LY3200882 / Eli Lilly - LARVOL DELTA

Progranulin promotes glioma progression through the M2-TGF-β axis: targeted therapy with SORT1-loaded HAMA hydrogel microspheres. (PubMed, Am J Transl Res) - "Transwell experiments further showed that GRN promoted GBM invasion in a macrophage-dependent manner via the TGF-β pathway, an effect that was abrogated by the TGF-β receptor I inhibitor LY3200882...Collectively, our findings identify GRN as a key driver of GBM progression and TME immunosuppression through M2 macrophage polarization and TGF-β signaling. Targeting GRN with SORT1-loaded HAMA microspheres represents a promising adjuvant therapeutic strategy for GBM."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • CD163 • CD86 • GRN • IL10 • MRC1 • TGFB1

Overcoming TGFβ-mediated immunosuppression to enhance B7-H3 CAR-T cell therapy in Group 3 Medulloblastoma (ISPNO 2026) - "Pharmacological inhibition of TGFβ signalling was tested using the selective TGFBRI inhibitors Vactosertib and LY3200882.Robust TGFβ pathway activation was observed across preclinical models and patient samples, with significantly higher pSMAD3 levels in Group 3 tumours compared with other medulloblastoma subgroups (SHH n=71, Group 3 n=63, Group 4 n=71, WNT n=15). Drug treatment protected CAR-T effector function (cytokine release and proliferation) upon repeated tumour and TGFβ challenge. In vivo studies are evaluating efficacy, safety, feasibility, and pharmacokinetic and pharmacodynamic profiles.These findings provide an initial preclinical rationale for combining TGFβ pathway inhibition with anti-B7H3 CAR T-cell therapy in G3 medulloblastoma."

CAR T-Cell Therapy • IO biomarker • Brain Cancer • Medulloblastoma • Solid Tumor • CD276 • SMAD3 • TGFB1

Transcriptional Profile Change of NK-92 Cells in Presence of Cytokines, TGFβ Signaling Pathway Inhibitor and CDK7/12/13 Kinase Inhibitor. (PubMed, Int J Mol Sci) - "Both LY3200882 and THZ1 affected the NK cell transcription even without cytokine treatment. The independent effects of synthetic inhibitors on NK cells, as well as their influence in the presence of tumor cells, should be considered."

IO biomarker • Journal • Oncology • B3GAT1 • CDK7 • GATA3 • IL10 • IL12A • IL15 • IL18 • KLRC1 • KLRC2 • NCAM1 • NCR2 • NKG2D • TBX21 • TNFA

A Study of LY3200882 in Participants With Solid Tumors (clinicaltrials.gov) - P1 | N=223 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Aug 2026 ➔ Aug 2027

Trial completion date • Oncology • Solid Tumor

A Study of LY3200882 in Participants With Solid Tumors (clinicaltrials.gov) - P1 | N=223 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Solid Tumor

LY3200882 and Capecitabine in Advanced Resistant TGF-beta Activated Colorectal Cancer (EORTC1615) (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: The Netherlands Cancer Institute | N=31 ➔ 0 | Unknown status ➔ Withdrawn

Enrollment change • Trial withdrawal • Colorectal Cancer • Oncology • Solid Tumor • TGFB1

Enhancing the therapeutic efficacy of gemcitabine in bladder cancer through TGF-β1 inhibition and pluronic F-127-based microsphere delivery. (PubMed, J Biol Eng) - "The present research was designed to explore the impact of TGF-β1 inhibitors (LY2109761 and LY3200882) with or without gemcitabine on bladder cancer cells and to develop Pluronic F-127-based microspheres (MSs) for drug delivery. Systemic and local bladder toxicity assessments in mice demonstrated the in vivo safety of drug-loaded MSs. This study concludes that combining TGF-β1 inhibitors with gemcitabine in Pluronic F-127-based MSs enhances therapeutic efficacy against bladder cancer, promoting apoptosis, inhibiting cell invasion, and reducing tumor growth and metastasis while maintaining safety."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • TGFB1

Effect of Buzhong Yiqi Decoction on Treg cells in rats with autoimmune thyroiditis through TGF-β/Smad signaling pathway (PubMed, Zhongguo Zhong Yao Za Zhi) - "The extracted Treg were divided into blank group, Buzhong Yiqi Decoction group, TGF-β group, antagonist(LY3200882), and antagonist(LY3200882)+Buzhong Yiqi Decoction group...After Buzhong Yiqi Decoction-containing serum was added to the antagonist group, the mRNA levels of TGF-β1, FoxP3, Smad2, Smad3, Smad4, and Smad7 were not statistically significant. In conclusion, Buzhong Yiqi Decoction could promote the stability and activity of Treg cells by promoting the secretion of TGF-β1 and regulating the expression of key signaling molecules TGF-β1, Smad2, and Smad4 in the TGF-β/Smad signaling pathway, thus affecting the immune balance of Th17/Treg and inhibiting the inflammatory response of rats with EAT."

Journal • Preclinical • Endocrine Disorders • Immunology • Inflammation • FOXP3 • SMAD2 • SMAD3 • SMAD4 • SMAD7 • TGFB1

Advancements in TGF-β Targeting Therapies for Head and Neck Squamous Cell Carcinoma. (PubMed, Cancers (Basel)) - "While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy."

Journal • Review • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • TGFB1

SIRT3 sulfhydration using hydrogen sulfide inhibited angiotensin II-induced atrial fibrosis and vulnerability to atrial fibrillation via suppression of the TGF-β1/Smad2/3 signalling pathway. (PubMed, Eur J Pharmacol) - "Moreover, we observed suppression of the TGF-β1/Smad2/3 pathway when Ang-II was combined with NaHS treatment, and the effect of this co-treatment was consistent with that of Ang-II combined with LY3200882 (Smad pathway inhibitor) on reducing atrial fibroblast proliferation and cell migration in vitro. Supplementation with dithiothreitol (DTT, a sulfhydration inhibitor) and adenovirus SIRT3 shRNA blocked the ameliorating effect of NaHS and AngII co-treatment on atrial fibrosis in vitro. Finally, continued treatment with NaHS in rats ameliorated atrial fibrosis and remodelling, and further improved AF vulnerability induced by Ang-II, which was reversed by DTT and adenovirus SIRT3 shRNA, suggesting that SIRT3 sulfhydration might be a potential therapeutic target in atrial fibrosis and AF."

Journal • Atrial Fibrillation • Cardiovascular • Fibrosis • Immunology • SIRT3 • TGFB1

Increased EHD1 in trophoblasts causes RSM by activating TGFβ signaling. (PubMed, Biol Reprod) - "Increased expression of EHD1 impaired the invasion of EVTs mediated by the TGFBR1-SMAD2/3 signaling pathway and induced abnormal syncytialization of STB, which is at least partially responsible for RSM."

Journal • EHD1 • TGFBR1

Galangin Promotes Tendon Repair Mediated by Tendon-Derived Stem Cells through Activating the TGF-β1/Smad3 Signaling Pathway. (PubMed, Chem Pharm Bull (Tokyo)) - "Moreover, GLN was also found to upregulate the protein levels of transforming growth factor β1 (TGF-β1) and p-Smad3 to activate the TGF-β1/Smad3 signaling pathway, while GLN mediated collagen deposition in TDSCs was reversed by LY3200882, a TGF-β receptor inhibitor. The study concluded that GLN-mediated TDSCs enhanced tendon repair by activating the TGF-β1/Smad3 signaling pathway, suggesting a novel therapeutic option in treating tendon repair."

Journal • Orthopedics • COL1A1 • SMAD3 • TGFB1

A Study of LY3200882 in Participants With Solid Tumors (clinicaltrials.gov) - P1 | N=223 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Aug 2024 ➔ Aug 2025

Trial completion date • Oncology • Solid Tumor

Targeting TGFβ pathway to enhance CAR-T therapy for glioblastoma (SITC 2023) - P1 | "We demonstrated that pretreatment with a TGFβR1 inhibitor (LY3200882) significantly augmented the efficacy of CAR-T therapy and improved overall survival of mice bearing large established tumors...Based on these results, we next evaluated TGFβ-resistant CAR-T cells in vivo and demonstrated that blocking TGFβ-signaling through TGFβR2 knockout augmented the efficacy of CAR-T cells in a large immunosuppressive GBM tumor model in syngeneic mice. Conclusions Collectively, our results indicate that inhibiting the TGFβ pathway either in TME or CAR T cells is essential for enhancing CAR-T cell efficacy in GBM."

IO biomarker • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • IL13RA2 • TGFB1 • TGFBR2

A Study of LY3200882 in Participants With Solid Tumors (clinicaltrials.gov) - P1 | N=223 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Aug 2023 ➔ Aug 2024

Trial completion date • Oncology • Solid Tumor

Bone marrow mesenchymal stem cells paracrine TGF-β1 to mediate the biological activity of osteoblasts in bone repair. (PubMed, Cytokine) - "Our findings provide evidence that the biological mechanism of BMSC-produced TGF-β1 promotes bone regeneration and repair, providing a theoretical basis and new directions for the application of BMSC transplantation in the treatment of osteonecrosis and bone injury."

Journal • Transplantation • TGFB1

A Study of LY3200882 in Participants With Solid Tumors (clinicaltrials.gov) - P1 | N=223 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2022 ➔ Aug 2023

Trial completion date • Oncology • Solid Tumor

The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment. (PubMed, Biomaterials) - "Notably, the synergistic effect of LY and siPD-L1 remarkably enhanced the tumor antigen presentation and immunosuppressive microenvironment remodeling, thus efficiently inhibiting the TNBC growth, metastasis, and recurrence. Therefore, the programmed site-specific delivery nanosystem is a promising drug delivery platform for boosting anti-tumor immunotherapy efficacy for TNBC."

Biomarker • IO biomarker • Journal • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MMP2 • TGFB1

TGFβ receptor inhibition unleashes interferon-β production by tumor-associated macrophages and enhances radiotherapy efficacy. (PubMed, J Immunother Cancer) - "These data shed new light on the role of TGFβ in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGFβR inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer."

Journal • Immune Modulation • Immunology • Inflammation • Lung Cancer • Oncology • Solid Tumor • IFNB1 • TGFB1 • TGFBR2

Tumor Microenvironments-Adapted Polypeptide Hydrogel/Nanogel Composite Boosts Antitumor Molecular Targeted Inhibition and Immunoactivation. (PubMed, Adv Mater) - "LY3200882 (LY), a selective transforming growth factor-β (TGF-β) inhibitor, was encapsulated in the ROS-responsive nanogel and dispersed uniformly with regorafenib (REG) in a thermo-sensitive hydrogel (Gel/(REG+NG/LY)). LY contributed to preventing the epithelial-mesenchymal transition and immune escape of tumor cells induced by elevated TGF-?. In subcutaneous and orthotopic colorectal tumor-bearing mouse models, Gel/(REG+NG/LY) effectively inhibited tumor growth and liver metastasis by increasing the tumor infiltration of CD8 T cells, reducing the recruitment of tumor-associated macrophages and myeloid-derived suppressor cells, and promoting the polarization of macrophages from M2 to M1 type, indicating the significant potential in improving the prognosis of advanced cancer patients."

Biomarker • Journal • Tumor microenvironment • Colorectal Cancer • Gastrointestinal Cancer • Immunology • Oncology • Solid Tumor • CD8 • TGFB1

First-In-Human Phase I Study of a Next-Generation, Oral, Transforming Growth Factor-Beta Receptor 1 Inhibitor, LY3200882 in Patients with Advanced Cancer. (PubMed, Clin Cancer Res) - P1 | "LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in PC. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced PC are warranted."

Clinical • Journal • P1 data • Brain Cancer • Cardiovascular • Gastrointestinal Cancer • Glioblastoma • Glioma • Head and Neck Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Study of LY3200882 in Participants With Solid Tumors (clinicaltrials.gov) - P1; N=223; Active, not recruiting; Sponsor: Eli Lilly and Company; Trial completion date: Sep 2021 ➔ Dec 2022

Clinical • Trial completion date • Oncology • Solid Tumor

The culture microenvironment of juvenile idiopathic arthritis synovial fibroblasts is favorable for endochondral bone formation through BMP4 and repressed by chondrocytes. (PubMed, Pediatr Rheumatol Online J) - "JFLS are chondrocyte-like, and Ch-conditioned media can abrogate this phenotype. The addition of exogenous BMP4 causes JFLS-Ch to restore this chondrocyte-like phenotype, suggesting that JFLS create a microenvironment favorable for endochondral bone formation, thereby contributing to joint growth disturbances in juvenile idiopathic arthritis."

Journal • Idiopathic Arthritis • Immunology • Rheumatoid Arthritis • Rheumatology • COL1A1 • MMP9 • PCNA • TGFB1 • TGFBI

A Study of LY3200882 in Participants With Solid Tumors (clinicaltrials.gov) - P1; N=223; Active, not recruiting; Sponsor: Eli Lilly and Company; Trial completion date: Dec 2020 ➔ Sep 2021

Clinical • Trial completion date • Oncology • Solid Tumor

Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors. (PubMed, Eur J Med Chem) - "The most potent compound 15r inhibited the ALK5 enzyme and NIH3T3 cell viability with IC values of 44 and 42.5 nM, respectively. Compound 15r also displayed better oral plasma exposure and excellent bioavailability than LY-3200882, and in vivo inhibited 65.7% of the tumor growth in a CT26 xenograft mouse model."

Journal