A prevalent characteristic of solid tumors is the presence of hypoxic areas. Intra-tumoral hypoxia plays a well-known role in chemo-/radio-therapy resistance and is associated with poor prognosis as well as enhanced metastasis. Hypoxia-inducible factor 1-alpha (HIF-1- alpha) is a major mediator of the cellular response to hypoxia, which promotes malignant proliferation and progression in cancers. HIF-1-alpha expression is increased in a variety of tumors, but this is not restricted to hypoxic regions. Cyclin-dependent kinase 1 (CDK1) stabilizes HIF-1-alpha through direct phosphorylation of its Ser668 residue in a Von Rippel-Lindau (VHL)-independent manner, both under hypoxia, and at G2/M under normoxia. On the other hand, the heat shock protein 90 (HSP90), is a VHL-independent HIF-1-alpha stabilizer, that has been correlated with adverse prognosis and recognized as a therapeutic target in cancer. The crosstalk between CDK1-mediated and HSP90-mediated HIF-1-alpha stabilization and the involvement of therapeutic targeting has not been considered up to date.
Summary of the Invention
Renowned scientists at Fox Chase Cancer Center discovered that dual inhibition of CDK1 and HSP90 robustly reduces the level of HIF-1-alpha in several cancer cell lines and in immunodeficient mouse model. Use of CDK1 and HSP90 inhibitors, except for combination of R0-3306 and geldanamycin, is proposed for treatment of multiple cancers such as lung cancer, breast cancer, colon cancer, renal cancer, glioblastoma, or colorectal cancer.
- Mechanistic understanding of therapeutic action.
- Effective treatment of multiple cancers based on synergy.
- Cost-effective and fast reach of clinic for known drugs.
IP Status: The patent application was published US 2018/0243306 Al
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Inna Khartchenko, MS, MBA
Director, Technology Transfer and New Ventures