Developing drugs in cancer-related bone pain

Lucchesi, M; Lanzetta, Gaetano; Antonuzzo, Andrea; Rozzi, Antonio; Sardi, Iacopo; Favre, Claudio; Ripamonti, Carla; Santini, Daniele; Armento, Grazia

doi:10.1016/j.critrevonc.2017.08.005

Cited by 18 publications

(12 citation statements)

References 103 publications

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“…Advanced breast and prostate cancer frequently metastasize to bones and growth of these metastatic tumors is often associated with severe pain and discomfort (Roodman, 2004 ; Papachristou et al, 2012 ; Mantyh, 2013 ; Rucci and Angelucci, 2014 ; Schmidt, 2014 ). This type of pain is often undermanaged with existing analgesics, due to the development of tolerance and dose limiting side effects of traditional opioids (Mantyh, 2013 ; Schmidt, 2014 ; Lucchesi et al, 2017 ). While the precise mechanisms underlying metastatic bone cancer pain are poorly understood, it is thought to be initiated in part by sensitization of peripheral nociceptors innervating the site of bone tumor growth (Schmidt, 2014 ).…”

Section: Introducitonmentioning

confidence: 99%

Parathyroid Hormone-Related Peptide Elicits Peripheral TRPV1-dependent Mechanical Hypersensitivity

Shepherd

Mickle

Kadunganattil

et al. 2018

Front. Cell. Neurosci.

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Bone metastasis in breast, prostate and lung cancers often leads to chronic pain, which is poorly managed by existing analgesics. The neurobiological mechanisms that underlie chronic pain associated with bone-metastasized cancers are not well understood, but sensitization of peripheral nociceptors by tumor microenvironment factors has been demonstrated to be important. Parathyroid hormone-related peptide (PTHrP) is highly expressed in bone-metastasized breast and prostate cancers, and is critical to growth and proliferation of these tumors in the bone tumor microenvironment. Previous studies have suggested that PTHrP could sensitize nociceptive sensory neurons, resulting in peripheral pain hypersensitivity. In this study, we found that PTHrP induces both heat and mechanical hypersensitivity, that are dependent on the pain-transducing transient receptor potential channel family vanilloid, member-1 (TRPV1), but not the mechano-transducing TRPV4 and TRPA1 ion channels. Functional ratiometric Ca2+ imaging and voltage-clamp electrophysiological analysis of cultured mouse DRG neurons show significant potentiation of TRPV1, but not TRPA1 or TRPV4 channel activation by PTHrP. Interestingly, PTHrP exposure led to the slow and sustained activation of TRPV1, in the absence of any exogenous channel agonist, and is dependent on the expression of the type-1 parathyroid hormone receptor (PTH1), as well as on downstream phosphorylation of the channel by protein kinase C (PKC). Accordingly, local administration of specific small-molecule antagonists of TRPV1 to mouse hindpaws after the development of PTHrP-induced mechanical hypersensitivity led to its significant attenuation. Collectively, our findings suggest that PTHrP/PTH1-mediated flow activation of TRPV1 channel contributes at least in part to the development and maintenance of peripheral mechanical pain hypersensitivity, and could therefore constitute a mechanism for nociceptor sensitization in the context of metastatic bone cancer pain.

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Section: Introducitonmentioning

confidence: 99%

Parathyroid Hormone-Related Peptide Elicits Peripheral TRPV1-dependent Mechanical Hypersensitivity

Shepherd

Mickle

Kadunganattil

et al. 2018

Front. Cell. Neurosci.

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“…All of these, except for colorectal, follow a high pattern of bone metastasis in 60 to 84% of the cases [9,32]. In breast and prostate cancer patients particularly, it is expected that 90% develop bone metastases [33,34]. Additionally, there are primary bone tumors that have their origin within the bone and the most common type is an osteosarcoma with a worldwide incidence of 3.4 cases per million people per year [35].…”

Section: Epidemiology and Primary Vs Secondary Tumorsmentioning

confidence: 99%

Bone Cancer Pain, Mechanism and Treatment

Sliepen¹

2021

Recent Advances in Bone Tumours and Osteoarthritis

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The world health organization (WHO) has predicted a global amount of 19 million cancer cases by 2025. Breast, prostate and lung cancer are common cancer types and show metastasis in 60 to 84% of the cases, with 75 to 90% experiencing life-altering cancer-induced bone pain (CIBP), characterized by continuous, dull progressive pain with movement-induced incident peaks and random breakthrough spikes. Therefore, it is the most difficult pain condition to treat. CIBP is a unique type of pain with neuropathic and nociceptive components. Briefly, an invading tumor cell disturbs the healthy balance of the bone resulting in an acidic microenvironment, activating sensory fibers in the bone. The invaded tumor cell and adjacent stromal cells secrete mediators initiating an immune response with transcriptional signaling, resulting in increased cytokines and growth factors. Sensory nerve fibers are damaged and start to sprout, causing ectopic firing, and as tumors grow in size they activate mechanoreceptors. Aside from bisphosphonates and antibody therapy, CIBP is treated by a range of NSAIDs to strong opioids, but remains undertreated in one-third of cases. This chapter discusses the accompanying CIBP of bone tumors, the mechanism of action and current treatments.

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“…This nerve sprouting is associated with bone pain and has not been observed in a normal healthy bone. Therefore, novel anti-NGF and anti-TrkA drugs are under investigation for treatment of CIBP[115]. Studies have demonstrated that tanezumab, a humanized monoclonal antibody, blocks the binding of NGF to TrkA, which can significantly reduce pain and improve physical function and global scores in patients with CIBP[116,117].…”

Section: Neurotrophic Factors and Gi Cancermentioning

confidence: 99%

Role of the brain-gut axis in gastrointestinal cancer

Han

et al. 2019

WJCC

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Several studies have largely focused on the significant role of the nervous and immune systems in the process of tumorigenesis, including tumor growth, proliferation, apoptosis, and metastasis. The brain-gut-axis is a new paradigm in neuroscience, which describes the biochemical signaling between the gastrointestinal (GI) tract and the central nervous system. This axis may play a critical role in the tumorigenesis and development of GI cancers. Mechanistically, the bidirectional signal transmission of the brain-gut-axis is complex and remains to be elucidated. In this article, we review the current findings concerning the relationship between the brain-gut axis and GI cancer cells, focusing on the significant role of the brain-gut axis in the processes of tumor proliferation, invasion, apoptosis, autophagy, and metastasis. It appears that the brain might modulate GI cancer by two pathways: the anatomical nerve pathway and the neuroendocrine route. The simulation and inactivation of the central nervous, sympathetic, and parasympathetic nervous systems, or changes in the innervation of the GI tract might contribute to a higher incidence of GI cancers. In addition, neurotransmitters and neurotrophic factors can produce stimulatory or inhibitory effects in the progression of GI cancers. Insights into these mechanisms may lead to the discovery of potential prognostic and therapeutic targets.

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Developing drugs in cancer-related bone pain

Cited by 18 publications

References 103 publications

Parathyroid Hormone-Related Peptide Elicits Peripheral TRPV1-dependent Mechanical Hypersensitivity

Parathyroid Hormone-Related Peptide Elicits Peripheral TRPV1-dependent Mechanical Hypersensitivity

Bone Cancer Pain, Mechanism and Treatment

Role of the brain-gut axis in gastrointestinal cancer

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