Mesenchymal Stem Cell Control of Metastatic Prostate Cancer Cell Evolution and Therapy Resistance in the Bone Microenvironment
Abstract
Clinical Significance: This year, in the United States alone, prostate cancer will claim the lives of over 26,000 men. The reason for the demise of these patients is that their disease has spread/metastasized from the prostate to secondary sites and has become resistant to therapy. Castrate-resistant prostate cancer (CRPC) typically presents as metastatic castrate-resistant prostate cancer (mCRPC) in the skeleton. Studies have shown that 90% of men that succumb to the disease have evidence of bone metastasis. In the skeleton, prostate cancer cells manipulate the normal cells of the bone to generate lesions that have areas of extensive bone destruction caused by cells, known as osteoclasts, and bone formation caused by cells, known as osteoblasts. These bony metastases are very painful and greatly impact the patient’s quality of life. Clinically, androgen deprivation therapy (enzalutamide, abiraterone); chemotherapy (docetaxel, cabazitaxel); and radiation therapy (radium-223/Xofigo) have increased overall survival. Unfortunately, it is only a matter of time before the disease becomes castrate- and/or chemo-resistant to these therapies and progresses. Given the number of men dealing with bone metastases, understanding how resistance arises and identifying new therapies that extend overall survival are an urgent and unmet clinical need. Our group has been investigating mCRPC, and emerging work has revealed a number of new findings. Our Preliminary Findings: Mescenchymal stromal/stem cells (MSCs) reside in the bone marrow and, in response to prostate cancer-derived factors, can become osteoblasts and contribute to bone formation. We observed that, reciprocally, MSCs can promote the evolution of mCRPC cell populations that have enhanced resistance to cell death. Furthermore, the MSC-educated prostate cancer cells were also significantly more resistant to the chemotherapy, docetaxel. We have found that an MSC-secreted factor, interleukin-28 (IL-28), can promote prostate cancer cell death by binding to its receptor, IL-28R. The IL-28R receptor typically stimulates the activity of targets known as STAT1 and STAT3. We observed that the MSC-educated prostate cancer cells have reduced STAT1 activity and elevated STAT3 activity. STAT3 has been shown to be active in human cases of bone metastatic prostate cancer. Here at Moffitt, we have developed a novel inhibitor that blocks STAT3 activity, S3I-201. Our early results show that MSC-educated prostate cancer cells are sensitive to this inhibitor in vitro, and an expected outcome is that these cells will also be sensitive to STAT3 inhibition in preclinical mouse models of bone metastatic prostate cancer. We also expect that blocking STAT3 will make the resistant prostate cancer cells more sensitive to docetaxel chemotherapy. Major Expected Outcomes: Based on anticipated results, we expect to demonstrate that (1) MSC-educated prostate cancer cells will grow more rapidly in mouse models of bone metastatic prostate cancer; (2) that IL-28R plays a key role in controlling bone metastatic prostate cancer cell survival and growth; (3) that a novel STAT3 inhibitor, S3I-201, will be effective in treating bone metastatic prostate cancer and will also re-sensitize resistant disease to chemotherapy; and (4) that the analysis of human clinical specimens of the disease will reinforce the clinical relevance of our data. Translational Implications: We believe that the success of the proposed research program will fill important gaps in our knowledge as to how MSCs in the bone microenvironment can contribute to the evolution of resistant bone mCRPC. Understanding the molecular mechanisms at work can reveal new therapeutic targets. We predict one such target to be STAT3. We believe our STAT3 inhibitor will effectively treat bone metastatic prostate cancer and that the generated data from our studies will provide a strong rationale for clinical trials. A potential risk is tha
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810523
Entities
People
- Conor C Lynch
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army