Overcoming drug resistance and treating advanced prostate cancer

Abstract

Most of the prostate cancers (PCa) in advanced stage will progress to castration-resistant prostate cancer (CRPC). Within CRPC group, 50-70% of the patients will develop bone metastasis in axial and other regions of the skeleton. Once PCa cells spread to the bone, currently, no treatment regimens are available to eradicate the metastasis, and cancer-related death becomes inevitable. In 2012, it is estimated that there will be 28,170 PCa deaths in the United States. Thus, PCa bone metastasis-associated clinical complications and treatment resistance pose major clinical challenges. In this review, we will present recent findings on the molecular and cellular pathways that are responsible for bone metastasis of PCa. We will address several novel mechanisms with a focus on the role of bone and bone marrow microenvironment in promoting PCa metastasis, and will further discuss why prostate cancer cells preferentially metastasize to the bone. Additionally, we will discuss novel roles of several key pathways, including angiogenesis and extracellular matrix remodeling in bone marrow and stem cell niches with their relationship to PCa bone metastasis and poor treatment response. We will evaluate how various chemotherapeutic drugs and radiation therapies may allow aggressive PCa cells to gain advantageous mutations leading to increased survival and rendering the cancer cells to become resistant to treatment. The novel concept relating several key survival and invasion signaling pathways to stem cell niches and treatment resistance will be reviewed. Lastly, we will provide an update of several recently developed novel drug candidates that target metastatic cancer microenvironments or niches, and discuss the advantages and significance provided by such therapeutic approaches in pursuit of overcoming drug resistance and treating advanced PCa.

Fig. (1)

PCa progression. A; normal prostate tissue with intact basement membrane, and organized luminal and neuroendocrine (NE) cells, B; PCa progression is signified by disorganized expansion of luminal and NE cells, angiogenesis, and increased invasiveness of PCa cells, C; chemokine rich milieu of the bone marrow combined with adhesion molecules expressed within HSC niche play an important role in recruiting DTCs, D; extravasation of PCa into bone microenvironment, and bone metastasis.

Fig. (2)

PCa drug resistance may involve both intrinsic and extrinsic mechanism that include activation of AR receptor, activation of alternative survival pathway such as Akt/PI3K, MAPK/ERK or JAK/STAT3, cross talk of between cancer cells and surround microenvironment, and selective pressure due to various therapies. Additionally, more general drug resistance mechanisms may involve expression of efflux pump, and aberrant angiogenesis.

Fig. (3)

Inside a cell, testosterone is converted into DHT by 5α-reductase. In presence of either testosterone or DHT, AR is released from heat shock proteins (HSP), and gets phosphorylated and transported into nucleus as a homo-dimer. Once inside the nucleus, AR homo-dimer is joined with various coregulators such as LSD1, which leads to transcription activation, and consequently increased survival and growth of the cell.