a somewhat unique population of cells that could produce melanoma in highly immunocompromised mice; anywhere from 2.5 percent to 41 percent of cells in their human tumor samples expressed the marker. In additional experiments using similar mice on which human skin was engrafted, only tumor cells with the marker could produce tumors and metastases in the mice. (In his lab, Dr. Morrison noted, the same marker did not differentiate tumor-forming from nontumor-forming cells.)

The publication about CD271 is: Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271 by Alexander D Boiko and 11 colleagues, Nature 2010(Jul 1); 466(7302): 133-7. [PubMed citation].

Comments: The sentence: "In his lab, Dr. Morrison noted, the same marker did not differentiate tumor-forming from nontumor-forming cells" is noteworthy. Why the difference in results for CD271?

The publication by Boiko and co-authors was cited in a previous post to this blog, "Melanoma-initiating cells identified", dated July 1, 2010.

See also an earlier post to this blog, "Tumorigenic cells not rare in human melanoma", dated December 3, 2008.

CSC news update 2010-07-03

For links to recent news items about CSC, visit this [Topsy] page. An example of a news item that has received attention in the past week:

Cancer Stem Cells Are Not 'One Size Fits All,' Lung Cancer Models Show http://bit.ly/bE9F0V & http://bit.ly/amEkFR. Hashtag: #cancerSC. Posted to Twitter on Fri Jul 02 via TweetDeck

Melanoma-initiating cells identified

Melanoma-initiating cells identified by study by Krista Conger, News release, Stanford School of Medicine, June 30, 2010. Excerpt:

Scientists at the School of Medicine have identified a cancer-initiating cell in human melanomas. The finding is significant because the existence of such a cell in the aggressive skin cancer has been a source of debate. It may also explain why current immunotherapies are largely unsuccessful in preventing disease recurrence in human patients.

The news release is about this publication: Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271 by Alexander D Boiko and 11 co-authors, including Irving L. Weissman, Nature 2010(Jul 1); 466(7302): 133-7. [FriendFeed entry].

A blog post about this same publication is: Stanford scientists identify a melanoma-initiating cell by Krista Conger, Scope blog, Stanford School of Medicine, June 20, 2010.

See also a commentary about the publication: Cancer stem cells: Invitation to a second round by Peter Dirks, Nature 2010(Jul 1); 466(7302): 40-1. Excerpt:

Boiko et al. study a type of human skin cancer called melanoma and, in particular, cancer cells enriched in a stem-cell marker called CD271. They find that, unlike other cells from the same tumour, CD271-expressing (CD271+) cells could initiate and maintain tumour growth in vivo — an observation consistent with the existence of a melanoma-cell functional hierarchy.

This finding reflects a view different from that of an earlier study by Quintana et al.[3], which demonstrated that, in some cases, as many as 50% of human melanoma cells have tumorigenic potential. In addition, no marker tested identified a tumorigenic subpopulation. The authors[3] concluded that the frequency of cancer cells that can initiate tumorigenesis depends, in part, on the assessment techniques and assays.

Another news item, based on the same publication, is: New hope in fight against skin cancer as deadly 'master cells' are identified for first time, Mail Online, July 1, 2010. Excerpt:

However Dr Alexander Boiko, who made the discovery at Stanford University, said the newly discovered 'stem cells' in advanced skin cancers were often missed by conventional immunotherapy.

'Without wiping out the cells at the root of the cancer, the treatment will fail,' he said.

Comments: Boiko et al. and Dirks suggest reasons why results different from those of Quintana et al. were obtained. One possibility is that the melanomas that the latter authors studied were at an advanced stage. If, as a cancer progresses, more cells acquire the attributes of cancer stem cells, then advanced melanomas may contain very high frequencies of tumorigenic cells.

As Boiko et al. point out in their publication, "The most crucial test of the tumour stem cell hypothesis is that markers or pathways restricted to tumour stem cells can be targets for curative therapies in the patient, which has not yet been done."

On glioma recurrence and CSCs

Decreasing glioma recurrence through adjuvant cancer stem cell inhibition by Josh Neman and Rahul Jandial, Biologics: Targets & Therapy 2010(Jun 19); 4: 157-62 [OA review][FriendFeed entry]. Abstract:

Gliomas remain one of the most challenging solid organ tumors to treat and are marked clinically by invariable recurrence despite multimodal intervention (surgery, chemotherapy, radiation). This recurrence perhaps, is as a consequence of the failure to eradicate a tumor cell subpopulation, termed cancer stem cells. Isolating, characterizing, and understanding these tumor-initiating cells through cellular and molecular markers, along with genetic and epigenetic understanding will allow for selective targeting through therapeutic agents and holds promise for decreasing glioma recurrence.

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.

Patent application: Levels of Oct1 as a method of identifying CSCs

(WO2010065400) Cancer Biomarker and Methods of Using Thereof.

Excerpt from PCT Biblio. Data:

International Application No.: PCT/US2009/065742
Publication Date: 10.06.2010

Excerpt from Description:

Described herein are biomarkers which can be used for identifying a subject at risk for or evaluating the progression of cancer. In certain aspects, these biomarkers can be used to identify cancer stem cells. These biomarkers can include Octl or molecular variants thereof and downstream targets of Octl. In addition, described herein are methods for reducing the expression of these biomarkers associated with cancer.

CSCs responsible for metastasis identified

Cancer stem cells responsible for metastasis identified: HK study, Xinhua News Agency, June 4, 2010. Excerpt:

Hong Kong researchers have identified a subset of cancer stem cells responsible for metastasis in human colorectal cancer which can help better predict the prognosis and design a more suitable treatment for patients, according to a study made public by the University of Hong Kong on Friday.

The researchers from the university's medicine school discovered that cancer stem cells with a surface marker CD26, which marks a subset of cancer stem cells with metastatic capacity, are present in all terminal colon cancer cells and all metastatic cancer cells.

This news item is about the publication: A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer by Roberta Pang and 13 co-authors, including Wai Lun Law, Ronnie T Poon and Benjamin CY Wong [photos of authors], Cell Stem Cell 2010(Jun 4); 6(6): 603-15. [Summary][Twitter entry][Commentary][FriendFeed entry][Science Pond entry].

US Patent: Isolation and use of solid tumor stem cells

Isolation and use of solid tumor stem cells, United States Patent 7,713,710. [FreePatentsOnline][PatentStorm].
Publication Date: May 11, 2010.
Inventors: Clarke; Michael F. (Ann Arbor, MI), Morrison; Sean J. (Ann Arbor, MI), Wicha; Max S. (Ann Arbor, MI), Al-Hajj; Muhammad (Ann Arbor, MI).
Assignee: The Regents of the University of Michigan (Ann Arbor, MI) .
Appl. No.: 11/753,191
Filed: May 24, 2007
Abstract:

A small percentage of cells within an established tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. The solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells.

Parent Case Text:

CLAIM OF PRIORITY
This application is a Continuation of U.S. patent application Ser. No. 11/150,073, filed Jun. 10, 2005, which is a Continuation of U.S. patent application Ser. No. 09/920,517, filed Aug. 1, 2001, now U.S. Pat. No. 6,984,522, which claims priority to U.S. provisional applications Ser. No. 60/222,794, filed Aug. 3, 2000, and Ser. No. 60/240,317, filed Oct. 13, 2000, all of which are herein incorporated by reference in their entireties.

Google patents entry for Application Number 11/753,191 (The application that led to patent 7,713,710. The filing date was 24 May 2007).

Google patents entry for Application Number 11/150,073 (See Parent Case Text above: the filing date was 10 June 2005).

Google patents entry for Patent Number 6,984.522 (See Parent Case Text above: the filing date was 1 August, 2001 and the issue date was 10 Jan 2006). [FreePatentsOnline][PatentStorm].

Comment:

Not mentioned in the Parent Case Text above is United States Patent 7,115,360. [FreePatentsOnline][PatentStorm]. This patent was issued October 3, 2006 and filed on August 2, 2001.

The Parent Case Text for patent 7,115,360:

CLAIM OF PRIORITY
This patent is the United States national stage of PCT patent application PCT/US01/24243, published Feb. 14, 2002 as WO 02/12447, which is a continuation of U.S. Ser. No. 09/920,517, filed Aug. 1, 2001, now U.S. Pat. No. 6,984,522. This patent also claims priority to provisional patent applications U.S. Ser. Nos. 60/222,794, filed Aug. 3, 2000, and 60/240,317, Oct. 13, 2000.

Information about this patent was found via a Google search for "Isolation and use of solid tumor stem cells".

MicroRNA therapy could be a powerful tool to correct the CSC dysregulation?

Medical Hypothesis: No small matter: microRNAs - key regulators of cancer stem cells by Qing Ji, David Karnak, Ping Hao, Rongquan Wang and Liang Xu, Int J Clin Exp Med 2010(Mar 12); 3(1): 84-7 [FriendFeed entry][Connotea bookmark][Full text via PMC]. PubMed Abstract:

Emerging evidence demonstrates that both tumor suppressor and oncogenic miRNAs play an essential role in stem cell self-renewal and differentiation by negatively regulating the expression of certain key genes in stem cells. It seems logical that they may also be critical players in cancer stem cells. Though small in size, miRNAs play a key role in the epigenetic regulation of cancer stem cells. Specifically, the imbalance of oncogenic vs. tumor suppressor miRNAs may lead to dysregulation of cancer stem cells, thus causing excessive self-renewal and survival of cancer stem cells, and resistance to chemo/radiotherapy. We postulate that restoring the balance of miRNAs will correct this dysregulation via the direct and simultaneous modulation of downstream stem cell pathways involved in cancer stem cell self-renewal and/or differentiation. The resultant restoration of key regulatory pathways could improve therapeutic response. Restoring tumor suppressor miRNAs and/or inhibiting oncogenic miRNAs may provide a novel molecular therapy for human cancers, potentially via modulating cancer stem cells.

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).

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)

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.

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].

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 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].