galunisertib (LY2157299) / Eli Lilly - LARVOL DELTA

Investigating the interplay of transcription factor, ERG, and TGF-beta signaling in cervical cancer cells (AACR 2026) - "To further investigate the effects of ERG on TGF-β, galunisertib, a known inhibitor of TGF-β signaling, was used...ChIP-seq is being done to investigate the possible interactions between TGFB signaling and ERG occupancy on the genome in cervical cancer, which will be compared to ERG sites in extensively studied cancers. Together, these findings suggest that ERG promotes cervical cancer cell migration and invasion, at least in part by regulating TGF-β signaling."

Cervical Cancer • Oncology • Solid Tumor • ERG • SMAD2 • TGFB1

Crosstalk between ceramide and prostaglandin signaling mediates resistance to immune checkpoint blockade (AACR 2026) - "Targeting PGE2 production with celecoxib, but not aspirin, further enhanced responses when combined with LY2157299 and αPD-1 therapy. Finally, mIF analysis of nivolumab-treated pre-surgical human HNSCC specimens (responders vs. non-responders) corroborated these findings by demonstrating reduced tumor ceramide abundance, elevated PanCK+COX-2+ceramidelo populations, and decreased intratumoral CD8+ T cell density amongst non-responders. Collectively, these studies (1) establish a relevant model of ICB resistance, (2) define a mechanistic framework linking ceramide metabolism to prostaglandin-mediated immune suppression, and (3) highlight therapeutic strategies to target ICB resistance and improve patient outcomes."

Checkpoint block • Checkpoint inhibition • IO biomarker • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CAPRIN1 • CD8 • CERS4 • PACERR • PTGS2 • TGFB1

Extracellular vesicle-mediated co-delivery of FSL-1 and LY2157299 for immunotherapy of small-cell lung cancer liver metastases (AACR 2026) - "In vivo, EVs efficiently targeted intrahepatic tumor sites, decreased liver tumor growth, and prolonged mouse survival. These data support EV‑mediated co‑delivery of FSL‑1 and LY2157299 as a macrophage‑centric strategy for SCLC liver metastasis."

Hepatocellular Cancer • Liver Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • TLR2

Targeting HCC tumor microenvironment interactions using an advanced HCC patient-derived on-chip model (AACR 2026) - "The screen revealed that SoC drugs sorafenib and lenvatinib reduced culture viability and induced profound changes in vascular bed organization, while atorvastatin decreased viability without affecting vascular structures...Tocilizumab, galunisertib, and vactosertib lowered IL6 levels, whereas halofuginone increased IL6. These findings highlight the utility of the PDChip model in visualizing drug-induced responses at both molecular and morphological levels, providing detailed insights into drug effects on specific cellular compartments within the HCC TME. This platform enabled a detailed evaluation of drug-induced responses in the tumor and associated microenvironment, highlighting their importance in preclinical research for understanding diseases and developing new drugs."

Biomarker • Clinical • Metastases • Tumor microenvironment • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • IL6

PMEPA1 promotes mTOR inhibitor resistance in triple-negative breast cancer: Targeting the TGF-β/PMEPA1 axis as a therapeutic strategy to overcome resistance. (PubMed, Biochem Pharmacol) - "To model acquired resistance, we established two mTORi-resistant TNBC cell lines, MDA-MB-231/DREVE and MDA-MB-231/DRRIDA through chronic exposure to everolimus and ridaforolimus, respectively...Pharmacological inhibition of upstream TGF-β signaling with galunisertib suppressed PMEPA1 and synergistically restored sensitivity to mTORi in both invitro and xenograft models, resulting insignificant tumor regression...Collectively, these findings establish PMEPA1 as a dual modulator of canonical and non-canonical TGF-β signaling and a critical mediator of mTORi resistance in TNBC. Targeting the TGF-β/PMEPA1 axis represents a promising strategy to overcome resistance and improve clinical outcomes in mTORi-refractory TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • KRAS • PMEPA1 • PTEN • TGFB1

Precision-Cut Bladder Slices: A Novel Model for the Study of Bladder Fibrosis and Potential Anti-Fibrotic Agents. (PubMed, Int J Urol) - "This study demonstrates that PCBS provide a viable and reproducible platform for modeling bladder fibrosis and screening anti-fibrotic therapies. PFD, IMA, and GAL showed promising anti-fibrotic effects, supporting further investigation into their therapeutic potential."

Journal • Fibrosis • Immunology • BMP7 • COL1A1 • CTGF • TGFB1

Single-cell capture of on-ART SIV transcription reveals TGF-β-mediated metabolic control of viral latency. (PubMed, JCI Insight) - "We previously demonstrated that blocking TGF-β with galunisertib, a safe, orally available small drug, reactivated latent SIV in vivo by shifting T cells toward a transitional effector phenotype...High-dimensional flow cytometry demonstrated effects beyond CD4+ T cells, including fewer tissue-resident memory T cells, but more inflammatory macrophages. In conclusion, SCAP represents a specific tool for characterizing rare SIV-infected cells transcribing virus during ART, and it reveals TGF-β as a key mediator of viral latency in vivo through metabolic suppression."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4 • TGFB1 • TNFA

Mitophagy-related molecular signatures in ulcerative colitis revealed by machine learning and molecular dynamics. (PubMed, Front Genet) - "This study delineated the mitophagy-related molecular signatures of UC and identified CD55, CPT1A, and SLC16A1 as key biomarkers linking mitochondrial dysfunction, metabolic reprogramming, and immune activation. Furthermore, galunisertib was proposed as a potential therapeutic agent, providing a theoretical basis for UC therapy."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders • Ulcerative Colitis • CD55 • CPT1A • SLC16A1

Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome. (PubMed, Nat Aging) - "TGFBR1 inhibition with galunisertib or senolytic treatment reduces tumor progression driven by cisplatin-induced senescence, and concomitant use of TGFBR1 inhibitors with platinum-based chemotherapy reduces tumor burden and improves survival. Finally, we validate the translational relevance of tumor-promoting TGFβ-enriched SASP using clinical NSCLC and HGSOC samples from patients who received neoadjuvant platinum-based chemotherapy. Together, our findings identify a potential cancer therapy resistance mechanism and provide preclinical proof of concept for future trials."

Journal • Platinum resistant • High Grade Serous Ovarian Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • KRAS • TGFB1 • TGFBR1

Efficient Inhibition of TGF-β Signaling via Cytosolic Delivery of a Smad2/3-Binding Peptide Using the Cell-Penetrating PG-Surfactant DKDKC12-K5 to Block Smad2/3 Nuclear Translocation. (PubMed, Bioconjug Chem) - "Functionally, SARA-cpPG suppressed TGF-β1-induced actin polymerization and cell migration, comparable to the effects of receptor kinase inhibitor LY2157299...This suppression was absent in treatments with SARAm-cpPG, cpPG alone, or a non-cytoplasm-specific carrier conjugate (SARA-R8). These findings demonstrate that cpPG enables efficient cytosolic delivery of functional peptides and supports a strategy for intracellular peptide therapeutics targeting nuclear signaling pathways."

Journal • SMAD2 • TGFB1

CMS subtypes correlate with complete response in trial of neoadjuvant Galunisertib plus chemoradiation in rectal cancer. (PubMed, Transl Oncol) - "Differences in correlations between RNA based measures of cell composition and immunohistologic quantification of infiltrates and extracted MRI parameters were observed for CIBERSORT, MCPcounter, and xCell methodologies. Based on these data, we hypothesize that the stromal radioresistant phenotype driven by TGFβ can be overcome by the addition of galunisertib to chemoradiation in rectal cancer."

Journal • Colorectal Cancer • Oncology • Rectal Cancer • Solid Tumor • MYC • TGFB1

Rational Design of Combination Therapy for CRC: Multi-Omics Insights into Galunisertib and TAS-102 Synergy (I-OSICON 2026) - No abstract available

Combination therapy

Design, synthesis, and biological evaluation of quinoxalinyl and quinolinyl derivatives as ALK5 inhibitors. (PubMed, Mol Divers) - "Among all the compounds, compound 22f (IC50 = 0.267 μM) exhibited the highest ALK5 inhibitory activity, comparable to that of the positive control LY-2157299. This study revealed that introducing amino groups into the side chains of quinoxalinyl and quinolinyl derivatives is more effective in enhancing ALK5 inhibition than ether or ester groups. These findings provide new insights and a theoretical foundation for the development of pyrazole-based ALK5 inhibitors."

Journal • TGFBR1

Modeling hepatocellular carcinoma and its microenvironment on a chip. (PubMed, Cell Death Discov) - "Sorafenib, lenvatinib and atorvastatin also affected chemokine and cytokine release. Tocilizumab, galunisertib, and vactosertib decreased the level of IL6, a relevant prognostic marker for HCC, while IL6 was increased by halofuginone. In conclusion, HCC PDChip models enabled a detailed evaluation of drug-induced responses in the tumor and associated microenvironment, highlighting their importance in preclinical research for understanding diseases and developing new drugs."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • IL6

This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-βR1/ALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heightened TGF-β/SMAD-driven Astrocytic and Fibrotic Signaling (clinicaltrials.gov) - P2/3 | N=60 | Not yet recruiting | Sponsor: Gipfel Life Sciences GmbH

Biomarker • New P2/3 trial • Amyotrophic Lateral Sclerosis • CNS Disorders • Fibrosis • GFAP • TGFB1

PSMD14 drives lung adenocarcinoma progression through HMMR stabilization and dual activation of TGF-β/Smad and PI3K/AKT/mTOR signaling. (PubMed, Front Immunol) - "The PSMD14 inhibitor Capzimin exhibited potent anti-tumor effects in vitro and in vivo, and combination therapy with the TGF-β inhibitor galunisertib demonstrated enhanced efficacy...Consequently, the PSMD14-HMMR axis emerges as a promising therapeutic target. Inhibition of PSMD14 exhibited significant anti-tumor efficacy, underscoring its potential for clinical translation in LUAD treatment."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HMMR • PSMD14 • TGFB1

Study of TGF-β Receptor Inhibitor Galunisertib (LY2157299) and Enzalutamide in Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: May 2026 ➔ Dec 2026

Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Galunisertib attenuates pulmonary fibrosis with silicosis in mouse via TGF-β/TRAF6/Beclin1 signaling pathway. (PubMed, Front Pharmacol) - "On the other hand, Galunisertib regulates autophagy and inhibits the activation, proliferation and migration of Silica-stimulated fibroblasts, alleviating fibrosis in silicosis mice. Altogether, Galunisertib may be a potential candidate drug for preventing pulmonary fibrosis."

Journal • Preclinical • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • BECN1 • CASP3 • LAMP2 • TGFB1 • TRAF6

TGF-β facilitated mitochondria transfer in glioblastoma enhances tumor invasion and formate overflow (SNO 2025) - "For in vivo studies, orthotopic xenograft models were used to evaluate the impact of mitochondrial depletion, and immunohistochemistry was performed to quantify mitochondrial transfer. Here we show that TGF-β treatment of GB–astrocyte co-cultures significantly enhances mitochondria transfer rates and MT formation, which can be blocked by Galunisertib or SMAD inhibitors... This study identifies a regulatory role for TGF-β in glioblastoma–TME interactions, with SMAD signaling as a key pathway. Mitochondrial transfer from astrocytes supports GB proliferation, invasion, and survival.Reflection: Our findings offer new insights into communication of GB with its microenvironment, which may uncover novel treatment opportunities."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • TGFB1

TGF-β facilitated mitochondria transfer in glioblastoma enhances tumor invasion and formate overflow (SNO 2025) - "For in vivo studies, orthotopic xenograft models were used to evaluate the impact of mitochondrial depletion, and immunohistochemistry was performed to quantify mitochondrial transfer. Here we show that TGF-β treatment of GB–astrocyte co-cultures significantly enhances mitochondria transfer rates and MT formation, which can be blocked by Galunisertib or SMAD inhibitors... This study identifies a regulatory role for TGF-β in glioblastoma–TME interactions, with SMAD signaling as a key pathway. Mitochondrial transfer from astrocytes supports GB proliferation, invasion, and survival.Reflection: Our findings offer new insights into communication of GB with its microenvironment, which may uncover novel treatment opportunities."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • TGFB1

Targeting hepatocytic TβRI ameliorates liver metastatic outcomes by revitalizing stem-like CD8+ Tex subsets. (PubMed, Nat Commun) - "Furthermore, therapeutic delivery of Galunisertib using choline-modified lipid nanoparticles synergizes with αPD-1, fostering the conversion of exhausted CD8⁺ T cells into responsive Ly108⁺CX3CR1⁺ subsets and suppressing liver metastases. Collectively, our results identify hepatocyte TGFβ signaling as a targetable checkpoint against liver metastases."

IO biomarker • Journal • Oncology • CD4 • CD8 • CX3CR1 • LGALS9

Galunisertib attenuates pulmonary fibrosis with silicosis in mouse via TGF-β/TRAF6/Beclin1 signaling pathway (Frontiers) - "We found that Galunisertib has good anti-fibrosis activity both in vitro and in vivo. A 4-week Galunisertib treatment markedly ameliorated inflammation and fibrosis. Moreover, the results revealed that Galunisertib inhibited the expression of TGF-β, downregulated the major fibrotic protein expression of collagen I and a-smooth muscle actin (α-SMA), thereby switching the progression of fibroblast-to-myofibroblast transition (FMT)."

Preclinical • Fibrosis • Pulmonary Disease

TGF-β facilitated mitochondria transfer in glioblastoma enhances tumor invasion and formate overflow (WFNOS 2025) - "For in vivo studies, orthotopic xenograft models were used to evaluate the impact of mitochondrial depletion, and immunohistochemistry was performed to quantify mitochondrial transfer. Here we show that TGF-β treatment of GB–astrocyte co-cultures significantly enhances mitochondria transfer rates and MT formation, which can be blocked by Galunisertib or SMAD inhibitors... This study identifies a regulatory role for TGF-β in glioblastoma–TME interactions, with SMAD signaling as a key pathway. Mitochondrial transfer from astrocytes supports GB proliferation, invasion, and survival.Reflection: Our findings offer new insights into communication of GB with its microenvironment, which may uncover novel treatment opportunities."

Brain Cancer • CNS Tumor • Glioblastoma • TGFB1

TGF-β facilitated mitochondria transfer in glioblastoma enhances tumor invasion and formate overflow (WFNOS 2025) - "For in vivo studies, orthotopic xenograft models were used to evaluate the impact of mitochondrial depletion, and immunohistochemistry was performed to quantify mitochondrial transfer. Here we show that TGF-β treatment of GB–astrocyte co-cultures significantly enhances mitochondria transfer rates and MT formation, which can be blocked by Galunisertib or SMAD inhibitors... This study identifies a regulatory role for TGF-β in glioblastoma–TME interactions, with SMAD signaling as a key pathway. Mitochondrial transfer from astrocytes supports GB proliferation, invasion, and survival.Reflection: Our findings offer new insights into communication of GB with its microenvironment, which may uncover novel treatment opportunities."

Brain Cancer • Glioblastoma • Solid Tumor • TGFB1

The role of TGF-β1 in chronic multilobar segmental bronchial stenosis and advances in targeted drug research. (PubMed, Front Pharmacol) - "In recent years, groundbreaking progress has been made in research on therapeutics targeting the TGF-β1 signaling pathway, including monoclonal antibodies (e.g., Fresolimumab), small molecule kinase inhibitors (e.g., Galunisertib, TEW-7197), and novel targeted delivery systems. Furthermore, it proposes future research directions focused on CMBS-specific applications, such as validating these therapeutics in preclinical CMBS models, developing inhaled formulations for localized delivery, establishing biomarker-driven patient stratification, and exploring combination therapies with anti-fibrotic agents. This aims to provide a comprehensive theoretical foundation for elucidating the disease's pathology and developing novel, precise diagnostic and therapeutic strategies for CMBS."

Journal • Review • Asthma • Chronic Cough • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Tuberculosis • TGFB1