Method of treating cancers by inhibition of PERK, a master regulator of the UPR pathway critical for tumor growth and survival
Timothy J Cardozo, MD, PhD
Assistant Professor, Department of Pharmacology
Background and Description of Technology:
Human diseases such as cancer or neurodegenerative diseases share a common mechanism whereby abnormal cells survive longer than they should due to a mechanism called the Unfolded Protein Response (UPR). Development of therapeutics that modulate the UPR has recently been the subject of commercial interest. Sublethal doses of radiation and chemotherapy causing severe hypoxia (oxygen starvation) in tumor cells have been reported to activate UPR and lead to tumor survival. Therefore, modulation of the UPR in tumors would be a novel anti-cancer approach that targets a fundamental process that hinders current treatments. PERK is one of three UPR transducers activated in response to hypoxia. Tumors that lack PERK activity are small and diminished in ability to translate mRNAs involved in angiogenesis, tumor survival and growth. The clinical importance of PERK as a target for chemotherapeutic intervention is highlighted by the discovery that Bortezomib, a currently marketed treatment for multiple myeloma, has been shown to perturb the PERK signaling cascade as one of its anti-myeloma effects. Moreover, PERK inhibitors might be used to treat solid tumors that have increased UPR signaling such as lung, breast, liver, gastric, and colon cancer. To date, however, no high-throughput screening attempts have successfully identified PERK-specific small molecule inhibitors.
Dr. Cardozo has used novel technology involving in silico screening of the pharmacophore space for PERK inhibitors coupled with biochemical assays. This rational drug design method has led to the discovery of 14 selective PERK inhibitors, with several potent, lead compounds potentially ready for medicinal chemistry optimization, preclinical advancement and advancement to clinical trials for oncology. The technology platform is poised to identify chemically diverse anti-UPR compounds with potential activity against various clinical indications.
A patent application has been filed related to method of identifying and treatment of cancer with PERK inhibitors as well as a pharmaceutical composition. NYU is seeking commercial partners to initially focus on developing PERK inhibitors as anti-cancer therapeutics, either stand-alone or in combination with existing therapies. Given the broad technology platform, the startup or partnership could expand focus on developing leads for areas beyond cancer or form a drug development company.