Current and emerging therapies for bone metastatic castration-resistant prostate cancer

Abstract

Background: A paucity of therapeutic options is available to treat men with metastatic castration-resistant prostate cancer (mCRPC). However, recent developments in our understanding of the disease have resulted in several new therapies that show promise in improving overall survival rates in this patient population.

Methods: Agents approved for use in the United States and those undergoing clinical trials for the treatment of mCRPC are reviewed. Recent contributions to the understanding of prostate biology and bone metastasis are discussed as well as how the underlying mechanisms may represent opportunities for therapeutic intervention. New challenges to delivering effective mCRPC treatment will also be examined.

Results: New and emerging treatments that target androgen synthesis and utilization or the microenvironment may improve overall survival rates for men diagnosed with mCRPC. Determining how factors derived from the primary tumor can promote the development of premetastatic niches and how prostate cancer cells parasitize niches in the bone microenvironment, thus remaining dormant and protected from systemic therapy, could yield new therapies to treat mCRPC. Challenges such as intratumoral heterogeneity and patient selection can potentially be circumvented via computational biology approaches.

Conclusions: The emergence of novel treatments for mCRPC, combined with improved patient stratification and optimized therapy sequencing, suggests that significant gains may be made in terms of overall survival rates for men diagnosed with this form of cancer.

Fig 1

Approved and developing mCRPC therapies and their targets. mCRPC has experienced a rapid expansion of treatment options over the last decade. Better understanding of mechanisms of progression has allowed for the improvement of broad-acting options such as chemotherapy and hormonal therapy as well as the development of novel targeted therapies to modulate the immune system and microenvironment. mCRPC = metastatic castration-resistant prostate cancer.

Fig 2

A–C. Dormancy and the “vicious cycle” in bone marrow niches. (A) Disseminated tumor cells can home to the vascular niche and cluster on stable endothelium. Decreased expression of thrombospondin 1 combined with activation of transforming growth factor β and periostin in areas of “sprouting” vasculature can result in the outgrowth of tumor cells. (B) Cancer cells may also home to the endosteal niche via mechanisms such as chemokine motif 12/chemokine receptor 4 where they compete with quiescent hematopoietic stem cells for osteoblast interaction. Subsequently, the cancer cells can be maintained in a dormant state via interactions with GAS6- and ANXA2-expressing niche osteoblasts or proliferate into metastases. (C) A “vicious cycle” occurs between tumor cells and other cells of the bone microenvironment. Factors secreted by the tumor cells act on osteoblasts, leading to the increased production of RANKL. RANKL subsequently promotes the differentiation of osteoclast precursors into mature, bone-resorbing osteoclasts that degrade the bone and release additional factors into the microenvironment, providing positive feedback to the cancer cells. Matrix metalloproteinases 2, 7, and 9 contribute to the vicious cycle by regulating factors such as vascular endothelial growth factor A, RANKL, and transforming growth factor β, whereas myeloid-derived suppressor cells contribute by releasing protumorigenic factors, suppressing T cells, and differentiating into osteoclasts. RANKL = receptor activator of nuclear κB ligand.