Karmanos researchers publish article in ‘Nature Reviews Clinical Oncology’

Congratulations to Ramzi Mohammad, Ph.D., member, Molecular Therapeutics Research Program, Karmanos Cancer Institute and Wayne State University School of Medicine (WSU SOM) and Asfar Azmi, Ph.D., co-leader, Tumor Biology and Microenvironment Research Program, Karmanos Cancer Institute and assistant professor, WSU SOM. Their work has been featured on the cover of the March 2021 edition of “Nature Reviews Clinical Oncology.” 

This publication, originally published in November 2020, is co-authored by Hafiz Uddin, Ph.D., postdoctoral fellow, Department of Oncology, WSU SOM, continues their successful basic, translational and clinical research on nuclear protein transport pathways. The comprehensive article covers the biology of protein transport and the pre-clinical and clinical development of small molecule inhibitors that target this important protein. The article is published here.

This group has spent more than a decade researching the pre-clinical development of nuclear transport inhibitors. Their work was critical in developing Selinexor (XPOVIO), a drug that is now Food and Drug Administration (FDA)-approved for the treatment of cancer patients with relapsed or refractory multiple myeloma and non-Hodgkin’s lymphoma. The drug was also introduced in a global COVID-19 clinical trial. Karmanos served as one site for the study. Selinexor is now being developed further under the Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute’s (NCI) Cancer Therapy Evaluation Program (CTEP). Several national clinical studies are planned.

“Protein movement within cells is important for their normal function,” explained Dr. Mohammad. “Such movement is guided by specialized carrier proteins or transporters. Exportin 1 or XPO1 is the major exporter of nuclear proteins. In cancer, XPO1 becomes hyperactive and displaces the tumor suppressors to the incorrect compartment, thereby inactivating their function. XPOVIO is a drug that blocks such transport and retains the tumor suppressors in the correct cellular compartment and allowing them to control tumor growth.”

“This is a joint effort beginning from our basic science group, which was supported by collaborative pharma partner Karyopharm Therapeutics Inc., as well as clinical investigators at Karmanos who collectively helped move a concept from the lab to FDA approval. We continue to find ways to improve the efficacy of this drug through the discovery of novel combinations. There is a need to identify prognostic and therapeutic biomarkers that could guide a more tailored XPOVIO therapy and is currently being intensively investigated by our group,” Dr. Azmi said.

In line with this project, the team is currently conducting correlative research on two active clinical studies at Karmanos. The first is a National Institutes of Health (NIH) Method to Extend Research in Time (MERIT) Award-funded study on pancreatic cancer. This study is being led by Philip Philip, M.D., Ph.D., F.R.C.P., leader, Gastrointestinal and Neuroendocrine Tumor Multidisciplinary Team (MDT) at Karmanos Cancer Institute, professor, WSU SOM. The second study is on non-Hodgkin’s lymphoma and is led by Erlene Seymour, M.D., member of the Malignant Hematology MDT, Karmanos Cancer Institute, assistant professor, WSU SOM, and Jeffrey Zonder, M.D., leader of the Multiple Myeloma and Amyloidosis MDT, Karmanos Cancer Institute, and professor, Departments of Hematology and Oncology, WSU SOM.

“I am very proud that work done by our investigators on nuclear transport biology continues to bring success to this institution. Their tremendous work is emphasized by the publication of this high-impact article. I congratulate the Karmanos team for helping the development of a drug and for playing such a significant role in the FDA approval of Selinexor,” said Gerold Bepler, M.D., Ph.D., president and CEO of Karmanos.

In addition to the work conducted by Dr. Mohammad and Azmi’s team, several other Karmanos investigators contributed to the development of the drug. These clinical investigators include Karmanos physicians Anthony Shields, M.D., Ph.D.; Elisabeth Heath, M.D., FACP; and Ammar Sukari, M.D.