January 26, 2015

By: admin

By: Suzanne Canada, Ph.D.
Tanager Medical Writing

An exciting report was released in October about a new class of targeted anti-tumor drugs, in which genetically engineered stem cells were used to deliver cytotoxins to brain tumors.¹ Brain cancers known as glioblastomas (GBM) are notoriously difficult to treat because the tumors often re-grow after surgery and because most standard cancer therapies cannot pass the blood-brain barrier. Those cancer therapies that can reach the tumors must be delivered at high doses which can be toxic to the entire body, without specifically targeting the GBM tumor. In this case, a research team at Massachusetts General Hospital (MGH) in Boston used stem cells, added to mouse brain tumors after surgery, to deliver Pseudomonas exotoxin directly at the site of the tumor itself. ²

Although this research is cutting-edge and an exciting development for GBM patients, the idea of using toxins attached to targeting molecules such as antibodies or specific ligands has long been explored as a way of fighting diseases, especially cancer. One popular approach has been to use antibodies linked to toxins to aid in targeting the therapy. (See Chari 2008 and Goldmacher 2011 for reviews).^{3, 4} An example is the approach taken by group of researchers looking for ways to increase the effectiveness of Herceptin®, a monoclonal antibody that is best known for targeting HER-overexpressing malignant breast cancer tumors. Antibody was coupled to both diphtheria toxin and multi-walled carbon nanotubes. They found that both conjugates were more effective in specifically killing HER-2 expressing cells than Herceptin® alone.⁵

An elegant approach to targeting toxins is to activate the toxin by cleavage at the site of therapy. This is precisely the approach used by Schafer and colleagues.⁶ Their model system exploited the fact that metalloproteinases are commonly overexpressed on the surface of squamous cell cancers. Anthrax toxin was engineered to be activated by cleavage by urokinase plasminogen activator (uPA) on the cell surface and metalloproteinases. This approach seemed to work on xenografted human head and neck squamous cell carcinoma (HNSCC) cell lines by inducing apoptotic and necrotic tumor cell death. However, cultured cancer cell lines were found to be insensitive to the engineered toxin, so the researchers concluded that the regulation of two-fold activation was not straightforward as anticipated.

Shiga toxin– produced by an organism responsible for bacterial dysentery – has properties that could be harnessed for cancer research⁷. A group of researchers took advantage of the binding of the Shiga toxin B pentamer to the glycosphingolipid globotriaosylceramide (Gb3) on the cell surface. After binding, the Shiga toxin complex is internalized by eukaryotic cells where the Shiga toxin A moiety can exert its toxic effect. Gb3 is reportedly over-expressed in throat, gastric, and ovarian cancers—and researchers hope that this overexpression pattern could be used to attain more targeted therapy. Specific binding of GB3 by the Shiga toxin B pentamer could also be exploited for imaging of these tumors and for delivering a genetically engineer Shiga toxin A chimera that would only be activated in cancer cells.

In their quest for new and more effective therapies, researchers have noted that bacterial toxins are examples of highly toxic, but also targeted and regulated systems that have co-evolved with the eukaryotic hosts (humans).^{8, 9} In the words of Fabbri et al., “Knowledge of their properties could be used for medical purposes.”  List Biological Laboratories, Inc. provides purified bacterial toxins for research purposes, including Anthrax toxins (Product # 169, 172, & 176), Shiga toxins (Product # 161 & 162), Diphtheria toxins (Product # 149, 150, & 151), and others.

 

1. Paddock C., (2014) Stem cells that release cancer-killing toxins offer new brain tumor treatment. Last accessed: 06 January 2015.
2. Stuckey DW, Hingtgen SD, Karakas N, Rich BE, Shah K (2015) Engineering toxin-resistant therapeutic stem cells to treat brain tumors Stem Cells 33(2):589-600. doi: 10.1002/stem.1874. PMID: 25346520
3. Chari RV (2008) Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 41(1):98-107. PMID: 17705444
4. Goldmacher VS, Kovtun YV (2011) Antibody-drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells Ther Deliv 2(3):397-416. PMID: 22834009
5. Oraki KM, Mirzaie S, Zeinali M, Amin M, Said HM, Jalaili A, Mosaveri N, Jamalan M (2014) Ablation of breast cancer cells using trastuzumab-functionalized multi-walled carbon nanotubes and trastuzumab-diphtheria toxin conjugate Chem Biol Drug Des 83(3):259-65. PMID: 24118702
6. Schafer JM, Peters DE, Morley T, Liu S, Molinolo AA, Leppla SH, Bugge TH (2011) Efficient Targeting of Head and Neck Squamous Cell Carcinoma by Systemic Administration of a Dual uPA and MMP-Activated Engineered Anthrax Toxin. PLoS ONE 6(5): e20532. PMID: 21655226 
7. Engedal N, Skotland T, Torgersen ML, Sandvig K (2011) Shiga toxin and its use in targeted cancer therapy and imaging Microb Biotechnol 4(1):32-46. PMID: 21255370
8. Barth H, Aktories K, Popoff MR, Stiles BG (2004) Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins Microbiol Mol Biol Rev 68(3):373-402.
   PMID: 15353562
9. Fabbri A, Travaglione S, Falzano L, Fiorentini C (2008) Bacterial protein toxins: current and potential clinical use Curr Med Chem 15(11):1116-25. PMID: 18473807