Tissue Repair and Regeneration After Radiotherapy-Related Bone Damage
Radiotherapy with or without chemotherapy has been successful in treating people with cancer. With increased survivorship, the bystander effects of radiotherapy, including bone damage, result in a gamut of bone changes from osteopenia and osteoporosis to osteoradionecrosis and fractures. According to the American Cancer Society, 1 in 8 men and 1 in 10 postmenopausal women over the age of 60 will develop invasive cancer. Elderly populations are predisposed to osteoporotic fractures and are at a higher risk of bone damage from radiotherapy. Dr. Chandra's lab is working to develop a viable therapeutic intervention that alleviates radiotherapy-induced osteoporosis.
Radiotherapy is modeled in animals by focal radiation therapy (FRT). We have previously shown that radiation damage to rodent bone is caused in part by DNA damage and cellular apoptosis, thereby reducing functional osteoblasts and osteocytes. These cellular changes do not account for more than 90% suppression in bone formation rate. Dr. Chandra's research team reduced radiation-induced bone damage and cellular apoptosis and improved bone formation using bone anabolic drugs, such as parathyroid hormone, neutralizing antibodies against sclerostin, and by stabilizing DNA repair proteins using proteasome inhibitors.
However, activating DNA repair pathways comes with concerns, especially with recurring cancers. Cellular senescence is one of the major pathways that influences the fate of a cell with significant DNA damage in the absence of apoptosis, and is accompanied with a pro-inflammatory senescence-associated secretory phenotype (SASP). Mesenchymal stem cells are more resistant to DNA damage and apoptosis, can transdifferentiate into adipocytes post-radiotherapy leading to increased bone marrow adiposity (BMA).
Dr. Chandra's lab and others have shown that FRT-induced BMA occurs at the expense of the total mesenchymal stem cell population, but whether increase in the senescence burden drives BMA, has not yet been established. Moreover, the relationships of BMA and pro-inflammatory factors (SASP, for example) that are abundant in a senescent bone marrow environment have not been determined. Our goal is to provide viable therapeutics to alleviate radiotherapy-related bone deterioration and thus improve the quality of life for cancer survivors.