Dual HER2/VEGFR2 Kinase Inhibitors Targeting Resistant Breast Cancer and Its Aggressive Brain Metastasis: From Design to Formulation.

Summary

Cancer is one of the leading causes of mortality worldwide. According to the International Agency for Research on Cancer’s GLOBOCAN report, around 19.3 million new cases and nearly 10.0 million cancer deaths were reported in 2020. Breast cancer (BC) has the highest incidence rate among different cancers with about 2.3 million new cases and 685,000 deaths. HER2+ metastatic BC represents an aggressive type of BC that do not respond well to conventional anti-HER2 therapy owing to the heterogeneity between the primary BC and BCBM, the presence of the BBB which impedes penetration of most molecules, and the protective efflux systems in the brain. Although several agents were FDA approved for treatment of BCBM, limited efficacy and side effects present an urgent necessity to develop more efficacious therapy targeting aggressive BC tumors. The proposed research builds on our advanced knowledge of drug discovery, structural optimization integrated with computer-aided drug design (CADD), and our recently discovered lead compounds as selective HER2 Is. Through this multifaceted approach for developing potent and selective compounds to overcome resistance and to properly target BCBM.

In light of the significant roles both HER2 and VEGFR2 play in aggressive BC, we propose the development of dual HER2/VEGFR2 TKIs to target HER2+ BC with brain metastases or mutations. To the best of our knowledge, no such dual kinase inhibitor was reported before, yet reports of dual blockade of HER2 and VEGFR2 indicated more effective inhibition of HER2+ BC and thus their therapeutic potential. Dual HER2/VEGFR2 TKIs holds the potential for higher efficacy and lower side effects over single targeting or even combination therapy of two TKIs. This approach represents a promising treatment opportunity for many BC patients. 

Achievements

List of Publications from the Project

Partners

• Hamed I. Alyismail

Project Members

• Maha Nasr
• Khaled Abouzid Mohamed Abouzid
• Eman Mahmoud Elawady Dokia

Project Leaders

• May Adel Mohamed