Milan G. Chheda, M.D.
ABSTRACT:
The long-term goal of these pilot studies is to prevent glioblastoma (GBM) recurrence, and brain
metastases, by removing the senescent microenvironment that supports them. In the current
studies, we are using GBM as a model and proof of principle. GBM is the most common and
aggressive brain tumor. It kills most people within 2 years. Despite surgery, radiation, and
temozolomide chemotherapy, most GBMs recur within 6 months. While the incidence of GBM
dramatically increases after age 60, and continues to increase with age, little research has
focused on the age-dependent microenvironmental factors that promote growth and recurrence.
Our central hypothesis is that the aging brain and senescent microenvironment created by
radiation promote tumorigenesis and recurrence. Using cell-based models, genetically modified
mice, and repurposing therapies safe in humans that have senolytic properties, we will test the
causal effects of the senescent brain microenvironment on tumor pathogenesis. Pertinent to the
mission of the Longer Life Foundation, we chart a path to clinical translation and deeper
mechanistic studies, so that this work will improve the longevity and quality of life of patients at
risk for brain tumor recurrence and metastases.
LAY SUMMARY:
Brain tumors increase in frequency with age. In addition, radiation, a common treatment for brain
tumors causes premature aging of the brain, called senescence. To date, all approved therapies
target the tumor cells themselves. We are taking a different approach, by treating the aging brain.
We hypothesize that the aging brain environment helps cause these tumors to grow and recur.
We also believe that the aging brain provides fertile soil for metastases from other organs like the
lung and breast to grow in the brain and cause significant morbidity and mortality. We will test
whether senescent cells play a causative role in the development of brain tumors. We will also
test whether therapies that target senescent cells in the brain can help prolong survival of animal
models of disease. If successful, this work can be rapidly brought to the clinic, and will change
the way we treat and prevent cancer.
