Esketamine inhibits the c-Jun N-terminal kinase pathway in the spinal dorsal horn to relieve bone cancer pain in rats.

Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the specific CIBP mechanisms remain unknown. Esketamine is a non-selective N-methyl-d-aspartic acid receptor (NMDA) inhibitor commonly used as an analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunofluorescence images showed activated microglia in the spinal cord on day 14 after TCI and co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection of the CXCR4 inhibitor AMD3100 reduced JNK and c-Jun phosphorylations, and intrathecal injection of the JNK inhibitor SP600125 and esketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway.

Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study.

PURPOSE: Refractory cancer-induced bone pain (CIBP) affects a patient's functional capacity and quality of life, but there is limited evidence to guide opioid choice. We assessed the feasibility, tolerability and possible efficacy of methadone rotation (MR) compared to other opioid rotations (OOR) in this cohort. METHODS: Adults with CIBP and worst pain intensity ≥ 4/10 and/or opioid toxicity graded ≥ 2 on the Common Terminology Criteria for Adverse Events were randomised 1:1 to methadone or another opioid rotation. Standardised assessment tools were used at pre-defined study time points up to 14 days. RESULTS: Of 51 eligible participants, 38 (74.5%) consented, and 29 (76.3%, MR: 14, OOR: 15) completed the fourteen days follow-up post-opioid rotation. Both groups displayed significant reduction in average (MR: d = - 1.2, p = 0.003, OOR: d = - 0.8, p = 0.015) and worst pain (MR: d = - 0.9, p = 0.042, OOR: d = - 0.6, p = 0.048) and total pain interference score (MR: d = - 1.1, p = 0.042, OOR: d = - 0.7, p = 0.007). Oral morphine equivalent daily dose was reduced significantly in MR compared to the OOR group (d = - 0.8, p = 0.05). The incidence of opioid-related adverse events following MR was unchanged but lower in the OOR group (d = 0.9, 95% CI 0.1,1.7, p = 0.022). There were no within-group or between-group differences in satisfaction with analgesia at the end of the study. CONCLUSION: This pilot study demonstrated that MR and OOR in patients with refractory CIBP are feasible, safe and acceptable to patients. Appropriately powered multi-centre randomised controlled studies are needed to confirm the efficacy of MR and OOR in this cohort. TRIAL REGISTRATION: ACTRN12621000141842 registered 11 February 2021.

Unveiling the therapeutic promise: exploring Lysophosphatidic Acid (LPA) signaling in malignant bone tumors for novel cancer treatments.

Malignant bone tumors, including primary bone cancer and metastatic bone tumors, are a significant clinical challenge due to their high frequency of presentation, poor prognosis and lack of effective treatments and therapies. Bone tumors are often accompanied by skeletal complications such as bone destruction and cancer-induced bone pain. However, the mechanisms involved in bone cancer progression, bone metastasis and skeletal complications remain unclear. Lysophosphatidic acid (LPA), an intercellular lipid signaling molecule that exerts a wide range of biological effects mainly through specifically binding to LPA receptors (LPARs), has been found to be present at high levels in the ascites of bone tumor patients. Numerous studies have suggested that LPA plays a role in primary malignant bone tumors, bone metastasis, and skeletal complications. In this review, we summarize the role of LPA signaling in primary bone cancer, bone metastasis and skeletal complications. Modulating LPA signaling may represent a novel avenue for future therapeutic treatments for bone cancer, potentially improving patient prognosis and quality of life.

Multiple myeloma-A painful disease of the bone marrow.

Multiple myeloma is a bone marrow neoplasia with an incidence of 6/100,000/year in Europe. While the disease remains incurable, the development of novel treatments such as autologous stem cell transplantation, proteasome inhibitors and monoclonal antibodies has led to an increasing subset of patients living with long-term myeloma. However, more than two thirds of patients suffer from bone pain, often described as severe, and knowledge on the pain mechanisms and its effect on their health-related quality of life (HRQoL) is limited. In this review, we discuss the mechanisms of myeloma bone disease, the currently available anti-myeloma treatments and the lessons learnt from clinical studies regarding HRQoL in myeloma patients. Moreover, we discuss the mechanisms of cancer-induced bone pain and the knowledge that animal models of myeloma-induced bone pain can provide to identify novel analgesic targets. To date, information regarding bone pain and HRQoL in myeloma patients is still scarce and an effort should be made to use standardised questionnaires to assess patient-reported outcomes that allow inter-study comparisons of the available clinical data.

Stomatin-like protein 3 modulates the responses of Aδ, but not C fiber bone afferent neurons to noxious mechanical stimulation in an animal model of acute experimental bone pain.

STOML3 is a membrane bound scaffolding protein that has been shown to facilitate the opening of mechanically sensitive ion channels and contribute to noxious mechanical sensation, allodynia and hyperalgesia. In this study, we aimed to determine the role of STOML3 in noxious mechanical sensitivity of bone afferent neurons and carrageenan-induced acute inflammation in the bone. An in vivo, electrophysiological bone-nerve preparation was used to make recordings of the activity and sensitivity of bone afferent neurons that innervate the tibial marrow cavity in anaesthetised rats, in response to noxious mechanical stimuli delivered to the marrow cavity, before and after injection of either the STOML3 oligomerisation inhibitor OB-1 or vehicle, in either naïve animals or animals with carrageenan-induced inflammation of the marrow cavity. A dynamic weight-bearing apparatus was used to measure weight bearing in response to inflammatory pain before and after injection of OB-1 or saline into the tibial marrow cavity in the presence of carrageenan-induced inflammation. Electrophysiological recordings revealed that Aδ, but not C bone afferent neurons have a reduced discharge frequency in response to mechanical stimulation, and that carrageenan-induced sensitisation of Aδ, but not C bone afferent neurons was attenuated by inhibition of STOML3 oligomerisation with OB-1. Animals treated with OB-1 spent a significantly greater amount of time on the limb injected with carrageenan than animals treated with saline. Our findings demonstrate that inhibition of STOML3 oligomerisation reduces inflammatory bone pain by reducing the sensitivity of Aδ bone afferent neurons to mechanical stimulation. Targeting STOML3 may be an effective approach to reduce pain from noxious pressure and/or painful inflammatory pathology in bone.

Epitranscriptomic profiling of N4-acetylcytidine-related RNA acetylation in the spinal dorsal horn of rat with cancer-induced bone pain.

Recently, epigenetics involved in the regulation of gene expression has become a research hotspot. This study evaluated N4-acetylcytidine (ac4c) RNA acetylation in the spinal dorsal horn (SDH) of rats with cancer-induced bone pain (CIBP). The ac4C-specific RIP sequencing and NAT10-specific RIP sequencing were performed to identify the differences in ac4C acetylation and gene expression in the SDH between CIBP and sham groups, the relationship with the acetylation-modifying enzyme NAT10, and association analysis was performed. By interfering with the NAT10 expression, the relationship between some up-regulated genes and ac4C acetylation in CIBP was verified. In this study, we demonstrated that bone cancer increases the levels of NAT10 and the overall acetylation, inducing differential ac4C patterns in the SDH of rats. Through verification experiments, it was found that ac4C acetylation of some genes is regulated by NAT10, and differential ac4C patterns in RNA determine the expression of this RNA. We exposed that some CIBP-related gene expression was altered in the SDH of rats, which was regulated by differentially expressed ac4C acetylation.

LncRNA NONRATT014888.2 contributes to cancer-induced bone pain through downregulation of natriuretic peptide receptor 3 in rats.

Long noncoding RNA (lncRNA) is implicated in both cancer development and pain process. However, the role of lncRNA in the development of cancer-induced bone pain (CIBP) is unclear. LncRNA NONRATT014888.2 is highly expressed in tibia related dorsal root ganglions (DRGs) in CIBP rats which function is unknown. CIBP was induced by injection of Walker 256 mammary gland tumor cells into the tibia canal of female SD rats. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of rats were measured. Down-regulation of NONRATT014888.2 by siRNA in CIBP rats markedly attenuated hind-paw mechanical pain hypersensitivity. LncRNA-predicted target mRNAs analysis and mRNA sequencing results cued Socs3, Npr3 were related with NONRATT014888.2. Intrathecal injection of NONRATT014888.2-siR206 upregulated Npr3 both in mRNA and protein level. Npr3 was co-expressed in NONRATT014888.2-positive DRGs neurons and mainly located in cytoplasm, but not in Glial fibrillary acidic protein (GFAP)-positive cells. Intrathecal injection of ADV-Npr3 upregulated Npr3 expression and enhanced the PWT of CIBP rats. Our results suggest that upregulated lncRNA NONRATT014888.2 contributed to hyperalgesia in CIBP rats, and the mechanism may through downregulation of Npr3.

Long-term bone outcomes in Italian patients with Gaucher disease type 1 or type 3 treated with imiglucerase: A sub-study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry.

BACKGROUND: Gaucher disease (GD) is a lysosomal storage disorder. We evaluated the "real-world" effectiveness of first-line imiglucerase on long-term bone outcomes in Italian patients in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. METHODS: Patients treated with imiglucerase for ≥2 years and with bone assessments at baseline and during follow-up were selected. Data on bone pain, bone crises, marrow infiltration, avascular necrosis, infarction, lytic lesions, Erlenmeyer flask deformity, bone fractures, mineral density, and imiglucerase dosage were evaluated. RESULTS: Data on bone manifestations were available for 73 of 229 patients (31.9 %). Bone crises frequency decreased significantly from baseline to the most recent follow-up (p < 0.001), with some improvement observed in bone pain prevalence. Bone pain and bone crises prevalence decreased significantly from baseline at 2 to <4 and 4 to <6 years (all p < 0.05). A low median (25th, 75th percentile) baseline imiglucerase dosage was identified in patients reporting bone pain or bone crises (15.0 [13.7, 30.0] and 22.8 [17.5, 36.0] U/kg once every 2 weeks, respectively). CONCLUSION: Our study suggests that the management of GD in Italy, with regards to imiglucerase dosage, is suboptimal and confirms the need for clinicians to monitor and correctly treat bone disease according to best practice guidelines.

Development and Initial Validation of the ONCOREUM Score to Differentiate Childhood Cancer with Arthropathy from Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and validate a weighted score, the ONCOREUM score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA). STUDY DESIGN: Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The ß coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively). RESULTS: Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively. CONCLUSIONS: The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA.

Management of cancer pain due to bone metastasis.

Bone metastases frequently occur in patients with cancer. Skeletal-related events (SREs), including pain, impaired mobility, hypercalcemia, pathological fracture, spinal cord and nerve root compression, and bone marrow infiltration, can decrease the quality of life of the patients and increase the risk of morbidity. The mechanism of pain due to bone metastasis is complicated and involves various interactions among tumor cells, bone cells, activated inflammatory cells, and bone-innervating neurons. Cancer pain due to bone metastasis can be crippling and a chronic state that causes sarcopenia. For pain management, it is important to diagnose whether the pain is based on background pain or breakthrough pain due to bone metastasis. In addition, the management goal of cancer pain due to bone metastasis is not only to achieve pain relief but also to prevent pain progression and SREs. Pain mechanisms should be applied to achieve optimal management. This review aims to discuss the mechanisms of cancer pain due to bone metastasis and review the recommended drug therapies.

Cancer-nerve interplay in cancer progression and cancer-induced bone pain.

INTRODUCTION: Cancer-induced bone pain (CIBP) is one of the most common and debilitating complications associated with bone metastasis. Although our understanding of the precise mechanism is limited, it has been known that bone is densely innervated, and that CIBP is elicited as a consequence of increased neurogenesis, reprogramming, and axonogenesis in conjunction with sensitization and excitation of sensory nerves (SNs) in response to the noxious stimuli that are derived from the tumor microenvironment developed in bone. Recent studies have shown that the sensitized and excited nerves innervating the tumor establish intimate communications with cancer cells by releasing various tumor-stimulating factors for tumor progression. APPROACHES: In this review, the role of the interactions of cancer cells and SNs in bone in the pathophysiology of CIBP will be discussed with a special focus on the role of the noxious acidic tumor microenvironment, considering that bone is in nature hypoxic, which facilitates the generation of acidic conditions by cancer. Subsequently, the role of SNs in the regulation of cancer progression in the bone will be discussed together with our recent experimental findings. CONCLUSION: It is suggested that SNs may be a newly-recognized important component of the bone microenvironment that contribute to not only in the pathophysiology of CIBP but also cancer progression in bone and dissemination from bone. Suppression of the activity of bone-innervating SNs, thus, may provide unique opportunities in the treatment of cancer progression and dissemination, as well as CIBP.

The Edmonton Classification System for Cancer Pain in Patients with Bone Metastasis: a descriptive cohort study.

PURPOSE: We describe the prevalence of the Edmonton Classification System for Cancer Pain (ECS-CP) features in patients with bone metastasis and cancer-induced bone pain (CIBP) and the relationship between ECS-CP features, pain intensity, and opioid consumption. METHODS: We assessed ECS-CP features and recoded pain mechanisms and opioid use in adult patients with bone metastasis. Validated measures were used to assess pain intensity, incident pain, psychological distress, addictive behavior, and cognition. RESULTS: Among 147 eligible patients, 95.2% completed the assessment. Mean participant age was 73.2 years, the majority female (52.1%) with breast cancer occurring most commonly (25.7%). One or more ECS-CP features were present in 96.4% and CIBP in 75.7% of patients. The median average and worst pain scores were 3 and 6, respectively. Neuropathic pain was the most prevalent pain mechanism (45.0%) and was associated with breakthrough pain frequency (p=0.014). Three-quarters had incident pain, which was strongly associated with a higher average and worst pain scores (3.5 and 7, p<0.001 for both), background oral morphine equivalent daily dose (26.7mg, p=0.005), and frequency of daily breakthrough analgesia (1.7 doses/day, p=0.007). Psychological distress (n=90, 64.3%) was associated with a significantly higher average pain score (4, p=0.009) and a slightly higher worst pain score (7, p=0.054). Addictive behaviour and cognitive dysfunction were relatively uncommon (18.6% and 12.9%, respectively). CONCLUSION: There is a need to promote standardized assessment and classification of pain syndromes such as CIBP. The ECS-CP may allow us to consider CIBP in a systematic manner and develop personalized pain interventions appropriate to the pain profile. TRIAL REGISTRATION: Retrospectively registered in ANZCTR ACTRN12622000853741 (16/06/2022).

AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation.

Bone metastasis of cancer cells leads to severe pain by disrupting bone structure and inducing central sensitization. Neuroinflammation in the spinal cord plays a decisive role in the maintenance and development of pain. In the current study, male Sprague-Dawley (SD) rats are used to establish a cancer-induced bone pain (CIBP) model by intratibial injection of MRMT-1 rat breast carcinoma cells. Morphological and behavioral analyses verify the establishment of the CIBP model, which represents bone destruction, spontaneous pain and mechanical hyperalgesia in CIBP rats. Activation of astrocytes marked by upregulated glial fibrillary acidic protein (GFAP) and enhanced production of the proinflammatory cytokine interleukin-1ß (IL-1ß) are accompanied by increased inflammatory infiltration in the spinal cord of CIBP rats. Furthermore, activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is consistent with increased neuroinflammation. Adenosine monophosphate-activated protein kinase (AMPK) activation is involved in attenuating inflammatory pain and neuropathic pain. Intrathecal injection of the AMPK activator AICAR in the lumbar spinal cord reduces dynamin-related protein 1 (Drp1) GTPase activity and suppresses NLRP3 inflammasome activation. This effect consequently alleviates pain behaviors in CIBP rats. Cell research on C6 rat glioma cells indicates that AICAR treatment restores IL-1ß-induced impairment of mitochondrial membrane potential and elevation of mitochondrial reactive oxygen species (ROS). In summary, our findings indicate that AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation in the spinal cord.

Methadone rotation versus other opioid rotation for refractory cancer induced bone pain: protocol of an exploratory randomised controlled open-label study.

BACKGROUND: A third of patients with advanced cancer and bone metastasis suffer from cancer induced bone pain (CIBP), impeding quality of life, psychological distress, depression and anxiety. This study will evaluate the impact of an opioid rotation, comparing methadone rotation with other opioid rotation in patients with refractory CIBP. METHODS: This open-label randomised controlled trial will recruit cancer patients with CIBP and inadequate pain control despite established baseline opioid and/or intolerable opioid side effects from cancer and palliative care services. Participants will be at least 18 years old, with a predicted prognosis of greater than 8 weeks, meet the core diagnostic criteria for CIBP, have a worst pain score of ≥ 4 of 10 from CIBP and/ or have opioid toxicity (graded ≥ 2 on Common Terminology Criteria for Adverse Events). Participants will have sufficiently proficient English to complete questionnaires and provide informed consent. Participants will be randomised 1:1 to be rotated to methadone to another opioid. The primary objective is to examine the impact of opioid rotation in improving CIBP by comparing analgesic efficacy, safety and tolerability in the two arms. Secondary objectives will assess changes in the intensity, duration and frequency of breakthrough pain, requirement of breakthrough analgesia, overall opioid escalation index, and time taken to observe improvement in pain reduction, pain interference and quality of life. DISCUSSION: Laboratory studies suggest the involvement of neuropathic involvement in the mechanism of CIBP, though there remains no clear evidence of the routine use of neuropathic agents. Methadone as an analgesic agent may have a role to play in this cohort of patients, thus warranting further exploratory studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry No: ACTRN12621000141842. Registered 11 February 2021.

Spontaneous Bone Marrow Edema: Perfusion Abnormalities and Treatment with Surgical Decompression.

Bone marrow edema (BME), also termed bone marrow lesions, is a syndrome characterized by bone pain and the appearance of high signal intensity on T2 fat-suppressed and short tau inversion recovery (STIR) MRI sequences. BME can be related to trauma or a variety of non-traumatic diseases, and current treatment modalities include non-steroidal anti-inflammatory drugs (NSAIDS), bisphosphonates, denosumab, extracorporeal shockwave therapy (ESWT), the vasoactive prostacyclin analogue iloprost, and surgical decompression. Spontaneous BME is a subset that has been observed with no apparent causative conditions. It is most likely caused by venous outflow obstruction and intraosseous hypertension. These are mechanistically related to impaired perfusion and ischemia in several models of BME and are related to bone remodeling. The association of perfusion abnormalities and bone pain provides the pathophysiological rationale for surgical decompression. We present a case of spontaneous BME and a second case of spontaneous migratory BME treated with surgical decompression and demonstrate resolution of pain and the high signal intensity on MRI. This report provides an integration of the clinical syndrome, MR imaging characteristics, circulatory pathophysiology, and treatment. It draws upon several studies to suggest that both the bone pain and the MRI characteristics are related to venous stasis, and when circulatory pathologies are relieved by decompression or fenestration, both the bone pain and the MRI signal abnormalities resolve.

Pericapsular Nerve Group Block as an Effective Intervention for Pain Relief and Improving Functional Mobility in Cancer Patients: A Case Series.

Pericapsular nerve group block (PENG) is an ultrasound-guided regional block technique that blocks the articular branches of the femoral nerve, accessory obturator nerve and obturator nerve. These nerves richly innervate the anterior capsule of the hip joint and blocking these nerves helps in hip analgesia. PENG block is commonly used in hip fracture pain perioperatively. In this case series, we have used PENG block in cancer patients with hip pain. PENG block was given to six patients with bupivacaine and triamcinolone, out of which five patients had good pain relief and their functional mobility to activities of daily living improved.

Glycogen synthase kinase-3ß inhibition decreases inflammation and relieves cancer induced bone pain via reducing Drp1-mediated mitochondrial damage.

Bone is the preferential site of metastasis for breast cancer. Invasion of cancer cells induces the destruction of bone tissue and damnification of peripheral nerves and consequently induced central sensitization which contributes to severe pain. Herein, cancer induced bone pain (CIBP) rats exhibited destruction of tibia, mechanical allodynia and spinal inflammation. Inflammatory response mainly mediated by astrocyte and microglia in central nervous system. Our immunofluorescence analysis revealed activation of spinal astrocytes and microglia in CIBP rats. Transmission electron microscopy (TEM) observations of mitochondrial outer membrane disruption and cristae damage in spinal mitochondria of CIBP rats. Proteomics analysis identified abnormal expression of proteins related to mitochondrial organization and function. Intrathecally, injection of GSK-3ß activity inhibitor TDZD-8 significantly attenuated Drp1-mediated mitochondrial fission and recovered mitochondrial function. Inhibition of GSK-3ß activity also suppressed NLRP3 inflammasome cascade and consequently decreased mechanical pain sensitivity of CIBP rats. For cell research, TDZD-8 treatment significantly reversed TNF-α induced mitochondrial membrane potential (MMP) deficiency and high mitochondrial reactive oxygen species level. Taken together, GSK-3ß inhibition by TDZD-8 decreases spinal inflammation and relieves cancer induced bone pain via reducing Drp1-mediated mitochondrial damage.

P2X7 receptor induces microglia polarization to the M1 phenotype in cancer-induced bone pain rat models.

BACKGROUND: The transition from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype presents a novel therapeutic strategy for chronic pain. OBJECTIVE: We investigated the role of microglia polarization in cancer-induced bone pain (CIBP), as well as the role of the P2X7 receptor in modulating M1 to M2 polarization. METHODS: Walker-256 breast cancer cells were administered into tibias of female rats to induce bone cancer-associated cancer. RESULTS: During bone cancer development, the P2X7 receptor and M1 microglia markers were upregulated. In contrast, inhibition of the P2X7 receptor by BBG, a blood-brain barrier-permeable P2X7R-specific antagonist, alleviated the pain and promoted microglia polarization toward the M2 phenotype, while suppressing the M1 phenotype in vivo and in vitro. CONCLUSION: P2X7 receptor-mediated spinal microglia polarization is involved in alleviation of CIBP. Therefore, P2X7R is a potential option for CIBP treatment.

Vascular endothelial growth factor-A/vascular endothelial growth factor2 signaling in spinal neurons contributes to bone cancer pain.

Tumor metastasis to bone is often accompanied by a severe pain syndrome (cancer-induced bone pain, CIBP) that is frequently unresponsive to analgesics, which markedly reduces patient quality of life and cancer treatment tolerance in patients. Prolonged pain can induce hypersensitivity via spinal plasticity, and several recent studies have implicated the involvement of vascular endothelial growth factor-A (VEGF-A) signaling in this process. Here, we speculated that CIBP is associated with VEGF-A/VEGFR2 signaling in the spinal cord. A mouse model of CIBP was established by intramedullary injection of Lewis lung carcinoma (LLC) cells in the mouse femur. Pain sensitization and potential amelioration via VEGF-A/VEGFR2 blockade were measured using paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to thermal. Spinal VEGF-A/VEGFR2 signaling was blocked by intrathecal injection of the VEGF-A antibody or the specific VEGFR2 inhibitor ZM323881. Changes in the expression levels of VEGF-A, VEGFR2, and other pain-related signaling factors were measured using western blotting and immunofluorescence staining. Mice after LLC injection demonstrated mechanical allodynia and thermal hyperalgesia, both of which were suppressed via anti-VEGF-A antibody or ZM323881. Conversely, the intrathecal injection of exogenous VEGF-A was sufficient to cause pain hypersensitivity in naïve mice via the VEGFR2-mediated activation of protein kinase C. Moreover, the spinal blockade of VEGF-A or VEGFR2 also suppressed N-methyl-D-aspartate receptor (NMDAR) activation and downstream Ca2+-dependent signaling. Thus, spinal VEGF-A/VEGFR2/NMDAR signaling pathways may be critical mediators of CIBP.

A single arm phase II study of bone-targeted Sn-117 m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases.

BACKGROUND: Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain since 1956, however, so far radium-223 dichloride is the first and only Food and Drug Administration (FDA) approved targeted alpha therapy for metastatic castration-resistant prostate cancer (mCRPC) based on ALSYMPCA phase 3 study. While radium-223 does improve pain and overall survival outcomes, the improvement can come at the expense of side effects such as bone marrow toxicity. The development of new and better treatment with long-standing pain relief is clearly an unmet medical need. METHODS: The study is a non-randomized phase II study. The study population consists of 25 patients with CRPC who had progressed on any lines of prior therapies and whose serum testosterone level is less than 50 ng/dl and have metastatic lesions to at least two bone sites, with at least one site that has clinically meaningful pain at baseline (≥ 4 on an 11-point intensity scale). Eligible patients will be given two cycles of Sn-117 m-DTPA every 8 weeks or 56 days. Treatment will be administered by slow IV injection over 5-10 min. Retreatment after two cycles is allowed if patients meet the following retreatment criteria. The primary objective is to evaluate the efficacy of Sn-117 m-DTPA on sustained pain response in patients with CRPC metastatic to at least two bone sites and at least one with clinically meaningful pain at baseline (≥ 4 on an 11-point pain intensity scale). Sustained pain response is defined as: 1) achieving pain index ≤ 3 within a 12-week period and 2) maintaining pain index ≤ 3 over a 16-week period. The secondary objectives are: safety and tolerability, measurement of Sn-117 m-DTPA activity by gamma-camera dosimetry scans, therapeutic efficacy, time to the first symptomatic skeletal event, duration of pain response, changes in PSA and ALP levels, patient-reported outcomes and progression free survival and overall survival. DISCUSSION: Sn-117 m-DTPA is a unique bone-targeting theranostic radiopharmaceutical agent that selectively binds most heavily to bone metastases sites. This study will be the first prospective phase II trial to assess the pain efficacy and anti-tumor activity of Sn-117 m-DTPA in mCRPC with at least one clinically meaningful pain at baseline. TRIAL REGISTRATION: ClincialTrials.gov Identifier: NCT04616547.