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.

A difference between normal and cancer SC biology in the nervous system

Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition by Pedro Castelo-Branco and 12 co-authors, including Uri Tabori, Clin Cancer Res 2011(Jan 1); 17(1): 111-121 [Full text]. Translational Relevance:

Pediatric neural tumors (brain tumors and neuroblastoma) are the leading cause of morbidity and mortality in childhood cancer. This is due to their ability to recur after minimal disease is achieved. Telomerase is active in most malignant pediatric neural tumors. Therefore, telomerase inhibition may offer an effective treatment option for such patients. Because normal stem cells may require telomerase for continuous self-renewal, this therapy may have devastating effects on normal nervous system development and maintenance.

This study reveals that telomerase activation exists only in the tumor-initiating cancer subpopulation and is critical to sustain their survival and self-renewal potential. Importantly, normal neural or neural crest stem cells do not require telomerase for their self-renewal. Furthermore, as opposed to conventional chemoradiation therapies, telomerase inhibition results in irreversible loss of self-renewal capacity of tumor initiating cells in vitro and in vivo.

These observations uncover a difference between normal and cancer stem cell biology in the nervous system and suggest that telomerase inhibition may offer a specific and safe therapeutic approach for these devastating tumors.

For a commentary on this article, see: Anita B Hjelmeland and Jeremy N Rich, Clin Cancer Res 2011(Jan 1); 17(1): 3-5 (unlike the article, the commentary is not publicly accessible). Abstract:

Telomerase is an important mechanism by which cancers escape replicative senescence. In neural tumors, cancer stem cells express telomerase, suggesting that this may explain their preferential tumorigenesis. Oligonucleotide telomerase targeting selectively disrupts cancer stem cell growth through the induction of differentiation, adding to the armamentarium of anticancer stem cell therapies.

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.

CSC as a future avenue of research on breast cancer

Neoadjuvant chemotherapy for early breast cancer by J Sven D Mieog‌ and Cornelis JH van de Velde‌, Expert Opin Pharmacother 2009(Jun); 10(9): 1423-34. [PubMed Citation][ResearchGATE entry][FriendFeed entry]. Last sentence of the abstract:

In the near future, intraoperative fluorescent imaging and targeting of cancer stem cells will become important avenues of research.