Wednesday, November 24, 2010

Verastem brings CSC target into “sharper” focus

The launch of Verastem, Inc., in Boston last week with the securing of $16 million Series A financing , signals the coming of age of cancer stem cells (CSCs) as a target for solid cancers. 

Verastem's approach is based on the research of its founders, Piyush Gupta, Eric Lander and Robert Weinberg (published in Cell 2008, 2009).  They showed that breast cancer epithelial cells undergo mesenchymal transition and acquire CSC markers, CD44(+)/CD24(-/low) when exposed to E-cadherin short hairpin RNA (E-cad shRNA; blocks CDH1 gene, which encodes E-cadherin).  This epithelial-mesenchymal transition (EMT) is known to enrich cells with stem-cell like properties and poor prognosis.  In a high throughput screen, Gupta and colleagues screened 16,000 compounds and found 32 that inhibited EMT – one of them, salinomycin, reduced CSCs by over 100-fold compared to paclitaxel.

The granddaddy and pioneer of CSC-based therapeutics is OncoMed which penned a $1.4 billion deal with GSK last year.  Their founders, Max Wicha and Michael F. Clarke, placed CSCs in the crosshairs of anti-cancer drug discovery with the separation of CD44(+)CD24(-/low)Lineage(-) tumorigenic (tumor initiating) cells from the nontumorigenic breast cancer cells in 2003, and establishment of  OncoMed in 2005.  While OncoMed is discovering and developing monoclonal antibody-based therapeutics, Verastem will use its proprietary CSC high throughput screening strategy to discover small molecules.  

The CSC-targeted approach is by no means exclusive to OncoMed or Verastem.  CSCs follow a genetic program similar to normal stem cells and is controlled by key developmental signaling pathways.  Four major developmental signaling pathways are also key to CSCs: Bmi-1, Notch, Sonic Hedgehog and Wnt.  Thus, many other companies, taking a side track targeting these pathways, are also strong contenders in developing CSC-targeted therapeutics.  For instance:  Merck compound MK-0752 which targets gamma-secretase (Notch pathway) reduced CSCs in women with advanced breast cancer in a study involving 35 women.  In fact,  OncoMed’s lead anti-cancer stem cell (anti-DLL4) humanized antibody, OMP-21M18, which is in Phase I/II trials, binds to the membrane-binding portion of DLL4 and prevents its interaction with Notch-1 and Notch-4 receptors.  Infinity Pharmaceuticals’ IPI-926 and Genentech/Curis’ GDC-0449, both derivatives of cyclopamine, interfere with hedgehog signaling, are also in clinical trials.  Another experimental compound, GSI-18 reduces frequency of neuospheres in glioblastoma model.  Since PI3K/Akt pathway and molecular chaperons are also involved, many drug candidates effecting this pathway are already in development.  A report from BioPharm lists over fifty R&D programs to target CSC.

(From: J Clin Invest. 2007;117(10):2740–2750, Fig 2 | DOI | FullText |)

"If effective drugs against cancer stem cells can be developed, one obvious strategy would be to use them in combination with standard chemotherapeutic agents, so that all types of cells in a tumor could be attacked. That way, cancer would be attacked as AIDS is now — with a cocktail of chemicals that blocks all escape paths. Both the AIDS virus and cancer cells can change DNA to dodge an effective drug, but are thought to perish if confronted with many drugs at once." - Quote from NYTimes


Further Readings:
Verastem's technology:
  • Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening.
  • Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES.  Cell. 2009 Aug 21;138(4):645-59. | DOI | Scholar |
  • The Epithelial-Mesenchymal Transition Generates Cells With Properties of Stem Cells.
  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. Cell. 2008 May 16;133(4):704-15. | DOI | Scholar |
  • Cancer stem cells: mirage or reality? Gupta PB, Chaffer CL, Weinberg RA. Nat Med. 2009 Sep;15(9):1010-2. | Scholar |
OncoMed's Technology:
  • Prospective identification of tumorigenic breast cancer cells. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-3988. | PubMed |
  • DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency. Timothy Hoey, Wan-Ching Yen, Fumiko Axelrod, Jesspreet Basi, Lucas Donigian,Scott Dylla, Maureen Fitch-Bruhns, Sasha Lazetic,In-Kyung Park, Aaron Sato,Sanjeev Satyal, Xinhao Wang, Michael F. Clarke, John Lewicki and Austin Gurney. Cell Stem Cell. 2009 5:168-177. | Scholar |
Others/General Refs:
  • Screening Could Lead to More Potent Cancer Drugs. Nicholas Wade. NYTimes. August 14, 2009 | WWWLink |
  • Firms Seek to Prove Cancer Stem Cell Hypothesis. Keith Markey. Genetic Engineering and Biotechnology News. 2009 Oct 15;29(18) | FullText |
  • Notch Pathway Inhibition Depletes Stem-like Cells and Blocks Engraftment in Embryonal Brain Tumors.  Cancer Res. 2006  Aug. 1;66:7445 | DOI | FullText |


  1. Update on OncoMed's OMP-21M18 monoclonal antibody (March 01, 2011 press release). --- OMP-21M18 blocks Delta-like 4 ligand (DLL4), an activator of Notch signaling. A study published in the March 1, 2011 issue of Cancer Research, showed that OMP-21M18 was equally efficacious against colon tumor xenografts containing KRAS mutation or wild type KRAS; on the other hand cetuximab (Erbitux) was inactive against KRAS mutant tumors. OMP-21M18 treated tumors had lower cancer stem cell frequency, higher apoptosis and it also increased the efficacy of chemotherapy (irinotecan). Currently, OMP-21M18 is in Phase 1b trials for colorectal, pancreatic and other cancers. --- (

  2. According to recent discussions at LinkedIn Oncology Pharma™ Group, agents targeting Notch signaling are being withdrawn (rumors!) from development due to GI toxicity; Notch signaling is also required for maintenance of intestinal stem cells in crypts. Furthermore, Joong Kyu Kim, Senior Scientist at PharmAbcine, pointed out, "early last year(2010), Genentech research group reported that prolonged inhibition of DLL4(which binds majorly to the Notch1 in the angiogenesis process and thymocyte development) induces vascular neoplasms." read full discussion at