De novo and scaffold-based design of GDF15 binders for cancer cachexia diagnostics and therapeutics.

12060 Background: Growth differentiation factor-15 (GDF-15) is an emerging therapeutic target in cancer cachexia. However, the association of circulating GDF-15 with the cancer cachexia phenotype remains poorly characterized. Methods: Serum GDF-15 was measured using the Roche Elecsys GDF-15 assay at screening in a phase 2, randomized trial of ponsegromab (an investigational anti-GDF-15 monoclonal antibody) in patients with cancer cachexia, and an elevated serum GDF-15 (≥ 1500 pg/mL) (NCT05546476). Cachexia was defined by international consensus criteria and sarcopenia by standardized sex-specific cut-off values for lumbar skeletal muscle index. Cross-sectional associations of GDF-15 with various demographic and clinical parameters were explored post-hoc using summary statistics and Pearson’s correlation (with GDF-15 on the log 10 scale). Results: A total of 187 patients were enrolled in this study with a median (IQR) age of 67 (60-74) years and 37% were female. Baseline median GDF-15 values were higher among patients with cachexia and colorectal and pancreatic cancers, compared to NSCLC. GDF-15 elevation was higher in patients with stage IV disease, sarcopenia, and worse performance status (Table). Higher GDF-15 levels were associated with lower serum albumin (r = -0.31 [95% CI: -0.44, -0.177]) and pre-albumin (r = -0.17 [95% CI: -0.31, -0.03]). No significant associations were observed between GDF-15 levels and appetite or fatigue assessments. Conclusions: Among patients with cancer cachexia, GDF-15 elevation was more pronounced in those with more advanced cancer, sarcopenia, and worse performance status. In addition, GDF-15 levels were negatively correlated with markers of nutritional status. Clinical trial information: NCT05546476 . Demographic or Clinical Characteristic n Median (IQR) serum GDF-15, pg/ml Age, years- 18-44- 45-64- ≥65 670111 2718 (2461, 8117)4197 (2366, 9425)3849 (2310, 7125) Type of cancer- NSCLC- Pancreatic- Colorectal 745954 2701 (2114, 4094)4714 (2408, 9561)6468 (4106, 10052) Interval from cancer diagnosis- <1 year- ≥1 year 9691 4259 (2447, 8919)3781 (2259, 6997) Stage of cancer- I/II- III- IV 1634137 3551 (2264, 6320)3232 (2461, 5704)4365 (2387, 8117) Body mass index (BMI), kg/m2- <20- ≥20 9988 3254 (2220, 6801)5052 (2712, 8749) % weight loss in 6 months prior to screening- < 10%- ≥ 10% 9988 3849 (2290, 7677)4118 (2381, 7595) Sarcopenia status- Yes- No 14440 4259 (2402, 7672)2928 (2136, 8052) ECOG Performance Status- 0- 1- 2/3 3312331 2842 (2408, 5673)4094 (2366, 8623)5119 (2272, 7667) Systemic anticancer therapy- Platinum-based therapy- Antimetabolite agents- Biological agents- Antimicrotubule agents- PD-1 or PD-L1 inhibitors 68100407330 5760 (3053, 10008)5914 (2847, 10768)5744 (3317, 9644)4891 (2762, 9425)2744 (2149, 4787)

e24153 Background: Growth differentiation factor 15 (GDF-15) is a cytokine that induces anorexia, weight loss and has been reported to be associated with cachexia and poor survival in illnesses characterized by inflammation such as cancer cachexia and heart failure. In preclinical cancer cachexia models, GDF-15 inhibition has been demonstrated to reverse cachexia and improve survival. Circulating GDF-15 is also elevated in patients with sepsis and is associated with increased complications and poor survival. However, the role of infection- and sepsis-induced GDF-15 in mouse models is controversial based on published reports. Methods: In this study, we examined the effect of GDF-15 inhibition on tumor and lipopolysaccharide (LPS)-induced anorexia, weight loss, and survival using a GDF-15 neutralizing antibody (mAB2) and GDF-15 knockout mice. Results: mAB2 efficacy was confirmed by reversing AAV-GDF-15-induced weight loss in wildtype mice. A cachectic (anorexia and weight loss) mouse tumor model was established with subcutaneous implantation of mouse renal cell carcinoma (RENCA) cells. The chemotherapy sorafenib was administered to slow tumor progression. Plasma GDF-15 was increased to ~2 ng/mL, similar to levels in cancer patients. Treatment with mAB2 rapidly reversed both anorexia and weight loss in the tumor-bearing mice. LPS injection (intraperitoneal, 5 mg/kg) increased circulating GDF-15 in wildtype mice reaching concentrations like that reported in septic patients within 90 minutes and remaining elevated after 48 hours (~1 ng/mL). LPS decreased food intake, body weight, and increased mortality (~20%). Different from the tumor model, GDF-15 neutralization with mAB2 did not prevent or exacerbate any of the effects of LPS. There were no observed detrimental effects of mAB2 treatment in either model. Similarly, in GDF-15 knockout mice the LPS effect on energy balance and survival was comparable to that observed in wildtype controls. Plasma GDF-15 was undetectable in the GDF-15 knockout mice. Conclusions: Taken together, these data suggest that GDF-15 is a critical regulator of energy balance and survival in selective pathophysiological states associated with weight loss.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine produced by tumour cells and peripheral cells. It is implicated in the development of cancer cachexia, a debilitating condition for which no effective pharmacological therapy currently exists. GDF-15 regulates appetite and metabolic processes through complex neural and hormonal networks. Furthermore, it has been implicated in chemotherapy-induced nausea and vomiting, representing a potential therapeutic target. GDF-15 negatively affects tumour immunity, suggesting that anti-GDF-15 therapy could potentially enhance immune responses and help overcome resistance to immunotherapy. Recently, early clinical trials have reported preliminary results of GDF-15-targeted therapies in alleviating cancer cachexia and potentially enhancing the efficacy of immunotherapy. This review aims to provide an overview of the role of GDF-15 in cancer cachexia, including the underlying neural mechanisms and their involvement in tumour immunity. This review also summarises recent clinical trial findings and discusses future perspectives on GDF-15-targeted therapy in oncology, offering important insights for future research.

Background GDF-15 is an inflammatory cytokine involved in cellular response to stress. Elevated GDF-15 levels are found in patients with cancer and are associated with cachexia, a multifactorial syndrome that co-occurs with various tumor types, characterized by involuntary weight loss and loss of skeletal muscle, leading to fatigue, functional impairment, increased treatment-related toxicity, poor quality of life, and reduced survival. GDF-15 has emerged as a target for cancer cachexia. Here, the GDF-15 levels in real-world clinical samples from patients with CRC or PANC are compared with a range of demographic and clinical parameters. Methods GDF-15 levels were measured in serum collected from adult patients undergoing standard-of-care treatment for either PANC or CRC. Patients were not receiving an anti-GDF-15 therapeutic. Samples were stored in a biobank with associated metadata until this analysis. Serum GDF-15 was quantified using a validated electrochemiluminescence immunoassay and parameters were analyzed using summary statistics. Cachexia status was unknown in all but two cases. Results The sample population (n=100 from USA [n=83], Ukraine [n=17]) included patients with a clinical diagnosis of CRC (56%) or PANC (44%) aged 42 years to >90 years (median: 67); 54% male, 44% female (2% unavailable). As for standard-of-care treatments 70% had systemic therapy (30% unknown), of those, 50% received platinum-based treatment; 3% had radiation (97% unknown), and 8% had surgery (92% unknown). The GDF-15 range in CRC was 490 to >57600pg/mL, with a median that increased by stage across stages: I/II: 1470pg/mL (12.5%), III: 2110pg/mL (55.4%), and IV: 3090pg/mL (23.2%). Males had a higher median GDF-15 (2575pg/mL [57.1%] vs females (1870pg/mL [39.3%]) as well as smokers (median 3070pg/mL [16.1%] vs. non-smokers median 2145pg/mL [35.7%]). The GDF-15 range in PANC was 446 to 22600pg/mL, with a median GDF-15 that was higher in patients with Stage IV disease (5470pg/mL [40.9%]) compared to Stage I/II (3415pg/mL [31.8%], or Stage III 1390pg/mL [15.9%]. Higher median GDF-15 was found in non-smokers (5010pg/mL [47.7%] vs. smokers 1945pg/mL [27.3%]), and in males (4755pg/mL [50%] vs. females 2235pg/mL [50%]). Overall, GDF-15 levels moderately correlated with age (Pearson correlation coefficient: 0.3, natural log scale; p-value= 0.0028). As expected, higher GDF-15 levels were reported in patients with co-morbidities like thalassemia, Parkinson’s and cardiovascular conditions. Conclusions In this real-world analysis, in CRC and PANC, positive correlations were found between increasing GDF-15 serum levels and age, and stage progression. Higher GDF-15 correlated with male sex but smoking status yielded conflicting results. A limited dataset was used therefore results should be interpreted with caution. More analyses of GDF-15 in real-world settings like these are needed to inform development of anti-GDF-15 cachexia treatments. Citation Format: Rowida Abdelgalel, Suga Subramaniam, Tripti Gaur, Victoria Mountain, Bo Jin, Hijung Cho, Claudia Lebedinsky. Cancer cachexia marker, Growth Differentiation Factor 15 (GDF-15), serum level mapping in real world samples from patients with pancreatic (PANC) or colorectal cancer (CRC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B032.

Growth differentiation factor 15 (GDF15) is a stress-induced cytokine. Although the exact physiological function of GDF15 is not yet fully comprehended, the significant elevation of circulating GDF15 levels during gestation suggests a potential role for this hormone in pregnancy. This is corroborated by genetic association studies in which GDF15 and the GDF15 receptor, GDNF family receptor alpha like (GFRAL) have been linked to morning sickness and hyperemesis gravidarum (HG) in humans. Here, we studied GDF15 biology during pregnancy in mice, rats, macaques, and humans. In contrast to macaques and humans, mice and rats exhibited an underwhelming induction in plasma GDF15 levels in response to pregnancy (∼75-fold increase in macaques vs. ∼2-fold increase in rodents). The changes in circulating GDF15 levels were corroborated by the magnitude of Gdf15 mRNA and GDF15 protein expression in placentae from mice, rats, and macaques. These species-specific findings may help guide future studies focusing on GDF15 in pregnancy and on the evaluation of pharmacological strategies to interfere with GDF15-GFRAL signaling to treat severe nausea and HG.NEW & NOTEWORTHY In the present study pregnancy-induced changes in circulating growth differentiation factor 15 (GDF15) in rodents, rhesus macaques, and humans are mapped. In sum, it is demonstrated that humans and macaques exhibit a tremendous increase in placental and circulating GDF15 during pregnancy. In contrast, GDF15 is negligibly increased in pregnant mice and rats, questioning a physiological role for GDF15 in pregnancy in rodents.

Background To develop sensitive and specific ELISAs for the quantitative measurement of total human GDF-15 and H-specific (H202D mutant) GDF-15 in human serum, and other biological fluids. Growth/differentiation Factor 15 (GDF-15) is a divergent member of the TGF-β superfamily of growth factors. It is encoded in humans by a gene in chromosome 19. The human GDF-15 gene encodes for a protein of 308 amino acid residues which consists of a signal sequence (residues 1-29), pro-domain (30-194), and mature growth factor domain (195-308). The molecular weight of a mature GDF-15 dimer is 25 kDa. Approximately 25% of humans have a missense polymorphism in the GDF-15 gene resulting in mutation of histidine 202 to aspartate (histidine 6 in the mature domain), close to the N-terminus of the mature growth factor. This variant is associated with phenotypes in prostate cancer, hyperemesis gravidarum, (severe morning sickness in pregnancy), and rheumatoid arthritis. Methods Highly specific and reproducible total GDF-15 (AL-1014-r) and H-specific GDF-15 (AL-1018-r) ELISAs have been developed using specific monoclonal antibodies to help estimate the total and mutant (DD) concentration in serum in the respective assays. The ELISAs use 10 uL sample volume and are calibrated to recombinant human GDF-15 from R & D Systems (Biotechne, USA). These ELISAs were validated for their specificity using HH, DD, HD recombinant preparations and their circulating levels in male, female, 1st, and 2nd-trimester serum samples. Results The Total GDF-15 ELISA assay detects total GDF-15 including histidine 202 to aspartate mutation (HH, HD & DD variant) in the mature domain in equimolar proportions. The H-specific GDF-15 assay is specific to histidine at 202aa in the GDF-15 sequence and does not detect histidine 202 to aspartate mutation (DD variant). Median Levels of total GDF-15 in healthy males (n=18), females (n=17), 1st trimester (n=20), and 2nd trimester (n=20) were 847.9 pg/mL, 1182.4 pg/mL, 12759.7 pg/mL, and 12951.2 pg/mL. Median Levels of H-specific GDF-15 in healthy males (n=18), females (n=17), 1st trimester (n=20), and 2nd trimester (n=20) were 723.2 pg/mL, 641.3 pg/mL, 8381.4 pg/mL and 4652.1 pg/mL. Method comparison between total GDF-15 and commercial GDF-15 assay using serum samples (HH, wild type) in the range of 400-2500 pg/mL yielded a slope of 0.98 (r=0.97). The HD and DD mutant samples in the total assay recovered at twice the concentrations of the commercial assay. The total and intact assays are highly reproducible with the total coefficient of variation less than 7%. Conclusions Use of total GDF-15 assay in combination with the GDF-15 H-specific assay (DD nondetectable) ELISA can accurately estimate the mutant (DD) concentration in serum. This will enhance the knowledge of the GDF-15 measurements in the literature as the commercial assays were compromised for its immunoreactivity to the HD DD genotypes which is highly prevalent.

Background: One of the most lethal and debilitating effects of cancer is the development of cancer-related anorexia-cachexia syndrome (CACS). It affects the majority of advanced cancer patients and is thought to be responsible for up to ∼30% of all cancer deaths. CACS is a complex metabolic syndrome associated with malnutrition and severe involuntary weight loss due to the loss of muscle and fat tissue, as well as the clinical manifestation of anemia, inflammation and suppression of immune functions. The precise molecular mechanisms responsible for cancer cachexia are poorly understood, thus limiting the development of effective therapeutics. Current evidence suggests that a pro-inflammatory state may be responsible for many of the symptoms associated with CACS. Growth Differentiation Factor 15 (GDF15) is a pro-inflammatory cytokine whose circulating levels are significantly increased in cachectic cancer patients and several animal models of cancer cachexia. Here we demonstrate that the inhibition of GDF15 function results in the compete reversion of the phenotypic and metabolic changes associated with CASC. Methods: Mice bearing HT-1080 human fibrosarcoma xenografts have increased plasma GDF15 levels and develop cachexia were used in this study. Tumor bearing animals were treated either with AV-380, a GDF15 neutralizing antibody or IgG1 control. The effect on body weight, muscle/fat mass and organ sizes were assessed. Metabolic changes induced by the treatment were measured by a comprehensive laboratory animal monitoring system (CLAMS). Results: Treatment with AV-380 restored body weight, muscle and fat mass as well as normal organ sizes. Analyses of the CLAMS data demonstrated that mice receiving AV-380 reversed the phenotypic and metabolic changes associated with the cachexia induced by this tumor model. Moreover, AV-380 treated mice showed an increase in locomotor activity and energy expenditure, achieving levels similar to non tumor bearing control animals. Conclusions: Inhibition of GDF15 function completely reverted body weight loss, restored normal body composition and triggered a catabolic to anabolic metabolic switch in this cancer cachexia model. The data highlights the therapeutic potential of the GDF15 inhibitory antibody AV-380 for the treatment for CACS. Citation Format: Lorena Lerner, Nianjun Tao, Brian Krieger, Richard Nicoletti, Bin Feng, Nesreen Ismail, William Winston, Yanyu Zhang, Jinwei Jiang, Solly Weiler, Jeno Gyuris. Effective treatment of cancer associated cachexia by AV-380, a GDF15 inhibitory antibody. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1153. doi:10.1158/1538-7445.AM2015-1153

ABSTRACTBackgroundGrowth Differentiation Factor 15 (GDF15), a nonspecific inflammatory marker and member of the TGF‐β superfamily, has a well‐established role in both inflammation and metabolic modulation, but lacks a comprehensive paediatric literature review. In several adult disease states, including cancer cachexia and pregnancy, circulation and expression of GDF15 has been of clinical and scientific interest, but little published paediatric data exists. As such, we aim to summarize existing paediatric studies.MethodsThis review follows the PRISMA‐ScR guidelines for reporting and aims to summarize existing paediatric studies including GDF15, describe disease entities in which GDF15 has been investigated including existing reference ranges, and identify literature gaps to present future clinical and research direction. Our search strategy queried Ovid MEDLINE, Ovid Embase, Cochrane Library and Scopus databases to find original scientific articles measuring GDF15 from birth through children up to age 18. Data relating to study participant demographic and disease pathology, GDF15 measurement methods and clinical outcomes of interest were extracted.ResultsSixty‐two studies were included, classified as cardiac, endocrine, mitochondrial, hematologic, neonatal, oncologic, infectious, rheumatologic, renal, neurologic or healthy. While several entities demonstrated elevated GDF15, the highest median GDF15 levels were observed in cardiac arrest 7089 pg/mL (interquartile range 3805–13 306) and mitochondrial diseases 4640 pg/mL (1896–14 064). In certain conditions, including cardiac stress, polycystic ovarian syndrome (PCOS), Kawasaki Disease (KD) and certain mitochondrial myopathies GDF15 can normalize with disease treatment or resolution. Of healthy children studied, GDF15 levels were highest in healthy neonates and followed a predictable pattern, decreasing over time. Mean and standard deviation values of GDF15 in healthy children were 343.8 ± 221.0 pg/mL, with a range of 90–1134 pg/mL for study averages.ConclusionsCirculating GDF15 has been studied in a variety of paediatric diseases. However, variable evaluated outcome measures and GDF15 measurement methodologies prevent generalizability and direct comparison of these published studies. Validating normal GDF15 levels in children with standardized and reproducible methodology will help clarify GDF15's utility as a diagnostic marker of disease, a necessary step to elucidate clinical implications of GDF15 over expression and its potential as a therapeutic target.

GDF15: from biomarker to target in cancer cachexia.

Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss2, and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3-7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G3. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous ('knockouts') and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15.

Background: Growth Differentiation Factor 15 (GDF15) has emerged as a key biomarker and therapeutic target in oncology, with roles extending beyond cancer cachexia. Elevated GDF15 levels correlate with poor prognosis across several solid tumors, including colorectal, gastric, pancreatic, breast, lung, prostate, and head and neck cancers. GDF15 modulates tumor progression through PI3K/AKT, MAPK/ERK, and SMAD2/3 signaling, thereby promoting epithelial-to-mesenchymal transition, metastasis, immune evasion, and chemoresistance via Nrf2 stabilization and oxidative stress regulation. Methods: We performed a narrative review of the literature focusing on the role of GDF15 in solid tumors, with a particular emphasis on head and neck cancers. Results: In head and neck squamous cell carcinoma (HNSCC), GDF15 overexpression is linked to aggressive phenotypes, radioresistance, poor response to induction chemotherapy, and failure of immune checkpoint inhibitors (ICIs). Similar associations are observed in colorectal, pancreatic, and prostate cancer, where GDF15 contributes to metastasis and therapy resistance. Targeting the GDF15-GFRAL axis appears therapeutically promising: the monoclonal antibody ponsegromab improved cachexia-related outcomes in the PROACC-1 trial, while visugromab combined with nivolumab enhanced immune response in ICI-refractory tumors. Conclusions: Further investigation is warranted to delineate the role of GDF15 across malignancies, refine patient selection, and evaluate combinatorial approaches with existing treatments.

Background: Cachexia is a common complication of heart failure (HF) and is associated with high mortality. Growth differentiation factor 15 (GDF15) regulates food intake and can cause cancer cachexia. GDF15 is a sensitive biomarker in humans, though its biologic function in HF is unknown. Objective: We sought to define the role of GDF15 in HF. Methods: We utilized a genetic mouse model of dilated cardiomyopathy (DCM) caused by a mutation in the phospholamban gene (PLNR9C). PLNR9C mice have dysregulated cardiac calcium handling (a common feature of nearly all forms of HF) and develop progressive DCM that leads to HF and premature death. Expression analyses were performed on tissue and isolated myocardial cells via flow cytometry and single nucleus RNA-sequencing (snRNA-seq) in PLNR9C and age-matched wild type (WT) mice. A double transgenic mouse was created by crossing PLNR9C with a constitutive Gdf15 knock-out (KO). Cardiac function and fibrosis were assessed using echocardiography and histochemistry, respectively. We measured food intake in individually housed mice, and tissue composition was quantified by weight at necropsy, dual-energy X-ray absorptiometry (DXA) and histochemistry. Survival was assessed by Kaplan-Meier. Results: GDF15 mRNA (43-fold; p<0.01) and protein (54-fold; p<0.01) were increased in LV tissue, and circulating GDF15 was elevated (8.3-fold; p=0.03) in PLNR9C mice. In other organs, Gdf15 expression was minimal and did not increase with DCM. Single nucleus sequencing revealed that Gdf15 was specifically increased in cardiomyocytes with progression to DCM. The GDF15-specific receptor GDNF-family receptor a-like (GFRAL) was selectively expressed in the hindbrain of these mice. PLNR9C mice consumed less food and developed cachexia (reduced fat and lean mass at necropsy, reduced fat mass by DXA and reduced skeletal muscle cross-sectional area; p<0.01 for all vs. WT), findings that were reversed in PLNR9C-Gdf15 KO mice. Gdf15 KO had no effect on cardiac structure or function by echocardiography and PLNR9C/Gdf15 KO mice displayed only a small reduction in cardiac fibrosis relative to PLNR9C mice (-3%; p<0.01). Despite this, Gdf15 KO prolonged survival in PLNR9C (29±3 vs. 25±3 weeks; p<0.01). Conclusions: Selective upregulation of GDF15 in failing cardiomyocytes triggers cardiac cachexia and worsens survival by an extra-cardiac mechanism. We therefore propose that GDF15 is a novel cardiac hormone produced in HF.

Platinum-based chemotherapy is associated with nausea/emesis, anorexia and weight loss which reduce patient quality of life and limit treatment adherence potentially leading to poor treatment outcomes. Cisplatin increases circulating growth differentiation factor 15 (GDF-15), a cytokine that induces conditioned taste aversion, anorexia and weight loss in preclinical models. GDF-15 signals through the hindbrain receptor glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). Cisplatin-induced anorexia/weight loss was attenuated in a GFRAL knockout mouse; therefore, we examined whether GDF-15 inhibition can prevent platinum-based chemotherapy-induced emesis, anorexia and weight loss, and also increase survival using mouse and/or nonhuman primate models. In cancer patients, platinum treatment increased circulating GDF-15 in non small cell lung carcinoma, colorectal, and ovarian cancer (~1.5 fold) compared to those receiving a non-platinum-based therapy. Furthermore, cisplatin, oxaliplatin and carboplatin administered individually all increased circulating GDF-15 in wildtype mice (≥ 5 fold) and induced anorexia, skeletal muscle wasting, and weight loss. GDF-15 mRNA was increased in kidney, liver, brain and white adipose tissue. These effects were prevented in GDF-15 knockout mice, however only a partial blockade was observed in the carboplatin group. In nonhuman primates, cisplatin treatment for 5 days (96% of the daily recommended clinical dose) also increased circulating GDF-15 (> 5 fold), and induced anorexia and emesis. Treatment with the anti-GDF-15 monoclonal antibody (mAB1) resulted in no detectable circulating levels of free GDF-15, and attenuated both cisplatin-induced anorexia and emesis. Furthermore, in a mouse cachectic tumor model (subcutaneous implantation of tumor tissue derived from human non-small cell lung carcinoma adenocarcinoma), cisplatin treatment inhibited tumor growth; however, GDF-15 levels were still elevated and additional weight loss occurred compared to vehicle control. When mAB1 was given in combination with cisplatin, weight loss was reversed and tumor growth inhibition was maintained, resulting in greater survival compared to cisplatin alone. Taken together, these data support the notion that GDF-15 inhibition with mAB1 holds the potential as an effective therapeutic approach to alleviate GDF-15 mediated emesis, anorexia and weight loss with the aim to enable optimal cancer treatment as well as to improve patient quality of life and potentially survival. Citation Format: Danna M. Breen, Kevin Beaumont, Donald Bennett, Julia Brosnan, Roberto Calle, Jeffrey R. Chabot, Susie Collins, Teresa Cunio, Ryan M. Esquejo, Stephanie Joaquim, Alison Joyce, Hanna Kim, Laura Lin, Betty Pettersen, Shuxi Qiao, Michelle Rossulek, Brendan Tierney, Karen M. Walters, Gregory Weber, Zhidan Wu, Bei B. Zhang, Morris J. Birnbaum. Growth differentiation factor 15 (GDF-15) inhibition attenuates platinum-based chemotherapy-induced emesis, anorexia and weight loss and increases survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3056.

Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are linked to weight loss in non-small cell lung cancer (NSCLC) patients. This study examines the role of the integrated stress response (ISR) cytokine growth differentiation factor 15 (GDF15) in regulating cachexia using patient-derived and engineered STK11/LKB1-mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing GDF15 from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type STK11/LKB1 in NSCLC lines with endogenous STK11/LKB1 loss reverses the ISR and reduces GDF15 expression rescuing the cachexia phenotype. Collectively, these findings implicate tumor-derived GDF15 as a key mediator and therapeutic target in STK11/LKB1-mutant NSCLC-associated cachexia.