The RANK–RANKL axis: an opportunity for drug repurposing in cancer?

Peters, Solange; Clézardin, Philippe; Márquez-Rodas, Iván; Niepel, Daniela; Gedye, Craig

doi:10.1007/s12094-018-02023-5

Cited by 34 publications

(34 citation statements)

References 96 publications

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“…Furthermore, numerous studies have demonstrated RANKL and RANK expression in neoplastic tissues. Interestingly, the expression level of RANKL/RANK in cancer tissues is related to the prognosis of numerous cancer types, including breast, lung, endometrial, renal cell, and gastric cancer [99]. Therefore, the RANKL/RANK axis may influence the development and progression of cancer, while the specific effects of RANKL/RANK may differ between cancer types.…”

Section: Rankl In Tumorigenesis and Metastasismentioning

confidence: 99%

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RANKL biology: bone metabolism, the immune system, and beyond

et al. 2020

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Receptor activator of NF-κB (RANK) ligand (RANKL) induces the differentiation of monocyte/macrophage-lineage cells into the bone-resorbing cells called osteoclasts. Because abnormalities in RANKL, its signaling receptor RANK, or decoy receptor osteoprotegerin (OPG) lead to bone diseases such as osteopetrosis, the RANKL/RANK/OPG system is essential for bone resorption. RANKL was first discovered as a T cell-derived activator of dendritic cells (DCs) and has many functions in the immune system, including organogenesis, cellular development. The essentiality of RANKL in the bone and the immune systems lies at the root of the field of "osteoimmunology." Furthermore, this cytokine functions beyond the domains of bone metabolism and the immune system, e.g., mammary gland and hair follicle formation, body temperature regulation, muscle metabolism, and tumor development. In this review, we will summarize the current understanding of the functions of the RANKL/RANK/ OPG system in biological processes.

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Section: Rankl In Tumorigenesis and Metastasismentioning

confidence: 99%

“…4d) [107,108]. The RANKL/RANK/OPG system is known to be involved in the development and metastasis of breast cancer, lung cancer, prostate cancer, melanoma, and renal cell carcinoma [99,107]. In addition, the relative expression levels of (See figure on previous page.)…”

Section: Bone Metastasismentioning

confidence: 99%

RANKL biology: bone metabolism, the immune system, and beyond

et al. 2020

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“…12,13 RANK and RANKL are increased in tumors and expressed by various immune cell types in the TME, including RANK by tumor-infiltrating myeloid cells (TAMCs) and RANKL expression variously by CD8 + and CD4 + T cells, tumor cells and other stromal components. 12,13 RANK and RANKL are increased in tumors and expressed by various immune cell types in the TME, including RANK by tumor-infiltrating myeloid cells (TAMCs) and RANKL expression variously by CD8 + and CD4 + T cells, tumor cells and other stromal components.…”

Section: Introductionmentioning

confidence: 99%

“…Recent preclinical and clinical evidence supports a potential for RANKL/RANK antagonism to enhance anti-tumor immunity, particularly in combination with ICI. 12,13 RANK and RANKL are increased in tumors and expressed by various immune cell types in the TME, including RANK by tumor-infiltrating myeloid cells (TAMCs) and RANKL expression variously by CD8 + and CD4 + T cells, tumor cells and other stromal components. 7,12 The combination treatment of anti-RANKL mAb with immune checkpoint blockade (e.g.…”

Section: Introductionmentioning

confidence: 99%

Retracted: Dual targeting of RANKL and PD‐1 with a bispecific antibody improves anti‐tumor immunity

2019

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Objectives The addition of RANKL/RANK blockade to immune checkpoint inhibitors (ICIs) such as anti‐PD‐1/PD‐L1 and anti‐CTLA4 antibodies is associated with increased anti‐tumor immunity in mice. Recent retrospective clinical studies in patients with advanced melanoma and lung cancer suggest the addition of anti‐RANKL antibody to ICI increases the overall response rate relative to ICI treatment alone. Based on this rationale, we developed a novel bispecific antibody (BsAb) co‐targeting RANKL and PD‐1. Methods We characterized target binding and functional activity of the anti‐RANKL/PD‐1 BsAb in cell‐based assays. Anti‐tumor activity was confirmed in experimental lung metastasis models and in mice with established subcutaneously transplanted tumors. Results The anti‐RANKL/PD‐1 BsAb retained binding to both RANKL and PD‐1 and blocked the interaction with respective counter‐structures RANK and PD‐L1. The inhibitory effect of anti‐RANKL/PD‐1 BsAb was confirmed by demonstrating a complete block of RANKL‐dependent osteoclast formation. Monotherapy activity of anti‐RANKL/PD‐1 BsAb was observed in anti‐PD‐1 resistant tumors and, when combined with anti‐CTLA‐4 mAb, increased anti‐tumor responses. An equivalent or superior anti‐tumor response was observed with the anti‐RANKL/PD‐1 BsAb compared with the combination of parental anti‐RANKL plus anti‐PD‐1 antibodies depending upon the tumor model. Discussion Mechanistically, the anti‐tumor activity of anti‐RANKL/PD‐1 BsAb required CD8+T cells, host PD‐1 and IFNγ. Targeting RANKL and PD‐1 simultaneously within the tumor microenvironment (TME) improved anti‐tumor efficacy compared with combination of two separate mAbs. Conclusion In summary, the bispecific anti‐RANKL/PD‐1 antibody demonstrates potent tumor growth inhibition in settings of ICI resistance and represents a novel modality for clinical development in advanced cancer.

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“…Introduction of new compounds into clinical practice is both, time constraining and a financial endeavour, which more often than not is subject to failure. Drug repurposing brings a selective advantage to the field of drug discovery as it is easier and more costeffective to authorize the approved drug for a new indication 9 .…”

Section: Introductionmentioning

confidence: 99%

Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukaemia cells

Jiang

Malik

Acedo

et al. 2019

Preprint

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p53 is a tumor suppressor, which belongs to the p53 family of proteins. The family consists of p53, p63 and p73 proteins, which share similar structure and function.Activation of wild-type p53 or TAp73 in tumors leads to tumor regression, and small molecules restoring the p53 pathway are in clinical development.Protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid, is a clinically approved drug applied in photodynamic diagnosis and therapy. PpIX induces p53-and TAp73-dependent apoptosis and inhibits TAp73/MDM2 and TAp73/MDM4 interactions.Here we demonstrate that PpIX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and activates apoptosis in B-cell chronic lymphocytic leukaemia cells without illumination and without affecting normal cells. PpIX stabilizes p53 and TAp73 proteins, induces p53-downstream apoptotic targets and provokes cancer cell death at doses non-toxic to normal cells. Our findings open up new opportunities for repurposing PpIX for treating lymphoblastic leukaemias with wtTP53.

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The RANK–RANKL axis: an opportunity for drug repurposing in cancer?

Cited by 34 publications

References 96 publications

RANKL biology: bone metabolism, the immune system, and beyond

RANKL biology: bone metabolism, the immune system, and beyond

Retracted: Dual targeting of RANKL and PD‐1 with a bispecific antibody improves anti‐tumor immunity

Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukaemia cells

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