2016-529 Inhibitors of IRES-Mediated Protein Synthesis

Inhibitors Of Ires-Mediated Protein Synthesis

 

SUMMARY

The Gera group at UCLA has discovered a novel analog of a known compound with significant anti-glioblastoma potential when used in combination with mTOR inhibitors.

 

BACKGROUND

Glioblastoma (GBM) is one of the most aggressive and lethal brain cancers. Patients that undergo treatment have a median survival of only 12 months. Since mTOR kinase is hyperactive in approximately 90% of glioblastoma tumors, the use of mTOR inhibitors has been proposed as a treatment for the disease. Unfortunately, they have been largely unsuccessful in the clinic due to tumor drug resistance. One of the primary mechanisms of resistance to mTOR inhibitors is the activation of a protein synthesis salvage pathway dependent on internal ribosome site (IRES)-mediated protein synthesis. Using this pathway, glioblastoma tumor cells can continue to produce proteins that are critical to their survival despite the inhibition of mTOR. A compound that blocks this pathway could potentially be used in combination with mTOR inhibitors to effectively treat a number of cancers, including glioblastoma.

 

INNOVATION

The Gera group at UCLA has discovered an analog of a previously studied compound that has significant anti-cancer effects when used in combination with mTOR inhibitors. The novel small molecule inhibits Cyclin D1 and c-MYC IRES-mediated protein synthesis, which is crucial to cancer survival. The inventors have shown that this small molecule demonstrates strong synergistic anti-GBM responses when used in conjunction with mTOR inhibitors, both in vitro and in vivo. This novel therapy has great potential as a life-prolonging treatment for patients with GBM.

 

APPLICATIONS

This small molecule analog can be used to improve the success rate of mTOR inhibitor treatment in:

    - Glioblastoma

    - Multiple myeloma

    - Other cancers that have been approved for treatment with mTOR inhibitors, including advanced renal cell carcinoma and advanced hormone receptor-positive HER2-negative breast cancer

 

ADVANTAGES

    - Can improve the effectiveness of mTOR inhibitors, which have not been a successful monotherapy for glioblastoma.

    - Blocks Cyclin D1 and c-MYC IRES-mediated protein synthesis, which is a crucial resistance mechanism for mTOR inhibitor-treated cancer cells.

 

STATE OF DEVELOPMENT

The inventors have in vitro and in vivo mouse xenograft data that support the therapeutic potential of their newly developed IRES-mediated protein synthesis inhibitor for glioblastoma when used in combination with mTOR inhibitors. The inhibition of IRES-mediate protein synthesis resulted in a significant decrease of the expression of crucial cell cycle proteins. The researchers previously published that this combinatory treatment is also effective for multiple myeloma.

 

RELATED MATERIALS

Shi Y, Yang Y, Hoang B, et al. Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress. Oncogene. 2016;35(8):1015-24.

Holmes B, Lee J, Landon KA, et al. mTOR Inhibition synergizes with reduced IRES-mediated translation of cyclin D1 and c-myc to treat glioblastoma. J Biol Chem. 2016 May 11. pii: jbc.M116.726927. [Epub ahead of print].

Patent Information:
For More Information:
Mark Wisniewski
Senior Director
mark.wisniewski@tdg.ucla.edu
Inventors:
Michael Jung
Joseph Gera
Alan Lichtenstein
Angelica Benavides-Serrato
Jihye Lee