A researcher at the Barbara Ann Karmanos Cancer Institute in Detroit was awarded more than $2 million to identify new ways to treat metastatic prostate cancer.
The National Institutes of Health/National Cancer Institute awarded the five-year grant to Izabela Podgorski, co-leader of the prostate cancer research team and associate professor of pharmacology at the Wayne State University School of Medicine.
Podgorski is continuing her studies in the ways that prostate cancer cells are affected by bone marrow fat and how they adapt and survive in bone. She was the first researcher to suggest a link between bone marrow fat cells and metastatic prostate cancer in 2010.
Her new study hypothesizes that tumor cell and bone marrow adipocyte (cells specialized for the storage of fat) interactions enhance prostate cancer metastatic progression while reducing the tumor cells’ response to current treatments.
“Bone by itself is a very harsh microenvironment that is difficult to treat,” she says. “For a long time, people thought bone marrow fat cells were just energy storage units. We knew they were abundant in adult bones and that their numbers prematurely increased with obesity and metabolic diseases. But we had no idea what role, if any, they played in metastatic prostate cancer. In the past few years, our studies and others began to reveal that when you have tumor cells in the bone marrow, they trigger some changes in the metabolism of adipocytes, and those changes ultimately help the tumor cells to survive and escape therapy.”
Adipocytes expel lipids, which are fatty acids.
“Cancer cells take up those fatty acids and use them as energy,” Podgorski says. “Tumor cells push the adipocytes to expel more lipids. They have this interactive relationship that supports (tumor) growth and promotes resistance to standard chemotherapy treatments, which includes docetaxel and cabazitaxel.”
The team has discovered that marrow fat cells can modify normal functions of metabolic enzymes or inflammatory molecules, which helps tumor cells grow more robust and resist therapeutic agents. With the latest grant, the team is trying to demonstrate that inhibiting lipid release by adipocytes will improve therapy response and uncover new molecule targets for therapy.
The researchers are using a variety of techniques to identify the new molecules, including 3-D culture techniques, patient samples, mouse models, models that mix human and mouse samples, the study of cellular proteins, and RNA sequencing approaches.
“I think we have a lot of tools to answer the questions we’ve asked,” Podgorski says. “We already identified potential molecules to target, including PKM2 or interleukin 1B. Fat cells change the activity of these targets in the tumor to help it live. They also affect other processes, such as iron metabolism. The design of this study promises to show that lipids supplied by fat cells in the bone marrow are key contributors to chemoresistance. The study is also likely to identify new mechanistic targets for therapy.”
Men who are diagnosed with prostate cancer typically have a five-year survival rate of close to 100 percent if the cancer is contained in the original site, Podgorski says. If it metastasizes, or moves to other parts of the body, the cancer cells will often migrate to a portion of the skeleton such as the hip, pelvis, or ribs. Metastatic prostate cancer cells can also target visceral organs or travel to the lymph nodes.
According to Podgorski, 85-90 percent of men with metastatic prostate cancer have bone metastases. This lowers a man’s five-year survival rate to below 30 percent. If the tumor cells migrate to the bone and a visceral organ, it creates the most lethal scenario.
Karmanos is headquartered in Detroit with 16 locations throughout Michigan. It is part of McLaren Health Care.