A Fred Hutchinson Cancer Research Center group has used a cell-based screen to identify 12 potential therapeutic targets in MYC-driven cancers that could be more druggable than MYC.1 The researchers hope to find an industry or academic partner to help develop inhibitors of some of the targets.

Aberrant overexpression of c-Myc (MYC) occurs in a variety of cancers. For example, 50% of ovarian cancers and 30% of hepatocellular carcinomas are driven by MYC overexpression.2,3

But the structure of MYC lacks any druggable domains, and as a result it has been impossible to design compounds that cleanly hit the protein. Previous studies have suggested other nonmutated genes and signaling pathways that are active within cancer cells and are required for survival of MYC-driven malignancies.4 However, only a handful of druggable targets, such as cyclin dependent kinases (CDKs), have been identified by these efforts so far.5

In addition to these screening efforts, two papers have also recently implicated bromodomain containing 4 (BRD4) as a potential therapeutic target in MYC-driven cancers. A team from Cold Spring Harbor Laboratory and Dana-Farber Cancer Institute and a team from GlaxoSmithKline plc, Cellzome AG and the UK independently showed evidence for efficacy of BRD4 inhibitors in mouse models of leukemias characterized by MYC activation.6,7

The Fred Hutchinson team, led by Carla Grandori, has now developed an additional screening approach to identify new pathways and genes that could serve as therapeutic targets for cancers that overexpress MYC.

The team screened a small interfering RNA library that targeted about 3,300 genes encoding known cancer-associated proteins, including tyrosine kinases, ubiquitin ligases, DNA repair proteins and other known druggable targets.

The screen identified 148 genes that reduced cell survival following siRNA knockdown in MYC-overexpressing human fibroblasts. Based on predicted druggability, potential involvement in cancer pathways and potential toxicity, the researchers pared the list down to 48.

Next, the researchers looked at the 48 genes in a cell culture model of MYC-driven neuroblastoma. In those cells, siRNA against 12 of the targets selectively induced cell death.

Among the 12 candidates, the team selected casein kinase 1e (CSNK1E; CKI-e) for the remainder of the study because its knockdown potently and selectively inhibited MYC-amplified cancer cell survival and because research tool inhibitors of the protein are available.

In mice with human neuroblastoma xenografts, a CSNK1E inhibitor decreased tumor growth compared with vehicle control.

The findings were published in the Proceedings of the National Academy of Sciences. The paper also included researchers from the University of Washington.

"This screening approach shows that we can target nonmutated genes that are essential for the expression and function of MYC," Grandori told SciBX. Grandori is a research member at Fred Hutchinson.

"As MYC is a nondruggable target as far as small molecules go and other approaches such as oligonucleotides or RNAi have either failed or have the drawbacks of biologics, the approach described by the authors, as well as others, is very elegant and offers a way around the druggability issue," said Dominique Cheneval, founder, president and COO of Novation Pharmaceuticals Inc.

The others include a group from Baylor College of Medicine, who earlier this year used a similar approach with an RNAi library to identify pathways that support MYC-driven cancers. The team identified and focused on genes involved in SUMOylation including SUMO1 activating enzyme subunit 1 (SAE1) and SAE2 (UBA2) as potential druggable targets.8

Novation has a cell-based assay technology to identify small molecules that influence mRNA stability and translation. The company
has identified MYC inhibitors that alter MYC mRNA expression and translation using the technology, but it has not released functional data.

Teaming up

The Fred Hutchinson group now has 11 targets "including kinases and proteins with known druggable domains that could be very promising for MYC-amplified cancers," Grandori told SciBX. "We are doing additional bioinformatics and validation experiments for some of the targets, including CSNK1E, but we can't go after them all."

Thus, the team's next hope is to partner with a company or academic institution to develop and test inhibitors of CSNK1E and other validated targets for drug discovery.

Grandori also believes that the importance of her study extends beyond the identification of potential therapeutic targets for MYC-driven cancers.

She noted that her approach is unique from other cancer-directed siRNA screening efforts because it uses a different cell system. "Many discovery screens in use today utilize genetically and phenotypically diverse human cancer cell lines that have been cultured for years and then resort to bioinformatics to infer synthetic lethal interactions. It is clear that there is too much noise," said Grandori.

Her team utilized human foreskin fibroblasts that were engineered to allow researchers to study the effects of a single oncogene at a time, and unlike other noncancerous cells, this cell line is able to express oncogenes without losing cell viability, she added.

Grandori told SciBX that Fred Hutchinson has filed patent applications for the use of inhibitors toward CSNK1E and provisional patent applications for the other identified targets. The IP is available for licensing. The screening technology has not been patented.

Martz, L. SciBX 5(27); doi:10.1038/scibx.2012.696
Published online July 12, 2012


1.   Toyoshima, M. et al. Proc. Natl. Acad. Sci. USA; published online May 21, 2012; doi:10.1073/pnas.1121119109
Contact: Carla Grandori, Fred Hutchinson Cancer Research Center, Seattle, Wash.
e-mail: cgrandor@fhcrc.org

2.   Chen, C.H. et al. Int. J. Gynecol. Cancer 15, 878-883 (2005)

3.   Takahashi, Y. et al. Pathol. Int. 57, 437-442 (2007)

4.   Mizuarai, S. et al. Curr. Mol. Med. 8, 774-783 (2008)

5.   Horiuchi, D. et al. J. Exp. Med. 209, 679-696 (2012)

6.   Zuber, J. et al. Nature 478, 524-528 (2011)

7.   Dawson, M.A. et al. Nature 478, 529-533 (2011)

8.   Kessler, J.D. et al. Science 335, 348-353 (2012)


      Baylor College of Medicine, Houston, Texas

      Cellzome AG, Heidelberg, Germany

      Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.

      Dana-Farber Cancer Institute, Boston, Mass.

      Fred Hutchinson Cancer Research Center, Seattle, Wash.

      GlaxoSmithKline plc. (LSE:GSK; NYSE:GSK), London, U.K.

      Novation Pharmaceuticals Inc., Burnaby, British Columbia, Canada

      University of Washington, Seattle, Wash.