Androgen deprivation therapy (ADT) can be an effective treatment for men diagnosed with prostate cancer. By blocking testosterone, the therapy can slow or stop the cancer, contributing to a disease with high survival rates.
Prostate cancer is one of the most common cancers in men, and its growth is driven in part by male sex hormones called androgens. For patients who survive cancer, living with the side effects of ADT treatment can be challenging.
During and after ADT, patients can experience bone loss, frailty, decreased energy and a decline in cognitive function. For some men, the cognitive effects can be extreme, affecting not only themselves but their families and caregivers.
“It becomes not just about treating the cancer but about managing quality of life after cancer treatment,” said David Morilak, PhD, director of the Center for Biomedical Neuroscience and a professor of pharmacology at the Joe R. and Teresa Lozano Long School of Medicine at UT San Antonio’s Health Science Center.
The problem first came to Morilak’s attention during a meeting with a colleague from Mays Cancer Center at UT Health San Antonio, the academic health center and health system of UT San Antonio.
The colleague was studying prostate cancer and its treatment. Morilak was studying therapeutics for cognitive impairment associated with stress and changes in brain function.
“As we started to share what we do, it became really clear that there was a point of convergence,” Morilak said.
While ADT can be effective against prostate cancer, cognitive impairment associated with ADT can be an unfortunate, but expected, consequence of cancer treatment.
An unexpected candidate
Around the time this problem first came to Morilak’s attention, his lab was investigating a new antidepressant called vortioxetine for its potential ability to improve cognitive impairment related to stress and depression.
Vortioxetine is an FDA-approved antidepressant that also acts on several different serotonin receptors. Studies suggested that some people taking the drug experienced improvements in cognition, particularly older adults.
Morilak wondered whether vortioxetine could help address cognitive impairment caused by ADT.
With pilot funding from Mays Cancer Center, his team developed an animal model to investigate the question.
The research team focused on the brain’s ventromedial prefrontal cortex and hippocampus, which are centers for cognitive flexibility, the ability to use learned information and adapt when circumstances change, memory and spatial navigation.
The initial results showed that androgen deprivation produced cognitive deficits and vortioxetine reversed the effects. The findings established a working model of ADT-related cognitive impairment and a potential treatment.
Follow-up studies found that vortioxetine did not interfere with ADT’s effectiveness against cancer.
Separating aging from treatment
The next question was whether vortioxetine would work in older animals, where some cognitive decline occurs naturally.
With support from the National Institute on Aging, Morilak started to study older animals, about 14 months old, an age corresponding roughly to the late 50s or early 60s in humans, when the animals start to show some modest age-related cognitive decline.
Androgen deprivation made the impairment worse and, while vortioxetine improved the cognitive impairment related to the therapy, it did not affect natural age-related decline.
The findings suggest that vortioxetine is not acting as a cognitive enhancer but instead acts on pathological changes associated with androgen deprivation.
Building a model that includes cancer
To understand these effects in the context of cancer pathophysiology and potential interactions among the cancer itself, ADT and vortioxetine, Morilak developed an animal model that included prostate tumors.
Morilak obtained prostate cancer tumor fragments using a cell line originally derived from Copenhagen rats. To avoid the need for immune-suppressing drugs, which could be a factor in cognitive impairment, the implanted tumors needed to be genetically compatible with the recipient animal. Because Copenhagen rats are not commercially available and rarely used in research, Morilak’s team had to establish its own colony to support the study.
With National Cancer Institute funding, the team is currently using this model to study prostate tumors, ADT and cognitive impairment together.
This study was reviewed and approved by the UT Health San Antonio Institutional Animal Care and Use Committee, consistent with National Institutes of Health guidelines.
The team’s research shows that cancer itself also has an effect on cognition that is not reversed by vortioxetine. But when the tumor is treated with degarelix, an androgen-deprivation drug used to treat humans with prostate cancer, vortioxetine resolves the resulting cognitive impairment. This means there may be different mechanisms behind cognitive effects of cancer itself versus those associated with its treatment.
Looking beyond one drug
Morilak’s team is now seeking to understand how vortioxetine works and whether other existing medications could produce similar effects.
The underlying biology in question involves neuroplasticity, the brain’s ability to change.
Morilak said the brain is constantly adjusting and adapting. Connections between neurons become stronger, communication between regions develops, and neural circuits shift the balance between competing activities. When plasticity is impaired, a person may still be able to function but will have difficulty adapting to changing circumstances.
Morilak believes that vortioxetine’s effects on multiple receptors could restore lost plasticity. His team is now working to determine which targets are most responsible for the beneficial effect.
Cancer, treatment and beyond
Because vortioxetine is already FDA-approved, scientists may be able to move toward clinical testing faster than they could with a new drug.
“Clinical trials for drugs that are already approved can move more quickly, and it could have an immediate impact on patient outcomes,” Morilak said.
His broader goal is to create a roadmap for treating cognitive impairment associated with cancer and its therapies.
Each type of cancer, its treatment and the ways they affect the body are unique. Understanding the mechanisms involved could help scientists identify existing drugs that might be repurposed for different forms of treatment-related cognitive impairment.
The work also reflects the value Morilak sees in cross-disciplinary collaboration at the university.
“At UT Health San Antonio, we work together as one community and that makes it easy to cross disciplinary lines to see how we can help one another,” he said.
Morilak hopes this intersection between neuroscience and cancer research will open more possibilities for improving the quality of life for people who survive cancer.
“Many people are getting cancers at younger ages and living decades with the consequences of their treatment,” he said. “We can use this starting point to begin exploring other tools that we can use. I think it’s our job now to pay attention to what life is like after cancer. Instead of just aiming to help people live longer, we can aim to help them live better.”