Tumor-fighting compounds developed at Duquesne University that kill hard-to-treat cancer cells without damaging the body’s normal tissues will be further backed by a $2.8 million, five-year grant from the National Institutes of Health (NIH).
Principal investigator Dr. Aleem Gangjee, Distinguished Professor of Medicinal Chemistry at Duquesne, will continue the project with the Karmanos Cancer Center in Detroit, one of 40 National Cancer Institute-designated comprehensive cancer centers in the U.S.
Preliminary data from tests in mice show that the compounds kill tumor cells without toxicity to normal cells—avoiding the sickness and adverse reactions that accompany most existing cancer-fighting treatments.
This hyper-selectivity of the compounds is key to killing difficult-to-treat, slow-growing cancer cells, such as mesothelioma and some breast and liver cancers said Gangjee, who has five current NIH grants for his drug research.
“The government’s investment in Dr. Gangjee’s research, given the increasing difficulty of obtaining research funding, shows the huge potential that scientific reviewers believe these novel compounds hold and the scientific value of his cutting-edge research,” said Dr. Alan W. Seadler, associate academic vice president for the Office of Research.
With more than 1.5 million new cases of cancer diagnosed a year, Gangjee’s drug development could have a huge positive impact on many lives.
“His research has offered new ways to approach cancer chemotherapy and minimize adverse effects of these drugs,” said Pharmacy Dean J. Douglas Bricker. “This kind of research is absolutely necessary as more cancer cells become resistant to conventional therapy.”
Gangjee explained that the acidity of the cancer cell environment is critical to this process. Most cells function in a neutral environment, but cells in slow-growing, solid tumors exist in an acidic environment.
Growth in any cell requires folic acid, a B-complex vitamin, to build proteins and DNA so that the cells can replicate. The folic acid reaches individual cells via a molecular version of a taxi service—one that normally shuts down in an acidic environment. To overcome this hurdle, the clever cancer cells develop an alternative transport system with PCFT (proton-coupled folate transporters).
“PCFT functions spectacularly in acidic environments,” Gangjee explained. “Outside of these environments, they can function, but they have poor efficiency.”
Gangjee’s compounds exploit that weakness.
Ignoring transporters in normal cells, the compounds hitch rides on tumor PCFT transporters, carrying their drugs inside the tumor. Once inside, these compounds stifle DNA synthesis, killing the tumor.
“The normal cells look at the tumor cells and laugh because they don’t have any of the anti-tumor agents in them,” Gangjee said.
With this latest grant, Gangjee’s team of drug designers will optimize the efficiency of the compounds and their molecular structure, pinpointing specifically what contributes to the selectivity factor and to the inhibition of DNA inside the tumor.
“We hope the process, over five years, will provide compounds highly effective in killing tumor cells that could be ready for human trials,” he said.
One patent in the area that cover these drugs has been approved by the U.S. Patent Office.