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Study: Cells of three aggressive cancers annihilated by drug-like compounds that reverse chemo failure

Wet-lab experiments confirm the accuracy of an earlier computational discovery that three drug-like compounds successfully penetrate micro-tumors of advanced cancers to aid chemo in destroying the cancer.

Researchers at Southern Methodist University have discovered three drug-like compounds that successfully reverse chemotherapy failure in three of the most commonly aggressive cancers — ovarian, prostate and breast.

The molecules were first discovered computationally via high-performance supercomputing. Now their effectiveness against specific cancers has been confirmed via wet-lab experiments, said biochemistry professors Pia Vogel and John G. Wise, who led the study.

Wise and Vogel report the advancement in the Nature journal Scientific Reports.

The computational discovery was confirmed in the Wise-Vogel labs at SMU after aggressive micro-tumors cultured in the labs were treated with a solution carrying the molecules in combination with a classic chemotherapy drug. The chemotherapy drug by itself was not effective in treating the drug-resistant cancer.

“Nature designs all cells with survival mechanisms, and cancer cells are no exception,” said Vogel, a professor in the SMU Department of Biological Sciences and director of SMU’s Center for Drug Discovery, Design and Delivery. “So it was incredibly gratifying that we were able to identify molecules that can inhibit that mechanism in the cancer cells, thereby bolstering the effectiveness of chemotherapeutic drugs. We saw the drugs penetrate these resistant cancer cells and allow chemotherapy to destroy them. While this is far from being a developed drug that will be available on the market anytime soon, this success in the lab gives us hope for developing new drugs to fight cancer.”

The current battle to defeat cancer is thwarted by chemotherapy failure in advanced cancers. Cancer cells initially treated with chemotherapy drugs ultimately evolve to resist the drugs. That renders chemotherapy ineffective, allowing cancers to grow and spread.

Key to cancer cell resistance are often certain proteins typically found in all cells — cancerous or otherwise — that are outfitted with beneficial mechanisms that pump away toxins to ensure a cell’s continued survival. Nature has set it up that these pumps are prevalent throughout the body, with some areas naturally having more of the pumps than others.

“The cancer cell itself can use all these built-in defenses to protect it from the kinds of things we’re using to try to kill it with,” Wise said.

The most common of these beneficial defense mechanisms is a pump protein, P-glycoprotein or P-gp, as it’s called. Another is one seen in breast and many other cancers, called breast cancer resistance protein, BCRP. In the case of cancer cells on the first round of treatment, these pumps are typically not produced in high levels in the cells, which allows chemotherapy to enter most of the cells in the tumor. This often gives what looks like a good result.

Unfortunately, in the cancer cells that don’t die, the chemotherapeutic often changes the cell, which then adapts to protect itself by aggressively multiplying the production of its defensive pumps.

Upon subsequent rounds of chemo, the P-gp and BCRP pumping mechanisms have proliferated. They effectively resist the chemotherapy, which now is much less successful, or not successful at all.

“if enough of the pumps are present, the cancer isn’t treatable anymore,” said Wise, associate professor in the SMU Department of Biological Sciences. Researchers in the field have searched unsuccessfully for compounds to inhibit the pumps that could be used in the clinic as well.

The molecules that Wise and Vogel discovered stopped the pumps.

“They effectively bring the cancer cells back to a sensitivity as if they’d never seen chemotherapy before,” said Vogel. “And our data indicated the molecules aren’t cancer specific. They can be used to treat all kinds of cancers because they inhibit not just the P-gp pump, but also the breast cancer protein pump.”

To test the compounds, the researchers used amounts of chemotherapeutic that would not kill these multi-drug resistant cancers if the pumps were not blocked.

“We wanted to make sure when using these really aggressive cancers that if we do knock out the pump, that the chemotherapy goes in there and causes the cell to die, so it doesn’t just stop it temporarily,” Wise said. “We spent a fair amount of time proving that point. It turns out that when a cell dies it goes through very predictable morphological changes. The DNA gets chopped up into small pieces, and we can see that, and so the nucleus becomes fragmented, and we can see that. Under the microscope, with proper staining, you can actually see that these highly drug-resistant prostate cancer cells, for example, are dead.”

The Scientific Reports article, “Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells,” is available open access at this link.

Other co-authors are SMU Ph.D. doctoral candidate Amila K. Nanayakkara, and Courtney A. Follit and Gang Chen, all in the SMU Department of Biological Sciences; and Noelle S. Williams, Department of Biochemistry, UT Southwestern Medical Center, Dallas.

Getting at the heart of the problem
Unique to the experiment is that the molecules were also tested on three-dimensional micro-tumors. That is a departure from the usual cell-culture experiments, which are a two-dimensional film.

In two-dimensional experiments, every cell is exposed to the chemotherapeutic because the film is just one layer of cells thick. That method ignores one of the key challenges to reversing tumors — how to get drugs into the middle of a tumor, not just on its surface.

“We show that with the help of our inhibitor compounds, we actually make the tumor penetrable to chemotherapeutic,” Vogel said. “We can kill the cells in the middle of the tumor.”

A pathway to personalized medical treatments
Chemotherapy’s harmful side effects on non-cancerous organs is well-known. The discovery of molecules that target a specific pump may mitigate that problem.

A patient’s tumor can be sampled to see which pump is causing the drug resistance. Then the molecule that knocks out that specific pump can be added to the chemotherapy.

“That means you don’t open the door wide to toxins in the central nervous system,” Wise said. “That has some real implications for the future and for personalized medicine. In most of the previous clinical trials, inhibitors have opened the brain up to toxins. From what we can tell so far, our inhibitors do not increase the toxicity of chemotherapeutics in normal cells.”

An audacious discovery
P-gp is present in one form or another in everything that lives.

“It’s in your dog, it’s in your cat, it’s in yeast cells, it’s in bacteria, it’s everywhere,” Wise said. “Why is it everywhere? Because it’s a really wonderful solution to the problem of getting toxins out of a cell. P-gp is a tremendously sophisticated evolutionary solution to that problem. And as with most things in biology that work well, everybody gets it, because if you don’t have it, you didn’t survive.”

Biologists say that P-gp can pump out 95 of 100 chemotherapeutics, indicating it can grab almost any drug and throw it out of a cell.

“So there’s a certain audacity to say that we can use a computer and target one part of this protein — the motor — and totally avoid the part of the protein that has evolved to pump almost anything that looks like a drug out of the cell,” Wise said. “That’s an audacious claim and the findings surprised us.”

In their computational and wet-lab experiments, Wise and Vogel searched for molecules that inhibit ATP hydrolysis — the chemical energy reaction that powers the P-gp pump.

“We targeted the motor of the pump instead of the pump part of the pump because almost all the clinical trial failures in other studies were actually compounds that targeted the pump part of the pump — and they would just slow down the pumping of the chemotherapeutic,” Vogel said. “The time was ripe to do these structural models. We hypothesized that we could completely avoid the pumping mechanism and just target the motor.”

Computational method highly predictive
The wet-lab experiments confirmed the accuracy of the computational findings, Vogel said.

“The predictiveness of the computational methods was really high,” she said. “It completely exceeded my expectations. We had selected certain molecules that were predicted in those computational experiments to interact with the pump in certain ways and not in others, and we could show in our wet-lab experiments that the predictions were spot on.”

Fascinated by the novel approach to the research, the National Institute of General Medical Sciences funded much of the research.

Wise and Vogel tapped the high-performance computing power of SMU’s Maneframe, one of the most powerful academic supercomputers in the nation. Wise sorted through 15 million commercially available drug-like compounds made publically available in digital form from the pharmacology database Zinc at the University of California, San Francisco.

Then, again using ManeFrame, Wise ran the compounds through a computer-generated model of P-gp. The virtual model, designed and built by Wise, is the first computational microscope of its kind to simulate the actual behavior of P-gp in the human body, including interactions with drug-like compounds while taking on different shapes. He reported the dynamic functioning of the model in 2015 in the journal Biochemistry in “Multiple drug transport pathways through human P-glycoprotein.”

Process of elimination finds needle in the haystack
Out of 15 million drug-like compounds that were virtually screened, the researchers found 180,000 that in the computer were predicted to interact strongly with the ATP harvesting power plant part of the pump motor. From those, Wise and Vogel eliminated the ones that interact well with the pump part. Roughly 0.15 percent survived — several hundred.

“So that tells you how promiscuous that binding site is for compounds,” Wise said.

From there, they bought and tested in the lab a number of the remaining molecules.

“It was a process of elimination,” Vogel said. “Of the first 38 we tested, we found four. And because of the computational approach we took, it made failure relatively cheap. This is proof of principle that at least in those cases the compounds behave exactly in the lab as predicted in the computer. Which thrills the heck out of me — I never, ever would have thought that.”

The Vogel and Wise research labs are part of the Center for Drug Discovery, Design and Delivery in SMU’s Dedman College. The center’s mission is a novel multi-disciplinary focus for scientific research targeting medically important problems in human health. — Margaret Allen, SMU

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Dallas Innovates: SMU Researchers, Gamers Partner on Cancer Research

Adding the processor power of the network of “Minecraft” gamers could double the amount of computer power devoted to the SMU research project.

Reporter Lance Murray with Dallas Innovates reported on the research of biochemistry professors Pia Vogel and John Wise in the SMU Department of Biological Sciences, and Corey Clark, deputy director of research at SMU Guildhall.

The researchers are leading an SMU assault on cancer in partnership with fans of the popular best-selling video game “Minecraft.”

They are partnering with the world’s vast network of gamers in hopes of discovering a new cancer-fighting drug. Vogel and Wise expect deep inroads in their quest to narrow the search for chemical compounds that improve the effectiveness of chemotherapy drugs.

A boost in computational power by adding crowdsourcing may help the researchers narrow their search.

The Dallas Innovates article, “SMU Researchers, Gamers Partner on Cancer Research,” published June 5, 2017.

Read the full story.

EXCERPT:

By Lance Murray
Dallas Innovates

Game developers and researchers at SMU are partnering with a worldwide network of gamers who play the popular game in a crowdsourcing effort to beat the disease.

The project is being led by biochemistry professors Pia Vogel and John Wise of the SMU Department of Biological Sciences, and Corey Clark, deputy director of research at SMU Guildhall, the university’s graduate video game development program.

“Crowdsourcing as well as computational power may help us narrow down our search and give us better chances at selecting a drug that will be successful,” Vogel said in a release. “And gamers can take pride in knowing they’ve helped find answers to an important medical problem.”

Vogel and Wise have been utilizing the university’s ManeFrame supercomputer, one of the most powerful academic supercomputers in the country, to sort through millions of compounds that potentially could work in the fight against cancer.

Now, they’re going to try crowdsourced computing.

The researchers believe that the network of gamers will be able to crunch massive amounts of data during routine game play by pooling two weapons — human intuition and the massive computing power of the networked gaming machine processors.

Adding gamers could double processing power
That should more than double the amount of processing power aimed at their research problem.

“If we take a small percentage of the computing power from 25,000 gamers playing our mod we can match ManeFrame’s 120 teraflops of processing power,” said Clark, who is also an adjunct research associate professor in the Department of Biological Sciences.

“Integrating with the ‘Minecraft’ community should allow us to double the computing power of [SMU’s] supercomputer.”

The research labs of Vogel and Wise are part of the Center for Drug Discovery, Design, and Delivery in SMU’s Dedman College, whose mission is a multidisciplinary focus for scientific research that targets medically important problems in human health, the release said.

According to SMU, the research is partly funded by the National Institutes of Health.

The researchers narrowed a group of compounds that show potential for alleviating the issue of chemotherapy failure after repeated use.

Using gamers in research has happened before
Using human gamers to enhance data-driven research has been done before with success and is a growing practice.

Vogel cited the video game “Foldit.”

Read the full story.

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SMU Guildhall and cancer researchers level up to tap human intuition of video gamers in quest to beat cancer

Massive computational power of online “Minecraft” gaming community bests supercomputers

Video gamers have the power to beat cancer, according to cancer researchers and video game developers at Southern Methodist University, Dallas.

SMU researchers and game developers are partnering with the world’s vast network of gamers in hopes of discovering a new cancer-fighting drug.

Biochemistry professors Pia Vogel and John Wise in the SMU Department of Biological Sciences, and Corey Clark, deputy director of research at SMU Guildhall, are leading the SMU assault on cancer in partnership with fans of the popular best-selling video game “Minecraft.”

Vogel and Wise expect deep inroads in their quest to narrow the search for chemical compounds that improve the effectiveness of chemotherapy drugs.

“Crowdsourcing as well as computational power may help us narrow down our search and give us better chances at selecting a drug that will be successful,” said Vogel. “And gamers can take pride in knowing they’ve helped find answers to an important medical problem.”

Up to now, Wise and Vogel have tapped the high performance computing power of SMU’s Maneframe, one of the most powerful academic supercomputers in the nation. With ManeFrame, Wise and Vogel have sorted through millions of compounds that have the potential to work. Now, the biochemists say, it’s time to take that research to the next level — crowdsourced computing.

A network of gamers can crunch massive amounts of data during routine gameplay by pairing two powerful weapons: the best of human intuition combined with the massive computing power of networked gaming machine processors.

Taking their research to the gaming community will more than double the amount of machine processing power attacking their research problem.

“With the distributed computing of the actual game clients, we can theoretically have much more computing power than even the supercomputer here at SMU,” said Clark, also adjunct research associate professor in the Department of Biological Sciences. SMU Guildhall in March was named No. 1 among the Top 25 Top Graduate Schools for Video Game Design by The Princeton Review.

“If we take a small percentage of the computing power from 25,000 gamers playing our mod we can match ManeFrame’s 120 teraflops of processing power,” Clark said. “Integrating with the ‘Minecraft’ community should allow us to double the computing power of that supercomputer.”

Even more importantly, the gaming community adds another important component — human intuition.

Wise believes there’s a lot of brainpower eager to be tapped in the gaming community. And human brains, when tackling a problem or faced with a challenge, can make creative and intuitive leaps that machines can’t.

“What if we learn things that we never would have learned any other way? And even if it doesn’t work it’s still a good idea and the kids will still get their endorphin kicks playing the game,” Wise said. “It also raises awareness of the research. Gamers will be saying ‘Mom don’t tell me to go to bed, I’m doing scientific research.”

The Vogel and Wise research labs are part of the Center for Drug Discovery, Design and Delivery (CD4) in SMU’s Dedman College. The center’s mission is a novel multi-disciplinary focus for scientific research targeting medically important problems in human health. Their research is funded in part by the National Institutes of Health.

The research question in play
Vogel and Wise have narrowed a group of compounds that show promise for alleviating the problem of chemotherapy failure after repeated use. Each one of those compounds has 50 to 100 — or even more — characteristics that contribute to their efficacy.

“Corey’s contribution will hopefully tell us which dozen perhaps of these 100 characteristics are the important ones,” Vogel said. “Right now of those 100 characteristics, we don’t know which ones are good ones. We want to see if there’s a way with what we learn from Corey’s gaming system to then apply what we learn to millions of other compounds to separate the wheat from the chaff.”

James McCormick — a fifth year Ph.D. student in cellular molecular biology who earned his doctoral degree this spring and is a researcher with the Center for Drug Discovery, Design and Delivery — produced the data set for Clark and Guildhall.

Lauren Ammerman, a first-year Ph.D. student in cellular and molecular biology and also working in the Center for Drug Discovery, Design and Delivery, is taking up the computational part of the project.

Machines can learn from human problem solving
Crowdsourcing video gamers to solve real scientific problems is a growing practice.

Machine learning and algorithms by themselves don’t always find the best solution, Clark said. There are already examples of researchers who for years sought answers with machine learning, then switched to actual human gamers.

Gamers take unstructured data and attack it with human problem-solving skills to quickly find an answer.

“So we’re combining both,” Clark said. “We’re going to have both computers and humans trying to find relationships and clustering the data. Each of those human decisions will also be supplied as training input into a deep neural network that is learning the ‘human heuristic’ — the technique and processes humans are using to make their decisions.”

Gamers already have proven they can solve research problems that have stymied scientists, says Vogel. She cites the video game “Foldit” created by the University of Washington specifically to unlock the structure of an AIDS-related enzyme.

Some other Games With A Purpose, as they’re called, have produced similar results. Humans outperform computers when it comes to tasks in the computational process that are particularly suited to the human intellect.

“With ‘Foldit,’ researchers worked on a problem for 15 years using machine learning techniques and were unable to find a solution,” Clark said. “Once they created the game, 57,000 players found a solution in three weeks.”

Modifying the “Minecraft” game and embedding research data inside
Gamers will access the research problem using the version of “Minecraft” they purchased, then install a “mod” or “plugin” — gamer jargon for modifying game code to expand a game’s possibilities — that incorporates SMUs research problem and was developed in accordance with “Minecraft” terms of service. Players will be fully aware of their role in the research, including ultimately leaderboards that show where players rank toward analyzing the data set in the research problem.

SMU is partnering with leaders in the large “Minecraft” modding community to develop a functioning mod by the end of 2017. The game will be heavily tested before release to the public the second quarter of 2018, Clark said.

The SMU “Minecraft” mod will incorporate a data processing and distributed computing platform from game technology company Balanced Media Technology (BMT), McKinney, Texas. BMT’s HEWMEN software platform executes machine-learning algorithms coupled with human guided interactions. It will integrate Wise and Vogel’s research directly into the SMU “Minecraft” mod.

SMU Guildhall will provide the interface enabling modders to develop their own custom game mechanic that visualizes and interacts with the research problem data within the “Minecraft” game environment. Guildhall research is funded in part by Balanced Media Technology.

“We expect to have over 25,000 people continuously online during our testing period,” Clark said. “That should probably double the computing power of the supercomputer here.”

That many players and that much computing power is a massive resource attacking the research problem, Wise said.

“The SMU computational system has 8,000 computer cores. Even if I had all of ManeFrame to myself, that’s still less computing and brainpower than the gaming community,” he said. “Here we’ve got more than 25,000 different brains at once. So even if 24,000 don’t find an answer, there are maybe 1,000 geniuses playing ‘Minecraft’ that may find a solution. This is the most creative thing I’ve heard in a long time.” — Margaret Allen, SMU

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NCI grant funds SMU research into cancer-causing viruses that hide from the immune system

Genes common to both the human T-cell leukemia virus and high-risk human papillomaviruses activate survival mechanisms in cancer cells. An SMU lab, with National Cancer Institute funding, is hunting ways to inhibit those genes to halt the development of cancer.

SMU virologist and cancer researcher Robert L. Harrod has been awarded a $436,500 grant from the National Cancer Institute to further his lab’s research into how certain viruses cause cancers in humans.

Under two previous NCI grants, Harrod’s lab discovered that the human T-cell leukemia virus type-1, HTLV-1, and high-risk subtype human papillomaviruses, HPVs, share a common mechanism that plays a key role in allowing cancers to develop.

Now the lab will search for the biological mechanism — a molecular target — to intervene to block establishment and progression of virus-induced cancers. The hope is to ultimately develop a chemotherapy drug to block the growth of those tumor cells in patients.

“The general theme of our lab is understanding the key molecular events involved in how the viruses allow cancer to develop,” said Harrod, an associate professor in SMU’s Department of Biological Sciences whose research focuses on understanding the molecular basis of viral initiation of cancer formation.

While HTLV-1 and HPV are unrelated transforming viruses and lead to very different types of cancers, they’ve evolved a similar mechanism to cooperate with genes that cause cancer in different cell types. The lab discovered that the two viruses tap a common protein that cooperates with cellular genes to help the viruses hide from the immune system.

That common protein, the p30 protein of HTLV-1, binds to a different protein in the cell, p53, which normally has the job of suppressing cancerous growth or tumor development. Instead, however, p30 manages to subvert p53’s tumor suppressor functions, which in turn activates pro-survival pathways for the virus.

From there, the virus can hide inside the infected cell for two to three decades while evading host immune-surveillance pathways. As the cell divides, the virus divides and replicates. Then ultimately the deregulation of gene expression by viral encoded products causes cancer to develop.

“They are essentially using a similar mechanism, p30, to deregulate those pathways from their normal tumor-suppressing function,” Harrod said.

Tumor suppression, DNA damage-repair pathways, begin to fail with age
About 15 percent to 20 percent of all cancers are virus related. Worldwide, about 10 million people are infected with HTLV-1 and, as with other viral-induced cancers, about 3 percent to 5 percent of those infected go on to develop malignant disease.

Cancer is often associated with the process of normal aging, because our tumor suppression and DNA damage-repair pathways begin to break down and fail, explained Harrod. Our pathways don’t as easily repair genetic mutations, which makes us more susceptible to cancers like adult T-cell leukemia and HPV-associated cervical cancers or head-and-neck carcinomas, he said.

The human T-cell leukemia virus is transmitted through blood and body fluid contact, usually infecting infants and children via breastfeeding from their mother. A tropical infectious disease, it’s endemic to Southeast Asia, primarily Japan, Taiwan, China and Malaysia, as well as certain regions in the Middle East, Northern Africa and islands of the Caribbean. In the United States, Hawaii and Florida have the highest incidence of adult T-cell leukemia. HTLV-1 is highly resistant to most modern anticancer therapies, including radiotherapy and bone marrow or matching donor stem cell transplants. The life expectancy of patients with acute or lymphoma-stage disease is about six months to two years after diagnosis.

In the case of HPV, certain high-risk sub-types aren’t inhibited by today’s available HPV vaccines. It’s considered the high-risk HPVs are sexually transmitted through direct contact with the tissues of the virus-producing papillomas or warts. High-risk HPVs can also cause cervical cancers and head and neck carcinomas, many of which are associated with poor clinical outcomes and have high mortality rates.

How do viruses cause cancer?
For both HTLV-1 and HPV, the virus itself does not cause cancer to develop.

“It’s cooperating with oncogenes — cellular genes that become deregulated and have the potential to cause cancer,” Harrod said. “The role of these viruses, it seems, is to induce the proliferation of the cell affected with cancer. We’re trying to understand some of the molecular events that are associated with these cancers. ”

The lab’s three-year NCI grant runs through 2019. Harrod’s two previous grants awarded by the National Institutes of Health were also three-year-grants, for $435,000 and $162,000. Each one has targeted HTLV-1 and the p30 protein.

The lab’s first NCI grant came after the researchers provided the first demonstration that p30 could cooperate with cellular oncogenes, which have the potential to cause cancer, to cause deregulated cell growth leading to normal cells transforming into cancer cells. That original discovery was reported in 2005 in the article “A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions,” in the high-profile journal Molecular and Cellular Biology.

“We find that the p30 protein is involved in maintaining the latency of these viruses. These viruses have to persist in the body for 20 to 40 years before a person develops disease. To do that they have to hide from the immune response,” Harrod explained. “So p30 plays a role in silencing the viral genome so that the affected cells can hide, but at the same time it induces replication of the affected cells. So when the cell divides, the virus divides. We call that pro-viral replication.”

The term “latency maintenance factor” in reference to p30 originated with Harrod’s lab and has gained traction in the HTLV-1 field.

Under the lab’s second NCI grant, the researchers figured out how to block pro-survival pathways to kill tumor cells.

In the current grant proposal, Harrod’s lab demonstrated that by inhibiting specific downstream targets of p53 — essentially blocking pathways regulated by the p53 protein — they could cause infected tumor cells to collapse on themselves and undergo cell death.

“We do that independent of chemotherapy,” Harrod said. “So that was a big find for us.”

Goal is to eliminate cancer cells by inhibiting pathway
Each grant project builds upon the one before it, and the third grant extends the work, to now include high-risk HPVs.

“Now that we’ve shown we can block one or two of these factors to cause cell death, we’re starting to get an eye really on how we can inhibit these cancer cells and what potentially down the road may lead to a therapeutic,” Harrod said. “That’s the ultimate goal.”

One of the biggest challenges will be to inhibit the pathways in the tumor cells without targeting normal cells, he said. The lab’s recent findings indicate the researchers may soon be within reach of identifying a new strategy to eliminate cancer cells by inhibiting pathways key to their survival.

Harrod’s lab collaborates on the research with: Lawrence Banks, Tumor Virology Group Leader, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy; Brenda Hernandez, Associate Director, Hawaii Tumor Registry, University of Hawaii Cancer Center, Honolulu; and Patrick Green, Director, Center for Retrovirus Research, The Ohio State University. — Margaret Allen, SMU

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SMU biochemists, students probe membrane proteins that thwart cancer chemotherapies

“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.

SMU Cancer Research

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