“Recurring cancers have ‘learned’ how to evade chemotherapy by pumping it out of the cancer cells so that only sub-therapeutic concentrations remain in the cell, making the drug useless.” — SMU biochemist Pia Vogel
The SMU undergraduate students and Dallas-area high school students get hands-on experience working on cancer research in the combined SMU Department of Biological Sciences laboratories of Wise and Vogel.
The researchers and students are working to find ways to treat cancer patients whose cancer has either returned after initial chemotherapy or was initially hard to treat using chemotherapeutics. The research is funded in part by the National Institutes of Health.
Students recently in the lab included Victoria Bennet, Hockaday School, and Shaffin Siddiqui and Robert Luo, both from Highland Park High School. SMU undergraduates included Hamilton Scholar Alexis Sunshine, Clinton Osifo, Stefanie Lohse, Brianna Ramirez, Henry Thornton, Shirely Liu, Justin Musser, Jake Oien and Michael Fowler. Also currently working in the lab are M.S. student and Hamilton Scholar Collette Marchesseau (2016 SMU graduate), and Ph.D. students Amila Nanayakkara, Mike Chen, Courtney Follit, Maisa Oliveira and James McCormick.
“Often, recurring cancers have ‘learned’ how to evade chemotherapy by pumping the therapeutic out of the cancer cells so that only sub-therapeutic concentrations remain in the cell, making the drug useless,” said Vogel, a professor and director of the SMU interdisciplinary research institute, the Center for Drug Discovery, Design and Delivery.
The pumps that do the work are proteins that span the cell membranes and use the biological fuel ATP to actively pump chemotherapeutics and other toxins out of the cells.
“We like to compare these proteins to biological sump pumps,” said Wise, associate professor.
Wise and Vogel use a combination of computational, biochemical and human cell-based techniques to find new drug-like compounds that inhibit the action of the pumps. If successful, the novel drugs — or derivatives of them — will be given to patients with therapy-resistant cancer together with the chemotherapeutic.
“Since our novel compounds block the pumps, the chemotherapeutic will remain in the cell and kill the cancer that had not been treatable previously,” Vogel said.
The researchers have discovered drug-like compounds that can be modified and developed into medicines that target the protein, called P-glycoprotein.
The SMU researchers discovered the compounds after virtually screening more than 10 million small drug-like compounds made publically available in digital form from the pharmacology database Zinc at the University of California, San Francisco.
Using SMU’s Maneframe high performance computer, Wise ran the compounds through a computer-generated model of the protein. The virtual model, designed and built by Wise, is the first computational microscope of its kind to simulate the actual behavior of P-glycoprotein in the human body, including interactions with drug-like compounds while taking on different shapes. The promising compounds were then tested in the lab.
“We have been quite successful and already have identified close to 20 novel compounds that block the pumps in our cell-based assays,” said Wise. “In these experiments we culture therapy-resistant prostate or ovarian or colon cancer cells in the lab and then show that we can kill these cancer cells using normal amounts of commonly available therapeutics in the presence of our novel compounds — even though in the absence of our novel compounds, the cancer cells would not be treatable.”
A pharmaceutical hit compound, like those discovered by Vogel and her co-authors, is a compound that is a promising candidate for chemical modification so it can eventually be delivered to patients as a therapeutic drug. In the case reported here, the compounds were commercially available for testing. The timeline from drug discovery to development to clinical trials and approval can take a decade or more.
SMU undergraduates and high school students experience world-class research
SMU undergraduate and high school students have been involved in different aspects of the research. Typically the beginning students work together with graduate or advanced undergraduate students to learn techniques used in the lab.
Some perform small research projects. Others have simply learned state-of-the-art techniques and “how science works” in the context of critical human health problems.
“High school student Robert Luo was interested in the computational side of our work, so he’s worked with senior SMU Ph.D. candidate James McCormick on trying to evaluate how strongly one of the therapy-sensitizing compounds we found potentially interacts with the pump protein at different proposed binding sites,” said Wise. “It is actually a significant project and will help with our research.”
The opportunities available for students to learn how science works using high performance computing, biochemistry and cell biology can be valuable even for those who won’t necessarily become practicing scientists, said Wise, citing as an example a recent SMU graduate who previously worked in the lab.
“Ketetha Olengue (SMU ’15) is a good example,” he said. “She is now in her second year at the Keck School of Medicine at the University of Southern California, where she is pursuing her M.D. degree in a novel program with USC Engineering.” — Margaret Allen, SMU