The Vicious Cycle

Contrary to your initial reaction, the title for this blog is not an illusion to that ingenious remake of the stationary bike. The vicious cycle I am referring to is instead the positive feedback loop between prostate adenocarcinoma cells and osteocytes resulting in growth of both cellular compartments and ultimately the formation of bone metastases.  While metastases can occur in many organ systems, there is a disproportionate frequency and number of bone metastases in prostate cancer, which drive much of the morbidity of this disease. For many patients, bone metastases are the only site of disease spread, and the vicious cycle is likely the culprit for this pattern. 

Two recent publications describe insights into this process.  The first, by Wenchu Wang et al from Evan Kellar’s team at the University of Michigan and published in Oncogene, revealed through a chemokine screen that osteocytes secrete growth- derived factor 15 (GDF-15) stimulates prostate cancer cell proliferation, migration, and invasion1.  This ligand binds to its cognate receptor expressed on prostate cancer cells, resulting in signaling through early growth response 1 (EGR1). Knockdown of either GDF-15 in osteocytes or EGR1 in prostate cancer cells dramatically inhibits this proliferative signal. 

The second paper, published by Guillaume Rieunier et al in this month’s Clinical Cancer Research, reviews the role of insulin-like growth factor (IGF) signaling in osseous metastases2. From its priming of tumor cells in their primary organ site, including the prostate gland, to colonization, growth, and migration within the bone marrow, IGF in its various forms plays a critical role in the positive feedback loop.  Unfortunately to date, targeting this biology in prostate cancer has been relatively unsuccessful.  That’s not entirely surprising given the concept of the vicious cycle – what starts out as a relatively weak and tenuous signal grows over time to a multifaceted, redundant and resistant biology. 

These papers remind me of the clinical context of M0 castration-resistant prostate cancer and why treatment with novel androgen receptor antagonists, enzalutamide, apalutamide, and most recently darolutamide, result in a median delay in metastases of two years or more, while in later settings the median time to progression maybe half as long 3-5.  Sure, tumor volume has a lot to do with this, but that is the point - by the time patients have significant tumor burden, particularly bone metastatic burden, this vicious cycle is well entrenched with multiple factors that are much less likely to be completely inhibited by these agents.  The other important point is to recognize the role that osteocytes and other stromal supporting cells play in the growth and resistance of these metastases. 

Targeting the stromal component of the vicious cycle is something we may need to do through combination therapy.  Also in this month’s issue of Clinical Cancer Research, De Bono et al, present a randomized phase II trial of abiraterone prednisone with or without the AKT inhibitor,  ipatasertib, demonstrating a significant improvement in progression-free survival for the combination over abiraterone prednisone alone, particularly in PTEN null patients6. I will cover this in more detail with next month’s blog, but for now, consider that inhibiting AKT (downstream of IGF signaling) may target both epithelial and stromal cells to create a double hit on this vicious cycle.  Perhaps this is the key to seeing more durable effects in patients with otherwise well-entrenched tumors.

Written by: Daniel J. George, MD, Medical Oncologist, Professor of Medicine, Professor of Surgery, Duke Cancer Institute, Durham, North Carolina

References: 
1. Wang W, et al. Oncogene. 2019 Feb 12. doi: 10.1038/s41388-019-0736-3.
2. Rieunier G et al. Clin Cancer Res. 2019 Feb 11. pii: clincanres.2697.2018. doi: 10.1158/1078-0432.CCR-18-2697
3. Hussain M, et al. N Engl J Med. 2018 Jun 28;378(26):2465-2474. doi: 10.1056
4. Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418. doi: 10.1056/NEJMoa1715546
5. Fizazi K, et al. Genitourinary Cancer Symposium 2019
6. De Bono et al. Clin Cancer Res. 2019 Feb 1;25(3):928-936.
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