Researchers have discovered that inhibiting CDK9, a DNA transcription regulator, reactivates genes that have been epigenetically silenced by cancer. Reactivation leads to restored tumor suppressor gene expression and enhanced anti-cancer immunity. It is the first time this particular kinase has been linked to gene silencing in mammals.
Jean-Pierre Issa, MD, Director of the Fels Institute for Cancer Research & Molecular Biology at the Lewis Katz School of Medicine at Temple University (LKSOM), led the research. The paper appears in the journal Cell.
It has been established that epigenetic mediators of gene silencing present new targets for cancer drugs. Hanghang Zhang, PhD, of the Fels Institute for Cancer Research & Molecular Biology at LKSOM, the first author on the report, performed a live cell drug screen with genetic confirmation to identify CDK9 as a target and to develop and test an effective inhibitor – MC180295. The new drug is highly selective, potentially avoiding the side effects associated with inhibiting the cell cycle. In the study it showed broad effectiveness against cancer both in vitro and in vivo. The drug was discovered in collaboration with investigators at the Moulder Center for Drug Discovery at the Temple University School of Pharmacy.
“In addition to reactivating tumor suppressor genes, CDK9 inhibition induces sensitivity to the immune checkpoint inhibitor α-PD-1 in vivo,” said Issa. “It is an excellent target for epigenetic cancer therapy.”
Other investigators contributing to the new study include Wayne Childers, George Morton, Marlene A. Jacobson and Magid Abou-Gharbia from the Moulder Center for Drug Discovery; Somnath Pandey, Hongxing Sun, Jozef Madzo, Woonbok Chung, Yasuyuki Okamoto, Takahiro Sato, Judit Garriga, Bela Patel, Jian Huang, Yi Zhang, Jaroslav Jelinek and Xavier Graña from the Fels Institute for Cancer Research & Molecular Biology; John Karanicolas from the Molecular Therapeutics Program at Fox Chase Cancer Center; Jittasak Khowsathit from the Molecular Therapeutics Program at Fox Chase Cancer Center and the Department of Molecular Biosciences at the University of Kansas; Oscar Perez-Leal, Carlos A. Barrero, Carmen Merali and Salim Merali from the Department of Pharmaceutical Sciences at the Temple University School of Pharmacy; Meghan Travers, Stephen B. Baylin and Cynthia A. Zahnow from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Joshua Pan and Cigall Kadoch from the Department of Pediatric Oncology at the Dana-Farber Cancer Institute and Harvard Medical School; Natarajan V. Bhanu, Johayra Simithy and Benjamin A. Garcia from the Epigenetics Institute, Department of Biochemistry and Biophysics at the Perelman School of Medicine at the University of Pennsylvania; and Noël J-M Raynal at the Département de pharmacologie et physiologie at the Université de Montréal.
Editor’s Note: Drs. Issa, Zhang, Childers and Abou-Gharbia, as well as Mr. Morton are co-inventors of the drug discovered during the course of this research. A patent is pending.