Growth And Differentiation Factor 15 Research Articles

Preventing obesity, insulin resistance and type 2 diabetes by targeting MT1-MMP

Obesity is one of the predominant risk factors for type 2 diabetes. Despite all the modern advances in medicine, an effective drug treatment for obesity without overt side effects has not yet been found. The discovery of growth and differentiation factor 15 (GDF15), an appetite-regulating hormone, created hopes for the treatment of obesity. However, an insufficient understanding of the physiological regulation of GDF15 has been a major obstacle to mitigating GDF15-centric treatment of obesity. Our recent studies revealed how a series of proteolytic events predominantly mediated by membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP14), a key cell-surface metalloproteinase involved in extracellular remodeling, contribute to the pathogenesis of metabolic disorders, including obesity and diabetes. The MT1-MMP-mediated cleavage of the GDNF family receptor-α-like (GFRAL), a key neuronal receptor of GDF15, controls the satiety center in the hindbrain, thereby regulating non-homeostatic appetite and bodyweight changes. Furthermore, increased activation of MT1-MMP does not only lead to increased risk of obesity, but also causes age-associated insulin resistance by cleaving Insulin Receptor in major metabolic tissues. Importantly, inhibition of MT1-MMP effectively protects against obesity and diabetes, revealing the therapeutic potential of targeting MT1-MMP for the management of metabolic disorders.

Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (GDFather-Neo).

TPS712 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Neoadjuvant immunotherapy (I/O) demonstrated clinical safety and efficacy in various solid tumors including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for treatment of MIBC. Increasing evidence emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive role. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. The Neo-GDFather trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: Multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. Other inclusion criteria comprise an ECOG performance status 0-1 and a pure/predominant UC histology. No statistical assumptions were undertaken at this stage.Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations of EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., #2501 ASCO Annual Meeting 2023 Oral Abstract Session. Clinical trial information: Not yet available.

GDF15 restrains myocardial ischemia-reperfusion injury through inhibiting GPX4 mediated ferroptosis.

Growth and differentiation factor 15 (GDF15) has been proved to regulate the process of Myocardial ischemia-reperfusion injury (MIRI), which is a serious complication of reperfusion therapy. The present study aimed to explore if GDF15 could regulate the MIRI-induced ferroptosis. MIRI animal model was established by ligating the left anterior descending coronary artery. Oxygen-glucose deprivation/reoxygenation (OGD/R) cell model was established to imitate MIRI in vitro. The indicators of ferroptosis including mitochondrial damage, GPX4, FACL4, XCT4, and oxidative stress markers were evaluated. Overexpression of GDF15 greatly inhibited MIRI, improved cardiac function, alleviated MIRI-induced ferroptosis. pc-DNA-GDF15 significantly inhibited the oxidative stress condition and inflammation response. The OGD/R-induced ferroptosis was also inhibited by pc-DNA-GDF15. We proved that the MIRI-induced ferroptosis could by inhibited by pc-DNA-GDF15 through evaluating mitochondrial damage, MDA, GSH, and GSSG. Our research provides a new insight for the prevention and treatment of MIRI, and a new understanding for the mechanism of MIRI-induced ferroptosis.

Relationships between Circulating Biomarkers and Body Composition Parameters in Patients with Metabolic Syndrome: A Community-Based Study.

Metabolic syndrome (MetS) is a complex disease involving multiple physiological, biochemical, and metabolic abnormalities. The search for reliable biomarkers may help to better elucidate its pathogenesis and develop new preventive and therapeutic strategies. In the present population-based study, we looked for biomarkers of MetS among obesity- and inflammation-related circulating factors and body composition parameters in 1079 individuals (with age range between 18 and 80) belonging to an ethnically homogeneous population. Plasma levels of soluble markers were measured by using ELISA. Body composition parameters were assessed using bioimpedance analysis (BIA). Statistical analysis, including mixed-effects regression, with MetS as a dependent variable, revealed that the most significant independent variables were mainly adipose tissue-related phenotypes, including fat mass/weight (FM/WT) [OR (95% CI)], 2.77 (2.01-3.81); leptin/adiponectin ratio (L/A ratio), 1.50 (1.23-1.83); growth and differentiation factor 15 (GDF-15) levels, 1.32 (1.08-1.62); inflammatory markers, specifically monocyte to high-density lipoprotein cholesterol ratio (MHR), 2.53 (2.00-3.15), and a few others. Additive Bayesian network modeling suggests that age, sex, MHR, and FM/WT are directly associated with MetS and probably affect its manifestation. Additionally, MetS may be causing the GDF-15 and L/A ratio. Our novel findings suggest the existence of complex, age-related, and possibly hierarchical relationships between MetS and factors associated with obesity.

Abstract LB_C18: A novel WNT-RIP1 signaling pathway promotes colorectal cancer metastasis via induction of EMT

Abstract We identified new potential roles of RIP1 (receptor-interacting protein kinase 1) in controlling WNT signaling to enhance metastasis of colorectal cancer (CRC). First, we showed that WNT3A treatment sequentially increased the expression of RIP1 and β-catenin. Next, Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary, and metastatic cancers showed that elevated RIP1 expression might be related to β-catenin expression and it also indicated inductions of carcinogenesis and metastasis. In in vivo experiments with mice, intravenous injection of RIP1 over-expressed CRC cells has demonstrated that RIP1 may promote metastasis. These results implied RIP1 might be major component of WNT signaling. Next, we performed immunoprecipitation (IP) to revealed intracellular signaling mechanism that WNT3A treatment could induce direct binding between RIP1 and β-catenin, and observed direct binding and stabilization of the β-catenin protein via regulation of RIP1 ubiquitination by a downregulation of the E3 ligase, cIAP1/2. Down-regulation of cIAP1/2 expression with siRNA treatment and inhibition of its ubiquitinase activity with pharmacological inhibitor treatment could enhance WNT3A-induced RIP1 and β-catenin protein expression and binding. These results also enhance the migration and invasion of CRC cells in vitro via induction of endothelial-mesenchymal transition (EMT). The in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally result in the direct binding of RIP1 and β-catenin. The enhanced RIP1 expression can destroy the β-catenin–β-TrCP complex. Additionally, we also identified GDF15 (Growth and differentiation factor 15) is located at down-stream of WNT3A-RIP1 pathway and involved in EM induction. Taken together, these results suggest an identification of novel WNT-RIP1 pathway to enhance EMT and suggest GDF15 also might contribute CRC malignancy. Citation Format: A-RAM KANG, DO HOON KIM, JONG KUK PARK. A novel WNT-RIP1 signaling pathway promotes colorectal cancer metastasis via induction of EMT [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C18.

GDF15 Interference Regulates Proliferation, Inflammation, and Autophagy of Lipopolysaccharide-induced Mesangial Cells by Inhibiting PI3K/ AKT/mTOR Signaling.

Chronic glomerulonephritis (CGN) is a primary glomerular disease. As a circulating protein, growth and differentiation factor 15 (GDF15) participates in a variety of biological processes. We aimed to investigate the role of GDF15 in CGN. HBZY-1 cells were induced by lipopolysaccharide (LPS). Cell viability was detected using a cell counting kit-8 (CCK-8) assay, and a western blot was applied for the detection of GDF15 protein expression. After GDF15 silencing, cell proliferation was evaluated by CCK-8 assay and 5-ethynyl-2'-deoxyuridine (EDU) staining. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the levels of inflammatory cytokines. Autophagy was assessed by GFP-LC3B assay. Besides, the expression of NF-κB signaling-, autophagy- (LC3II/I, Beclin l and p62) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling-related proteins were measured by western blot. Afterwards, PI3K agonist 740Y-P was used to clarify whether GDF15 affected LPS-induced HBZY-1 cells via PI3K/AKT/mTOR signaling. LPS induction increased cell viability and elevated GDF15 expression in HBZY-1 cells. After GDF15 expression depletion, the increased proliferation of LPS-induced HBZY-1 cells was decreased. Additionally, GDF15 knockdown suppressed the release of inflammatory factors in LPS-induced HBZY-1 cells and activated autophagy. Moreover, the PI3K/AKT/ mTOR signal was evidenced to be activated by GDF15 deficiency. The further addition of 740Y-P reversed the impacts of GDF15 deficiency on the proliferation, inflammation, and autophagy of LPS-induced HBZY-1 Conclusion: Collectively, GDF15 downregulation could protect against CGN via blocking PI3K/AKT/mTOR signaling.

Mitochondrial myopathy without extraocular muscle involvement: a unique clinicopathologic profile.

Mitochondrial myopathy without extraocular muscles involvement (MiMy) represents a distinct form of mitochondrial disorder predominantly affecting proximal/distal or axial muscles, with its phenotypic, genotypic features, and long-term prognosis poorly understood. A cross-sectional study conducted at a national diagnostic center for mitochondrial disease involved 47 MiMy patients, from a cohort of 643 mitochondrial disease cases followed up at Qilu Hospital from January 1, 2000, to January 1, 2021. We compared the clinical, pathological, and genetic features of MiMy to progressive external ophthalmoplegia (PEO) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) patients. MiMy patients demonstrated a more pronounced muscle involvement syndrome, with lower 6MWT scores, higher FSS, and lower BMI compared to PEO and MELAS patients. Serum levels of creatinine kinase (CK), lactate, and growth and differentiation factor 15 (GDF15) were substantially elevated in MiMy patients. Nearly a third (31.9%) displayed signs of subclinical peripheral neuropathy, mostly axonal neuropathy. Muscle biopsies revealed that cytochrome c oxidase strong (COX-s) ragged-red fibers (RRFs) were a typical pathological feature in MiMy patients. Genetic analysis predominantly revealed mtDNA point pathogenic variants (59.6%) and less frequently single (12.8%) or multiple (4.2%) mtDNA deletions. During the follow-up, a majority (76.1%) of MiMy patients experienced stabilization or improvement after therapeutic intervention. This study provides a comprehensive profile of MiMy through a large patient cohort, elucidating its unique clinical, genetic, and pathological features. These findings offer significant insights into the diagnostic and therapeutic management of MiMy, ultimately aiming to ameliorate patient outcomes and enhance the quality of life.

Association of growth and differentiation factor-15 with coronary artery calcium score and ankle-brachial index in a middle-aged and elderly Caucasian population sample free of manifest cardiovascular disease

Growth and differentiation factor-15 (GDF-15) is a stress-associated cytokine of the transforming growth factor-β superfamily. The inflammatory and angiogenic effects of GDF-15 in atherosclerosis are controversial, and its correlation with the long asymptomatic phase of the disease is not well understood. Coronary artery calcium score (CACS) and ankle-brachial index (ABI) are sensitive markers of subclinical atherosclerosis. To date, only a few studies have examined the impact of GDF-15 on coronary artery calcification, and the association between GDF-15 and ABI has not been evaluated. Therefore, we aimed to investigate the possible relationship between serum GDF-15 concentrations and CACS and ABI in a Caucasian population sample of middle-aged (35–65 years) and elderly (> 65 years) people. In addition to recording demographic and anthropometric characteristics, atherosclerotic risk factors, and laboratory tests including serum HDL-cholesterol, LDL-cholesterol, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP); GDF-15 level, cardiac computed tomography, and ABI measurements were also performed. A total of 269 asymptomatic individuals (men, n = 125; median age, 61.5 [IQR, 12.7] years) formed the basis of this study. Participants were divided into two groups according to their age (middle-aged, n = 175 and elderly, n = 94). Hypertension and diabetes mellitus were significantly more prevalent and CACS values and HbA1c, NT-proBNP, and GDF-15 levels were significantly higher (all p < 0.001) in the elderly group compared to the middle-aged group. Multivariate ridge regression analysis revealed a significant positive association between GDF-15 and CACS (middle-aged group: β = 0.072, p = 0.333; elderly group: β = 0.148, p = 0.003), and between GDF-15 and ABI (middle-aged group: β = 0.062, p = 0.393; elderly group: β = 0.088, p = 0.041) only in the elderly group. Our results show that GDF-15 is not only a useful biomarker of inflammation but can also predict early signs of asymptomatic atherosclerosis, especially in elderly people with chronic systemic inflammation associated with aging (inflammaging).

ELEVATED GROWTH AND DIFFERENTIATION FACTOR 15 (GDF-15) LEVELS AMPLIFIES THE ASSOCIATION BETWEEN HOME BLOOD PRESSURE VARIABILITY AND CARDIOVASCULAR OUTCOME

Objective: Growth and differentiation factor 15 (GDF-15) is a marker of cell senescence. Although age is strongly determinant of GDF-15 level, several studies suggest that GDF-15 reflects biological age rather than chronological age. Since age is also associated with increased blood pressure variability, we hypothesized that the association between day-by-day home blood pressure variability (HBPV) and cardiovascular outcome may be steeper in patients with elevated GDF-15. Design and method: We analyzed 4030 patients from a practitioner-based population (mean±SD age 64.9±10.9 years: 79.0% taking antihypertensive medication) with at least one cardiovascular risk factor who underwent home blood pressure monitoring in the Japan Morning Surge-Home Blood Pressure Study. The standard deviation was assessed as indexes of day-by-day home systolic blood pressure variability. We divided patients into elevated (1200 ng/L or more) and non-elevated GDF-15 (less than 1200 ng/L) groups. Results: During a mean follow-up of 6.2 years, 247 cardiovascular events occurred. Participants with the highest HBPV tertile without elevated GDF-15 (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.03-2.23) or those with elevated GDF-15 without the highest BPV tertile (HR, 1.52; 95%CI, 1.03-2.16) had approximately 1.5-fold higher risk of cardiovascular events compared with those with low HBPV without elevated GDF-15. Adjusted risk of cardiovascular events was approximately 2.3-fold higher among participants with elevated GDF-15 and the highest HBPV tertile, compared with those with low HBPV without elevated GDF-15 (HR, 2.34; 95%CI, 1.58-3.45). Conclusions: We conclude that elevated GDF-15 contributes to the association between home BP variability and cardiovascular events.

Initial results from the phase 2A trial of visugromab (CTL-002) + nivolumab in advanced/metastatic anti-PD1/-L1 relapsed/refractory solid tumors (The GDFATHER-TRIAL).

2501 Background: Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical role in tumoral immunosuppression. Apart from blocking immune-cell entry into the tumor microenvironment, GDF-15 also has a major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block immunotherapy success. Here we report initial results of the phase 2a part of the GDF-15 neutralizing antibody visugromab (CTL-002) in combination with nivolumab. Methods: At cut-off date (06-Feb-2023), a total of 79 pts with advanced/metastatic solid tumors have been enrolled and were treated with visugromab 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W in the phase 2a expansion part of the CTL-002-001 phase 1/2 trial (NCT04725474). The primary endpoint of the phase 2a expansion is the Objective Response Rate (ORR) according to RECIST v1.1. Tumor assessments were performed every 8 weeks and patients had to be relapsed/refractory to a minimum of 12 weeks continuous prior anti-PD1/-PD-L1-containing therapy, with relapse or progression after initial response to have occurred on continued anti-PD1/PDL1 therapy. Phase 2a contained several indication-specific expansion cohorts (e.g. NSCLC, Bladder Cancer, HCC, Melanoma), following a Simon 2-stage design, and two cohorts were already expanded to stage 2 in light of initial responses observed. An additional expansion cohort is a pan-tumor basket cohort with sequential tumor biopsies for biomarker analyses. A key component of this multi-arm trial is an extensive translational research program to identify response-predictive tumor and immunologic marker and pattern. Results: Across several expansion cohorts, durable tumor regressions were observed, including several partial responses (PR) and one complete response (CR) in heavily pretreated patients with a median of 3 prior lines of systemic therapy for advanced/metastatic cancer, including at least one prior line of anti-PD1/-PD-L1 therapy and being relapsed/refractory to it. In NSCLC, so far 13 pts underwent at least one tumor assessment. Of these, two experienced a PR (one confirmed), three additional tumor shrinkage &gt; 5% (TS) and one longer-term SD (LT-SD) were seen. In bladder cancer, 7 patients underwent at least one tumor assessment with 1 confirmed CR, 1 TS and 1 LT-SD. The treatment was overall well tolerated. Conclusions: These initial phase 2a results demonstrate promising clinical activity for the combination of visugromab and nivolumab in heavily pretreated anti-PD1/-PD-L1 refractory/relapsed solid tumor patients across various indications, including induction of confirmed partial and complete responses. Extensive biomarker evaluations are ongoing to further evaluate potential response-predictive markers identified during phase 1 development. Clinical trial information: NCT04725474 .

Overview of growth differentiation factor 15 in metabolic syndrome.

Growth and differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) superfamily. GDF15 has been linked with several metabolic syndrome pathologies such as obesity and cardiovascular diseases. GDF15 is considered to be a metabolic regulator, although its precise mechanisms of action remain to be determined. Glial cell-derived neurotrophic factor family receptor alpha-like (GRAL), located in the hindbrain, has been identified as the receptor for GDF15 and signals through the coreceptor receptor tyrosine kinase (RET). Administration of GDF15 analogues in preclinical studies using various animal models has consistently been shown to induce weight loss through a reduction in food intake. GDF15, therefore, represents an attractive target to combat the current global obesity epidemic. In this article, we review current knowledge on GDF15 and its involvement in metabolic syndrome.

Subjective assessment and biochemical evaluation of traction therapy in women with chronic low back pain: does body mass index matter? A clinical study

BackgroundApart from the positive effect of lumbar traction on structural changes within the spine in patients with low back pain, it is likely that therapeutic effects are correlated with pain biomarkers in the blood. Among them, systemic metabolic factors related to obesity may play an important role. This is the first study designed to examine the effectiveness of traction therapy in two experimental groups with considerably different BMI and to assess relationships between blood biomarkers and low back pain intensity.MethodsIn the prospective clinical trial, women suffering from chronic low back pain were allocated into the normal-weight or obesity groups. Patients in both groups underwent twenty sessions of lumbar traction therapy (30 min a day, continuous mode with a force level of 25–30% of body weight). Before and after therapy subjective assessments of pain (VAS and PPT) were performed, and serum concentrations of aggrecan chondroitin sulfate 846 epitope (CS-846), neuropeptide Y, leptin, adipsin and growth and differentiation factor 15 (GDF-15) were determined. The data were statistically evaluated for 28 women.ResultsAfter therapy, the maximal low back pain decreased in both groups, GDF-15 concentration was reduced in the normal-weight group and increased in the obesity group, and CS-846 concentration decreased in the obesity group. The sensation of PPT in the lumbar spine and mean concentrations of neuropeptide Y, leptin and adipsin did not change in both groups. However, the relationships of GDF-15, leptin, and adipsin concentrations with the perception of pain were revealed.ConclusionDistinct differences between the normal-weight and obesity groups pointed on the role of excessive adipose tissue in aggravating the inflammatory processes and in the development of low back pain. Adipsin, CS-846 and GDF-15 aspire to be the low back pain biomarkers in women with obesity, but there is a need for further research to answer whether they might be considered reliable biomarkers for the prognosis and monitoring of chronic low back treatment.Trial registrationNCT04507074, registered prospectively on July 6, 2020.

Mass spectrometry–based assessment of prostate cancer–associated crystalloids reveals enrichment for growth and differentiation factor 15

Intraluminal crystalloids are a common finding within malignant prostatic acini and are infrequently identified within benign glands. The proteomic composition of these crystalloids remains poorly understood and may provide insight regarding prostate cancer pathogenesis. Laser microdissection-assisted liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS) was performed to compare proteomic composition of corpora amylacea within benign acini (n=9), prostatic adenocarcinoma-associated crystalloids (n=8), benign (n=8), and malignant prostatic acini (n=6). The expression of candidate biomarkers was then measured in urine specimens from patients with (n=8) and without prostate cancer (n=10) using ELISA, and immunohistochemistry-based expression in adjacent prostate cancer and benign glands was assessed in 56 whole-slide sections from radical prostatectomy specimens. LMD-LC-MS/MS revealed enrichment for the C-terminal portion of growth and differentiation factor 15 (GDF15) in prostatic crystalloids. Although urinary GDF15 levels were higher in patients with prostatic adenocarcinoma compared to those without (median: 1561.2 versus 1101.3, arbitrary units), this did not meet statistical significance (P=0.07). Immunohistochemistry for GDF15 revealed occasional positivity in benign glands (median H-score: 30, n=56), and diffuse positivity in prostatic adenocarcinoma (median H-score: 200, n=56, P<0.0001). No significant difference was identified within different prognostic grade groups of prostatic adenocarcinoma, or within malignant glands with large cribriform morphology. Our results show that the C-terminal portion of GDF15 is enriched in prostate cancer-associated crystalloids, and higher GDF15 expression is seen in malignant rather than benign prostatic acini. Improved understanding of the proteomic composition of prostate cancer-associated crystalloids provides the rationale for evaluating GDF15 as a urine-based biomarker of prostate cancer.

Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (NEO-GDFATHER).

TPS595 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Recently, neoadjuvant immunotherapy (I/O) has demonstrated clinical safety and efficacy in various solid tumor indications including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for successful treatment of MIBC in the future. Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts have indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that has demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. This clinical trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: This is a multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. No statistical assumptions have been undertaken at this stage. Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations according to EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., Annals of Oncology (2022) 33 (suppl_7): S331-S355.

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

BackgroundA “mismatch” sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in “mismatch” girls with early puberty.MethodsRandomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.0–9.5 years; birthweight (BW) for gestational age: −2.5 < Z-score <0, body mass index (BMI): 0 < Z-score < +2.5 and early progressive puberty (Tanner B2 at 7.7–9.3 years)]. Pharmacological intervention will be with a half-dose version of SPIOMET (mini-spiomet), a combination that reverts the PCOS phenotype in “mismatch” adolescents; mini-spiomet will contain spironolactone (25 mg/day, to raise brown adipose tissue activity), pioglitazone (3.75 mg/day, to raise adiponectin and insulin sensitivity), and metformin (425 mg/day, to raise AMPK activity and GDF15). Recruitment: 1 year; double-blind treatment: 1 year; open follow-up: 1 year; analyses and reporting: 1 year. Interventions: randomization (1:1) for placebo vs mini-spiomet. Primary outcome: annualized bone age advancement (0–1 year) by BoneXpert; secondary outcomes: insulin, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), androgens, luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol, growth-and-differentiation factor 15 (GDF15), C-X-C motif chemokine ligand-14 (CXCL14), safety parameters, and quantification of hepato-visceral fat.DiscussionThe present study, if successful, may provide a first proof of the concept that the rapid maturation of girls with an upward mismatch between pre- and post-natal weight gain can be slowed down with a fixed low-dose combination of old and safe generics jointly targeting a reduction of ectopic fat without necessarily lowering body weight.Trial registrationEudraCT 2021-006766-21. Registered on May 30, 2022.

Serum myostatin decreases in exercising and aging Alaskan sled dogs, while growth and differentiation factor 15 remains unaltered.

To evaluate the serum concentrations of myostatin and growth and differentiation factor 15 (GDF-15) in Alaskan Husky sled dogs participating in a 350-mile (560-km) race and in an older population, and to examine correlations between changes in serum concentrations and body condition scores (BCSs). Dogs were recruited from 3 teams of Alaskan Huskies participating in the Alaskan-Yukon Quest sled-dog race and retirees from a research sled-dog colony. Serum samples and BCSs were collected prior to racing, midway, and postrace; and in an older cohort (13 to 14 years). Myostatin and GDF-15 concentrations were assessed using commercially available ELISA kits. The median myostatin prerace concentration (9,519 pg/mL) was significantly greater than the mid- and postrace concentrations (7,709 pg/mL and 3,247 pg/mL, respectively). The prerace concentration was also significantly greater than that of the retired sled group dogs at 6,134 pg/mL. GDF-15 median serum concentrations did not change significantly across any racing time point (approx 350 pg/mL) or in the older cohort. No significant correlations were observed between changes in BCS and myostatin or GDF-15 concentrations. Serum myostatin decreases dramatically, yet no correlations to loss of BCS could be found. Myostatin signaling may be involved in maintaining hypertrophic signaling during intense exercise. Neither racing distance nor geriatric/retirement status appears to have an effect on serum GDF-15 concentration. Myostatin was less in the older, retired sled dogs compared to the younger racing cohort. Such differences highlight the roles that fitness level and age play regarding myostatin levels.

The search for systemic biomarkers for monitoring degenerative lumbar spinal disorders

ObjectivesIn our previous study, we reported that low back pain (LBP) severity and disability significantly correlate with body composition and several blood biochemical factors. Herein, we tested the hypothesis that these covariates are associated with anatomical deformations of the lumbar spine, in particular, radiographic facet joint osteoarthritis (FJOA) and lumbar disc degeneration (LDD) features important contributors to LBP. MethodsCT and MRI images of the lumbar spine were obtained from 200 individuals suffering from LBP-sciatica. We examined the FJOA and total LDD score - the sum of the scores of the three radiographic features (intervertebral disc herniation, osteophythosis and spondylolisthesis) at the L1 - S1 vertebral levels. By implementing a bioelectrical impedance analysis, we assessed the participants for body composition, specifically, extracellular water (ECW). Plasma levels of growth and differentiation factor 15 (GDF-15) and visceral adipose tissue-derived serine protease inhibitor (vaspin), were detected by ELISA. ResultsBy conducting a series of multivariable regression analyses, we report that the circulating levels of GDF-15, vaspin, and ECW are significantly and independently associated with FJOA scores [βGDF15 ​= ​0.38 ​± ​0.08, p ​= ​0.0001; βVASPIN ​= ​0.36 ​± ​0.07, p ​= ​0.000004; βECW ​= ​0.24 ​± ​0.07, p ​= ​0.002]. The levels of GDF-15 (β ​= ​0.30 ​± ​0.10, p ​= ​0.007) and ECW (β ​= ​0.20 ​± ​0.09, p ​= ​0.03) were also found significantly associated with the LDD scores. ConclusionThe obtained new data suggest that GDF-15, vaspin and ECW may serve as biomarkers for FJOA and LDD phenotypes.

Knockdown of growth differentiation factor-15 inhibited nonsmall cell lung cancer through inactivating PTEN/PI3K/AKT signaling pathway.

Non-small cell lung cancer (NSCLC) is characterized by high morbidity and mortality in the world. Growth and differentiation factor 15 (GDF15) has been proved to play an important role in regulating tumor progression. However, the influence of GDF15 on NSCLC remains unclear. We aimed to investigate the regulatory role of GDF15 in NSCLC. The correlation between GDF15 expression and prognosis, stage of NSCLC was examined with bioinformatics method. The cell proliferation was detected with CCK8 and EdU staining. Wound healing, Transwell, flow cytometry assays were used to measure cell migration, invasion, and apoptosis, respectively. High expression of GDF15 is correlated with worse survival and malignant progression of NSCLC. Knockdown of GDF15 restrained the proliferation, invasion, migration, but accelerated apoptosis of lung cancer cells through regulating PTEN/PI3K/AKT signaling pathway. sh-GDF15 suppressed epithelial mesenchymal transition (EMT) process and promoted the chemotherapy sensitivity of lung cancer cells. GDF15 plays an important role in NSCLC progression. GDF15 mediated PTEN/PI3K/AKT signaling pathway might be the potential therapeutic targets for the prevention and treatment of GDF15.

Growth and differentiation factor 15 (GDF15) levels predict adverse respiratory outcomes in premature neonates.

Growth and differentiation factor 15 (GDF15) is a stress-responsive cytokine, and its expression increases during inflammation, hyperoxia, and senescence. Significantly, GDF15 is secreted by the placenta, and maternal levels increase throughout pregnancy. Serum GDF15 level is a promising biomarker for many lung diseases like pulmonary hypertension and pulmonary fibrosis. However, circulating GDF15 levels in preterm infants and their role as a predictor of respiratory outcomes have not been studied. We hypothesized that GDF15 levels would increase with gestational age at birth, and that postnatal GDF15 will be correlated with adverse respiratory outcomes in preterm infants. Scavenged blood samples were retrieved from 57 preterm infants at five time points, from birth until 36-weeks postmenstrual age (PMA). GDF15 levels were measured using ELISA in 114 samples. We performed two-sample t-test, correlation and linear regression, logistic regression, and mixed-effects linear models for statistical analysis, and significance was identified when p < 0.05. Contrary to our hypothesis, for every 1-week increase in gestational age at birth, the predicted GDF15 level decreased by 475.0 pg/ml (p < 0.001). Greater PMA was significantly associated with lower serum GDF15 levels (p < 0.001). Interestingly, higher GDF15 levels were associated with a longer need for mechanical ventilation (p = 0.034), prolonged respiratory support need (p < 0.001), and length of hospital stay (p = 0.006). In conclusion, in preterm infants, GDF15 levels show an inverse correlation with gestational age at birth, with higher levels in more preterm babies, and levels trend down postnatally. Furthermore, longitudinal GDF15 levels through 36 weeks PMA predict adverse respiratory outcomes in preterm infants.

37P Growth/differentiation factor-15 from biomarker to target in cancer

Growth and differentiation factor-15 (GDF-15) is a divergent member of the transforming growth factor β family associated with pathological conditions, including myocardial ischemia, autoimmune disease, and cancer. Studies on the role of GDF-15 in cancer are limited and controversial. Radioactive iodine (131I) ablation of the post-surgical thyroid remnants, as an immunomodulatory tool, is the standard treatment for differentiated thyroid carcinomas (DTC) and DTC associated with type 2 diabetes mellitus (DTC+T2DM).