Many drugs that address medical conditions can come with serious side effects. In drug commercials, the litany of potential side effects is often longer than the benefits being touted.
Carl Wagner is a professor in the the School of Mathematical and Natural Sciences at Arizona State University who came across the molecule bexarotene while designing a problem for an organic chemistry class he was teaching one year. It turns out that bexarotene can be used to treat the blood cancer T-cell lymphoma and is being explored as a treatment for both lung and breast cancer, among others.
The downside? It has serious side effects.
ASU News spoke with Wagner about his work with bexarotene and reducing its side effects, and how that work can be applied when creating future pharmaceutical solutions.
Question: Can you tell me about your work with bexarotene?
Answer: Bexarotene is an FDA-approved cancer drug that is essentially a molecule that binds to a protein, called RXR, that regulates gene expression — aka the amount and type of proteins cells make, along many pathways, some of which involve other proteins.
Q: Your team is working to understand what causes side effects like blood cholesterol and hypothyroidism for some people taking bexarotene. What does that process look like?
A: Because of the shape of the bexarotene molecule, some other gene expression regulated pathways are activated, and this activation results in raised triglyceride (and cholesterol) production, and this effect is observed in the blood of many patients taking bexarotene orally. Hypothyroidism is caused because bexarotene can also inhibit and activate pathways in the body that cause the hormones needed for correct thyroid function to be inhibited or made at incorrect levels.
Q: How are medicines modified to be effective without the long list of side effects often mentioned in commercials?
A: Sometimes the drug compounds can be modeled by 3D computer programs and AI in order to identify interactions that might give rise to wanted or unwanted effects. Often, it is a process of just slight structural modification and then experimentation to determine if the new molecule will provoke the unwanted side effects.
Bexarotene was approved in the late 1990s, and it has been very difficult to develop another molecule like it that is as effective against the cancer it treats while avoiding the raised triglycerides and hypothyroidism.
Q: How does someone weigh the side effects of a drug against its ability to address a medical problem?
A: Sometimes scientists who work in drug development characterize a "therapeutic index" for a drug, which can be thought of as a ratio of effectiveness to toxicity (or unwanted side effects).
Q: Why does the FDA approve drugs with so many side effects?
A: The FDA evaluates drugs in lengthy clinical trials that often move from pre-clinical work to small groups of human test subjects to larger and larger groups of patients. Even with this, it can be difficult to capture all potential side effects, and sometimes, all possible side effects for a given drug compound won't be known until it is being used to treat hundreds of thousands if not millions of people.
Additionally, the FDA may consider different thresholds for different types of drugs and treatments. So, a cancer drug may earn approval even though there are some severe side effects if it is effective, because many cancer drugs come with extreme side effects — hair loss, nausea, etc. Mostly, though, pharma tries to minimize potential side effects and de-risk drug treatments for the diseases for which they attempt to develop treatments.
Q: How can your work on this specific drug be used to address the larger problem of side effects?
A: We are working with molecular modelers and statisticians to try to develop sophisticated analyses of bexarotene ... that we hope, once we have worked out the modality fully, would be broadly applicable to other drugs. This model takes into account a wide array of biological outputs and the structural changes we make to try to determine the best structure and side effect profile.
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