Izabela Podgorski, Ph.D., co-leader of the Prostate Cancer Research Team at the Barbara Ann Karmanos Cancer Institute and associate professor of Pharmacology at Wayne State University (WSU) School of Medicine, was the first researcher to suggest a link between bone marrow fat cells (adipocytes) and metastatic prostate cancer back in 2010.
She has recently obtained a new five-year, $2,028,733 million RO1 grant from the National Institutes of Health/National Cancer Institute to continue her studies into how prostate cancer cells are affected by bone marrow fat and how they adapt and survive in bone in an effort to identify new ways of treating metastatic prostate cancer. The grant number is CA251394-01.
Her new study hypothesizes that tumor cell and bone marrow adipocyte interactions enhance prostate cancer metastatic progression, while simultaneously reducing the tumor cells’ response to current treatments.
"Bone by itself is a very harsh microenvironment that is a difficult to treat," she said. "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(s), 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 are cells specialized for the storage of fat. Those cells expel lipids, which are fatty acids.
"Cancer cells take up those fatty acids and use them as energy,” Dr. Podgorski said. “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."
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, according to Dr. Podgorski. But if it metastasizes, the cancer cells will often migrate to a portion of the axial skeleton such as the hip, pelvis or ribs. Metastatic prostate cancer cells could also target a visceral organ such as the liver or travel to the lymph nodes.
According to Dr. Podgorski, 85 to 90 percent of men with metastatic prostate cancer have bone metastases. That lowers a man’s five-year survival rate to below 30 percent. If the tumor cells migrate to bone and a visceral organ, it creates the most lethal scenario.
In Dr. Podgorski’s research, she and the researchers in her lab have discovered that marrow fat cells can modify normal functions of metabolic enzymes (such as PKM2) or inflammatory molecules (such as interleukin 1B). This helps tumor cells grow more robust and resist therapeutic agents. With the latest RO1 grant, she and her colleagues are striving to demonstrate that inhibiting lipid release by adipocytes will improve therapy response and uncover new molecular targets for therapy.
They are utilizing a variety of different techniques to identify these new molecules. These methods include 3D culture techniques, patient samples, mouse models, models that mix both human and mouse samples, proteomics (the study of cellular proteins) and RNA sequencing approaches. They will use these approaches to study previously unexplored mechanisms that link bone marrow adipocytes with the survival of cancer cells that also resist standard therapy.
Given the research they have already established about bone marrow adiposity, Dr. Podgorski is confident that this will provide progress in the development of new prostate cancer therapies.
"I think we have a lot of tools to answer the questions we’ve asked,” she said. “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."
We congratulate Dr. Podgorski and her Karmanos and WSU collaborators on the prestigious R01 grant, including James Granneman, Ph.D., Maik Hüttemann, Ph.D., Paul Stemmer, Ph.D., Elisabeth Heath, M.D. and Dr. Seongho Kim, Ph.D.