Targeting the Bone Microenvironment in Metastatic Castration-Resistant Prostate Cancer

Msaouel, Pavlos; Galeas, Jose Nahun; Boiles, Alejandro Recio; Ruiz, Ramiro Rancier; Koutsilieris, Michael

doi:10.2174/1389450116666150420143932

Cited by 7 publications

(6 citation statements)

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“…In contrast, biological mechanisms of resistance to conventional cytotoxic chemotherapeutics and targeted therapies designed for specific molecules share multiple features, including activated prosurvival pathways and disabled apoptotic machineries, together constituting response variation that awaits precise treatments [103]. For instance, metastatic castrationresistant prostate cancer (mCRPC) is usually incurable and represents an area of substantial unmet medical need, and multiple systems such as the RANKL/RANK/OPG, IGF-I, FGF and Wnt/DKK-1 pathways are targetable for suppression of tumor growth and therapeutic resistance [104]. Pathological roles of the TME in modulating tumor sensitivity are being increasingly recognized as a key aspect for development of modern anticancer therapeutics.…”

Section: Concluding Remarks and Future Avenuesmentioning

confidence: 99%

Tumor microenvironment and cancer therapy resistance

2016

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Innate resistance to various therapeutic interventions is a hallmark of cancer. In recent years, however, acquired resistance has emerged as a daunting challenge to anticancer treatments including chemotherapy, radiation and targeted therapy, which abolishes the efficacy of otherwise successful regimens. Cancer cells gain resistance through a variety of mechanisms in both primary and metastatic sites, involving cell intrinsic and extrinsic factors, but the latter often remains overlooked. Mounting evidence suggests critical roles played by the tumor microenvironment (TME) in multiple aspects of cancer progression particularly therapeutic resistance. The TME decreases drug penetration, confers proliferative and antiapoptotic advantages to surviving cells, facilitates resistance without causing genetic mutations and epigenetic changes, collectively modifying disease modality and distorting clinical indices. Recent studies have set the baseline for future investigation on the intricate relationship between cancer resistance and the TME in pathological backgrounds. This review provides an updated outline of research advances in TME biology and highlights the prospect of targeting the TME as an essential strategy to overcome cancer resistance and improve therapeutic outcomes through precise intervention. In the long run, continued inputs into translational medicine remain highly desired to achieve durable responses in the current era of personalized clinical oncology.

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Section: Concluding Remarks and Future Avenuesmentioning

confidence: 99%

Tumor microenvironment and cancer therapy resistance

2016

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“… 216 The increased levels of parathyroid hormone-related peptide (PTHrP) from osteoclasts can induce bone resorption by upregulating the receptor activator of RANKL, which promotes the release of various growth factors (such as ionized calcium and TGFβ) into the bone microenvironment to support cancer cell implantation and transformation. 217 – 221 Invading tumor cells secrete osteolytic cytokines, such as granulocyte-macrophage colony-stimulating factor, matrix metalloproteinases, interleukin (IL)-6, insulin-like growth factors (IGFs), fibroblast growth factors (FGFs), endothelin 1, growth differentiation factor 15 (GDF15), dickkopf-1 (DKK-1), and WNTs. 222 – 226 These osteolytic cytokines stimulate preosteoblast differentiation and promote osteoclast maturation to accelerate bone resorption.…”

Section: Targeting Bone Microenvironmentmentioning

confidence: 99%

Targeting signaling pathways in prostate cancer: mechanisms and clinical trials

Xiao

et al. 2022

Sig Transduct Target Ther

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Prostate cancer (PCa) affects millions of men globally. Due to advances in understanding genomic landscapes and biological functions, the treatment of PCa continues to improve. Recently, various new classes of agents, which include next-generation androgen receptor (AR) signaling inhibitors (abiraterone, enzalutamide, apalutamide, and darolutamide), bone-targeting agents (radium-223 chloride, zoledronic acid), and poly(ADP-ribose) polymerase (PARP) inhibitors (olaparib, rucaparib, and talazoparib) have been developed to treat PCa. Agents targeting other signaling pathways, including cyclin-dependent kinase (CDK)4/6, Ak strain transforming (AKT), wingless-type protein (WNT), and epigenetic marks, have successively entered clinical trials. Furthermore, prostate-specific membrane antigen (PSMA) targeting agents such as 177Lu-PSMA-617 are promising theranostics that could improve both diagnostic accuracy and therapeutic efficacy. Advanced clinical studies with immune checkpoint inhibitors (ICIs) have shown limited benefits in PCa, whereas subgroups of PCa with mismatch repair (MMR) or CDK12 inactivation may benefit from ICIs treatment. In this review, we summarized the targeted agents of PCa in clinical trials and their underlying mechanisms, and further discussed their limitations and future directions.

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“…The insulin-like growth factor (IGF) signaling axis, composed of two receptors (IGF-IR and IGF-IIR) and their specific ligands (IGF-I and IGF-II), was widely shown to be up-regulated in PCa cells and tissues [ 185 , 186 , 187 ] and is now considered an effective molecular target for PCa therapy [ 188 , 189 , 190 ]. We reported that, in CRPC cells, GnRH agonists interfere with the protumoral activity of IGF-I, by reducing IGF-IR expression and activation (i.e., tyrosine phosphorylation) [ 21 , 159 ].…”

Section: The Gnrh/gnrh-r Axis In Crpcmentioning

confidence: 99%

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

Fontana

Limonta

2021

Cells

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Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.

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Targeting the Bone Microenvironment in Metastatic Castration-Resistant Prostate Cancer

Cited by 7 publications

References 0 publications

Tumor microenvironment and cancer therapy resistance

Tumor microenvironment and cancer therapy resistance

Targeting signaling pathways in prostate cancer: mechanisms and clinical trials

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

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