Targeting the Osteogenic Niche for Preventing Kidney Cancer Bone Metastasis Progression
Abstract
Kidney cancer frequently spreads to bone, forming bone metastases that are destructive, painful, and untreatable. Skeletal-related events (SRE) are a common complication of these bone metastases and have serious consequences. These include fractures, high levels of calcium in the blood, and spinal cord compression. But the most devastating consequence is that once a patient has a SRE, their prognosis is much worse: their life expectancy is dramatically decreased from about 3 years, to less than a year. This has not changed despite the introduction of newer targeted drugs that interfere with the growth of cancer cells at the molecular level. There are no specific treatments for bone metastases from kidney cancer. It has been a decade since the U.S. Food and Drug Administration (FDA) approved the first medications, named tyrosine kinase inhibitors, for kidney cancer treatment, including Nexavar, Sutent, and Votrient. They interfere with certain cancer cell functions as they attempt to grow and divide uncontrollably, but do not treat bone metastases effectively. A recently approved second line tyrosine kinase inhibitor, Cabometyx (also known as Cabozantinib and Cometriq), seems to partially treat bone metastases, but has numerous toxicities that limit its use in many patients. Thus, physicians and patients face a daunting scenario of no additional therapy options when kidney cancer bone metastases progress while using these treatments. The destructive process triggered by kidney cancer cells when they invade bone is poorly understood, and may hold the key to discovering better treatments. Current treatment strategies (including radiation) that target bone metastases from kidney cancer are ineffective in comparison to prostate and breast cancer. Commonly used drugs such as bisphosphonates (Fosomax, Zometa), and denosumab [Xgeva]) target the activity of a particular type of bone cell called an osteoclast, which under normal circumstances is responsible for removing bone. Why these drugs are ineffective in kidney cancer patients while being effective for breast and prostate cancer, remains unknown. Consequently, the overall goal of our project is to study a proposed new mechanism that could be responsible for the relentless bone destruction that is resistant to current treatments. Our research has identified a new mechanism underlying and preceding SRE. Under normal conditions, other bone cells (osteoblasts and osteocytes) provide a perfect counterbalance to bone removal by adding new bone where osteoclasts have removed bone. In kidney cancer patients with untreatable bone metastases, we were able to show that osteoblasts and osteocytes are inhibited from doing their job--in other words, bone is being removed by osteoclasts, but is not replaced, leading to progressive bone destruction and resistance to treatments that target osteoclasts. Proving that bone repair is impeded in this scenario required identifying the ways that metastatic kidney cancer cells are actively preventing osteoblasts and osteocytes from doing their jobs. We therefore performed exploratory work to discover specific molecules that are secreted by kidney cancer cells when they invade bone. The breakthrough in our studies was in identifying a protein named BIGH3 (also known as TGFBIP), which is secreted at unusually high levels by kidney cancer cells as they invade bone. We confirmed that BIGH3 has the effect of interfering with osteoblasts that are attempting to counterbalance bone removal, appears to be lethal to osteocytes, and also may stimulate kidney cancer cells to invade bone. In addition, we determined that invading kidney cancer cells make direct physical contact with bone cells prior to producing destructive lesions. We therefore believe that this mechanism is the critical, previously unknown step, creating the severe bone destruction that does not respond to current treatments. It remains to be determined how bone cells and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010895
Entities
People
- Robert Satcher
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army