Asfar Azmi, Ph.D., assistant professor of Oncology at the Wayne State University School of Medicine and the Barbara Ann Karmanos Cancer Institute, secured a multi-year $1,761,375 RO1 grant from the National Institutes of Health and National Cancer Institute for his research titled, “Clinical Translation of Nuclear Protein Export inhibitor in Metastatic Pancreatic Cancer.”
The grant number is 1RO1CA215427-01A1 and continues into 2022.
His co-investigators include Ramzi Mohammad, Ph.D., professor in the Department of Oncology at Karmanos and WSU; Philip Philip, M.D., Ph.D., F.R.C.P., leader of the Gastrointestinal and Neuroendocrine Multidisciplinary Team at Karmanos and WSU; Aliccia Bollig-Fisher, Ph.D., and Greg Dyson, Ph.D., both of the Department of Oncology; and Vinod Shidham, M.D., vice chair and director of Cytopathology at Karmanos and WSU.
“Every cell in the body has a precise mechanism to move proteins in and out of a cell’s nucleus,” Dr. Azmi said. “The export of the majority of nuclear proteins is carried out by a specialized transporter called exportin 1, or XPO1. This is a highly-regulated process that controls normal cellular functions.
“However, in cancer, the function of XPO1 is enhanced. This causes unusually high export of good tumor suppressor proteins to the wrong cellular compartment, leading to their functional inactivation,” which could pave the way to possible cancer cell growth.
Dr. Azmi previously discovered that high expression of XPO1 causes therapeutic resistance in pancreatic cancer, one of the deadliest and most difficult to treat cancers.
A small molecule drug called selinexor, which is being developed by Dr. Azmi’s team in collaboration with Karyopharm Therapeutics Inc., of Newton, Mass., can block XPO1 and enhance the activity of chemotherapeutic agents, particularly those used for pancreatic cancer treatment. This work has led to a Phase Ib/II clinical study, led by Dr. Philip.
This study involves the combination of selinexor with gemcitabine and nab-paclitaxel -- two clinically-approved agents for pancreatic cancer treatment. In this funded grant, Dr. Azmi and his team will investigate the molecular mechanism of selinexor-based combinations in pancreatic cancer tumor models and biopsy specimens from ongoing clinical trials.
The path to receiving the RO1 grant was made possible in part by the Sky Foundation Inc., which provided initial seed funding for Dr. Azmi. The seed funding helped generate critical data to develop a strong grant application. The foundation has funded Dr. Azmi’s collaborative research efforts since 2015, totaling more than $122,000.
The Sky Foundation, based in Bloomfield Hills, Mich., raises awareness and advances research for the early detection and treatment of pancreatic cancer.
“I am extremely pleased that Dr. Azmi has received such a prestigious RO1 grant,” said Gerold Bepler, M.D., Ph.D., president and chief executive officer of the Karmanos Cancer Institute and chair of the WSU Department of Oncology. “It is extremely difficult to receive such a grant and it speaks highly of the innovative research conducted by Karmanos’ clinical and scientific researchers. Dr. Azmi’s work represents a significant step forward in finding a more effective treatment for such a challenging disease. It’s gratifying that the National Institutes of Health and the National Cancer Institute recognize the ability of our researchers to develop new cancer treatment pathways.”
Dr. Azmi’s work is not restricted to pancreatic cancer treatment. He has been instrumental in introducing the concept of XPO1-targeted therapy for several other tumor models. There are various clinical principal investigators at WSU and Karmanos who are conducting Phase I and Phase II studies using selinexor, he said. These clinicians include Anthony Shields, M.D., Ph.D., associate center director of Clinical Sciences at Karmanos (colon clinical trial completed), and Elisabeth Heath, M.D., F.A.C.P., the Patricia C. and E. Jan Hartmann endowed chair in Prostate Cancer Research at Karmanos, as well as professor of Oncology and Medicine for WSU (prostate clinical trial completed).
Other clinicians involved in clinical trials using selinexor include Ammar Sukari, M.D., assistant professor in the Department of Oncology (lung and head and neck completed), and Rod Ramchandran, M.D., member of the Bone Marrow Transplant Multidisciplinary Team (multiple myeloma) at Karmanos.
Dr. Azmi also is part of another Phase II study involving selinexor with a combination of cancer drugs called R-CHOP for treatment of Non-Hodgkin’s Lymphoma, which is being led by Erlene Seymour, M.D., assistant professor of Oncology.