Targeted FGFR Blockade for the Treatment of Tumor-Induced Osteomalacia.
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ABSTRACT:
SUBMITTER: Hartley IR
PROVIDER: S-EPMC7561341 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
| S-EPMC8247961 | biostudies-literature
Project description:Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed.
| S-EPMC3433741 | biostudies-literature
Project description:Tumor-induced osteomalacia (TIO) is a rare, acquired condition of phosphate wasting due to phosphaturic mesenchymal tumors. Because the incidence and prevalence of TIO is unknown, we conducted an observational cohort study using national Danish health registers for the period 2008 to 2018 to obtain such information. The study also aimed to describe the demographics of the TIO population and the prognosis. The operational definition was based on hypophosphatemia or adult osteomalacia diagnoses, combined with prescriptions used in the initial management and procedures consistent with advanced imaging used for locating tumors. The incidence of TIO in Denmark was found to be below 0.13 per 100,000 person years for the total population of the country and 0.10 per 100,000 in adult-onset disease. The prevalence of TIO was estimated to be no more than 0.70 per 100,000 persons for the total population and 0.43 per 100,000 in adults. In 2018, there were a maximum of nine new cases of TIO in Danish adults. Mortality was low but few patients fulfilled the protocol cure criterion during the observation period. TIO has no ICD-10 code and limitations to the study include lack of information on serum biochemistry and on the use of phosphate supplements. Strengths include the use of long-term longitudinal, national hospital and prescription data from a country with universal healthcare. Given the very small patient population with TIO and the known delay to diagnosis and cure, management of patients with suspected TIO should be centralized.
| S-EPMC8273058 | biostudies-literature
Project description: Not available
| S-EPMC8183716 | biostudies-literature
Project description:Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome. It is curable by excision of the causative tumor. However, a few cases may persist or relapse after tumor resection. We aimed to investigate the rate of these events and related factors. We retrospectively studied TIO patients treated with surgery in a tertiary hospital. TIO was established based on a pathologic examination or the reversion of hypophosphatemia. Refractory TIO patients consisted of those with nonremission or recurrent hypophosphatemia after surgery. A total of 230 patients were confirmed as having TIO. After primary surgery, 26 (11.3%) cases persisted, and 16 (7.0%) cases recurred. The overall refractory rate was 18.3%. The median time of recurrence was 33 months. Compared with patients in the recovery group, patients in the refractory group were more likely to be female (59.5% versus 41.0%, p = .029) and have a lower serum phosphate level (0.44 ± 0.13 versus 0.50 ± 0.11 mmol/L, p = .002). The refractory rate was lowest in head/neck tumors (7.5%) and highest in spine tumors (77.8%). Regarding the tissue involved of tumor location, the refractory rate was higher in tumors involving bone than tumors involving soft tissue (32.7% versus 7.0%, p < .001). The outcomes of malignant tumors were worse than those of benign tumors (p < .001): nonremission rate, 21.4% versus 9.7%; recurrence rate, 28.6% versus 6.5%. In the multivariate regression analysis, female sex, spine tumors, bone tissue-involved tumors, malignancy, and low preoperation serum phosphorus levels were identified as risk factors for refractory outcomes. High preoperative fibroblast growth factor 23 (FGF23) levels were also associated with refractory after adjusting for involving tissue and tumor malignancy. In summary, we are the first to report the rate and clinical characteristics of refractory TIO in a large cohort. For patients with multiple risk factors, especially spine tumors, clinical practitioners should be aware of a poor surgical prognosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
| S-EPMC7140180 | biostudies-literature
Project description:ContextPhosphaturic mesenchymal tumors (PMTs) are small, typically difficult to localize, and express somatostatin receptors. Recent work suggests imaging studies using 68Gallium (68Ga)-conjugated somatostatin peptide analogues, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)TATE, which enables somatostatin receptor imaging with positron emission tomography (PET), may be useful at identifying these tumors.ObjectiveOur objective was to evaluate the use of 68Ga-DOTATATE PET/computed tomography (CT) for tumor localization in tumor-induced osteomalacia (TIO).DesignThis was a single-center prospective study of patients with TIO.SettingThe study was conducted at the National Institutes of Health Clinical Center between February 2014 and February 2015.SubjectsEleven subjects (six females, five males) with TIO were included.InterventionSubjects underwent 68Ga-DOTATATE PET/CT in addition to 111In-pentetreotide single-photon emission CT (Octreoscan- SPECT/CT) and fluorodeoxyglucose-PET/CT (18F FDG-PET/CT) scan.Main outcome measuresLocalization of PMTs on the previously described imaging modalities were determined.ResultsThe tumor was successfully localized in 6/11 (54.5%) subjects (one was metastatic). The tumor was identified by 68Ga-DOTATATE in all six cases. Both Octreoscan-SPECT/CT and 18F FDG-PET each identified the tumor in 4/6. In no cases was 68Ga-DOTATATE the only imaging study to identify the tumor.ConclusionsIn this first prospective study comparing 68Ga-DOTATATE PET/CT to Octreoscan-SPECT/CT and 18F FDG-PET in TIO localization, 68Ga-DOTATATE PET/CT demonstrated the greatest sensitivity and specificity, suggesting that it may be the best single study for localization of PMTs in TIO.
| S-EPMC5052344 | biostudies-literature
Project description:BackgroundFibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients. MAIN: Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling.ConclusionHere, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the "cancer-immune cycle".
| S-EPMC10039534 | biostudies-literature
Project description:Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months-90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ - 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.
| S-EPMC9474374 | biostudies-literature
Project description:UnlabelledTumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by benign mesenchymal tumors. These tumors typically follow a benign clinical course and local recurrence occurs in <5% of cases. We investigated a 49-year-old man with a recurrent mesenchymal phosphaturic tumor showing no signs of malignancy. The patient suffered from chronic muscle weakness, myalgia and cramps. His medical record included the diagnosis of oncogenic osteomalacia, for which he was submitted to tumor resection in the left leg three times before. Laboratory examination showed hypophosphatemia, hyperphosphaturia and an elevated serum FGF23 level. A radical surgical approach (amputation) was advised, however, complete biochemical and clinical remission was not reached. Molecular analysis of the tumor cells demonstrated overexpression of growth factor receptors implicated in tumor angiogenesis and metastatic potential (platelet derived growth factor type A (PDGFRA), PDGFRB and vascular endothelial growth factor receptor) together with increased expression of FGF23, x-linked-phosphate-regulating endopeptidase and KLOTHO. TIO is usually associated with benign phosphauturic tumors and, when identified, resection of the tumor leads to complete remission in the majority of cases. The underlying pathophysiology of recurrences in these tumors is not known. This is the first report showing increased expression of growth factor receptors in a locally aggressive but histopathologically benign phosphaturic mesenchymal tumor.Learning pointsTIO is usually associated with benign soft tissue or bone neoplasms of mesenchymal origin.These tumors typically follow a benign clinical course and even in the rare malignant cases local recurrence occurs in <5%.Successful identification and removal of the tumor leads to full recovery in the majority of cases.
| S-EPMC4489167 | biostudies-literature
Project description:BackgroundTumor-induced osteomalacia (TIO) may result in a better prognosis after complete resection of the causative neoplasm. However, tumors located proximal to the articular surface of the metaphysis remain largely uninvestigated.MethodsA retrospective study of sixteen patients was undertaken to evaluate treatment of tumors with joint arthroplasty and tumor resection. The bone metabolism index, hip/knee joint function, arthroplasty complications and symptoms were followed up for at least 12 months in each patient.ResultsAll patients presented with neoplasms situated in the articular surface of the metaphysis, with 13 cases undergoing hip arthroplasty and 3 undergoing knee arthroplasty. Treatment of the tumors with joint arthroplasty and tumor resection significantly and rapidly ameliorate bone metabolism indexes in patients with TIO (p<0.01), with no identified tumor recurrence. The joint function evaluation score was improved in 15 patients (93.75%). Complications in these patients included post-operative pain, joint squeaking and secondary hyperparathyroidism.ConclusionsJoint arthroplasty that includes tumor-expanding resection appears to be a safe and appropriate method for the treatment of TIO patients with a neoplasm located in the metaphysis proximal to the articular surface.Level of evidenceTherapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
| S-EPMC5435341 | biostudies-literature