galunisertib (LY2157299)

Remarkably, the TGF-β inhibitor LY2157299 effectively countered TGF-β activity and significantly reversed tumor metastasis and EMT induced by CLIP170 knockdown. In summary, these findings collectively propose CLIP170 as a promising therapeutic target to mitigate metastatic tendencies in PTC.

Additionally, miR-431-5p enhances the efficacy of anti-PD1 treatment, particularly when combined with galunisertib, anti-PD1 treatment showing a synergistic effect in inhibiting GC progression in C57BL/6 mice. Collectively, these findings suggest that miR-431-5p may modulate the TGF-β1/SMAD2/3 pathways by targeting ZEB1 to impede GC progression, angiogenesis, and lymphangiogenesis, making it a promising therapeutic target for GC management.

Based on these findings, we designed nanogels that have two primary characteristics: (1) they encapsulate galunisertib (Gal), which is used clinically to inhibit TGF-β receptor activity, thereby blocking TGF-β signaling; and (2) they provide cells with a surface coating of 25 K bPEI...These findings suggest that Gal-loaded 25 K bPEI-coated nanogels exert anti-tumor effects via chemical priming, as well suppressing the effects of TGF-β on NK cells. We also expect 25 K bPEI-based nanogels to have great potential to overcome the suppressive effects of the TME through their NK cell-priming activity and delivery of the desired chemicals.

Effects of constant activation of the SMAD pathway by constitutive expression of ALK5 or knockdown of mediators of TLR signalling, IRAK1 and MyD88, on HCC proliferation, were investigated in the HCC cell line (HUH-7) after treatment with TGFβ1 cytokine or TGFβR1 kinase inhibitor (LY2157299) using PCNA and MTS assay...There is a balance between the canonical SMAD-driven tumour-suppressing arm and the non-canonical tumour-promoting arm of TGFβ signalling. Disruption of this balance, by inhibition of the canonical pathway, induces HCC proliferation through TLR signalling.

Neural involvement enhanced tumor aggressiveness through upregulating TGFβ signaling and PD-L1 expression in OSCC, while denervation of OSCC inhibited tumor growth, down-regulated TGFβ signaling, enhanced activities of CD8+ T cells and improved the efficacy of anti-PD-1 immunotherapy. This study will encourage further research focusing on denervation as a potential adjuvant therapeutic approach in OSCC.

In this study, we developed an oral microgel delivery system of EcN@(CS-SA) by electrostatic interaction between chitosan (CS) and sodium alginate (SA), aiming to enhance its bioavailability in the gastrointestinal tract (GIT). Notably, EcN@(CS-SA) microgel showed a synergistic enhancement of the anti-tumor efficacy of Galunisertib (Gal, a TGF-β inhibitor) by inducing apoptosis and immunogenic cell death (ICD) in tumor cells, as well as promoting increased infiltration of CD8 T cells into the tumor microenvironment (TME).

P1; N=29; Completed; Sponsor:Vanderbilt-Ingram Cancer Center

P2, N=180, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Sep 2024

P1; Active, not recruiting --> Completed

In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.

1. Increases in plasma TGF-β1 levels may be a valuable surrogate marker of AS progression. 2.

The results of this study provide compelling evidence that serological LBP can serve as a valuable diagnostic biomarker for the early detection of GC-LM. Mechanistically, GC-derived LBP mediates the crosstalk between primary GC cells and the intrahepatic microenvironment by promoting TGF-β1 secretion in intrahepatic macrophages, which induces intrahepatic fibrotic PMN formation to promote GC-LM. Importantly, selectively targeting the TGF-β/Smad signaling pathway with galunisertib represents a promising preventive and therapeutic strategy for GC-LM.

The autotaxin inhibitor IOA-289 suppressed NF-κB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared to those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib.

Our results suggest that the inhibitory effect of SIK1 on the TGF-β pathway contributes to the suppression of metastasis and oxaliplatin chemoresistance in CRC. However, this effect was reversed by galunisertib (LY2157299). In conclusion, our findings provide novel insights into the role of SIK1 in the regulation of the TGF-β pathway in CRC, suggesting its potential as a therapeutic target for the treatment of CRC. Further studies are required to fully characterize the mechanism underlying these observations and to validate these findings in animal models.

The study met its primary endpoint as galunisertib combined with nivolumab was well tolerated. Preliminary efficacy was observed in a subset of patients in the Phase 2 NSCLC cohort.

Blocking TGFβ signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERβ pathway in CRC patients.

More importantly, integrative transcriptomics using independent cohorts of patients with HCC demonstrates that galunisertib-induced transcriptional reprogramming in SNU-449 is associated with human HCC with a better clinical outcome (i.e. increased overall survival), while galunisertib-induced transcriptional reprogramming in PLC/PRF/5 is associated with human HCC with a worse clinical outcome (i.e. reduced overall survival), demonstrating that galunisertib could indeed be beneficial or detrimental depending on HCC subtypes. Collectively, our study highlights the importance of patient selection to demonstrate a clinical benefit of TGFβ pathway inhibition and identifies Serpin Family F Member 2 (SERPINF2) as a putative companion biomarker for galunisertib in HCC.

The TGF-β signaling-specific inhibitor LY2157299 reverses the enhanced EMT, proliferation, migration, and invasion abilities induced by the miR-34c-5p inhibitor...Overall, this study concludes that miR-34c-5p, induced by ING5 overexpression, is a tumor suppressor that targets Snail1 and mediates the inhibitory effects of ING5 on the EMT and invasion of NSCLC cells. These results provide a novel mechanism mediating the antitumor effects of ING5.

P1, N=66, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Sep 2024

A panel of 8 murine and human CCA cell lines and human hepatic stellate cells (HSC) and CAF were cultured in 2D or 3D to analyse response to TGF-β, TGF-beta receptor I inhibitor galunisertib and dual NOX1/NOX4 inhibitor GKT137831. GKT137831 inhibited fibroblast activation and reduced the size of CCA-fibroblast mixed spheroids.ConclusionDue to the strong suppressor effect of TGF-beta on the CCA tumour cell, inhibitors of the TGF-beta pathway as anti-cancer therapies may lead to counterproductive effects. Targeting the tumour microenvironment by inhibiting downstream mediators of the TGF-beta pathway, such as NOX4, may represent a therapeutic opportunity for CCA.This study is funded by Spanish Association for Cancer Research (AECC) #PRYGN211279FABR.

P2, N=60, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Jun 2023 --> Jun 2024

Herein, we prepared a nanodrug (NCG) encapsulating the transforming growth factor-β receptor inhibitor galunisertib (Gal) and the sonosensitizer chlorin e6 (Ce6), which was aimed to turn this type of cold tumor into a hot one to promote the ICB-based immunotherapy against it...Here, we reported a TGF-β-targeted inhibitory nanodrug that improved SDT in colon cancer and liver metastasis, reversed the immunosuppressive tumor microenvironment and boosted the immune response to anti-PD-L1 therapy in this cancer. It demonstrated the potential to cure this prevalent but incurable malignancy.

P1; Trial completion date: Apr 2023 --> Jan 2024

P1/2, N=35, Ongoing, Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hosp

To targeted block TGF-β at tumor site, we take advantages of nano-techniques to deliver TGF-β inhibitors LY2157299 (LY) towards the tumor sites, in order to help achieve a improved and long-term functions of CAR-T towards lymphoma...Combined therapy of LY/ICG@HES-PCL and CAR-T achieved 2.4 times higher antitumor activity and 2.7 times higher relapse inhibiting rates than CAR-T alone within 15 days and 11 days, respectively. The results suggested that LY/ICG@HES-PCL facilitated the enhanced therapeutic index of CAR-T cells towards lymphoma simply and safely, it may be further potentiated applied for other solid tumors.

Tumoroids werethen treated with stromal targeting strategies for TGF-beta (galunisertib), the FGF pathway(Dovitinib), FAK inhibitors (defactinib), and cell adhesion modulators (plerixafor) alone or incombination with nivolumab for 72-hours ex vivo. Treatment-mediated changes in the tumor immune microenvironment was furthercorroborated by a multiplex cytokine release assay detecting GM-CSF, sCD137, IFNγ, sFas,sFasL, Granzyme A, Granzyme B, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, MIP-1α, MIP-1β, TNF-α,Perforin in tumoroid culture media and correlated with clinicopathologic findings and PD-L1expression for individual tumnors. Further, this 3D-tumoroid platform provides unique insightinto the microenvironment of both treatment responsive and non-responsive tumors and can aidin the development of patient-centered therapeutic regimens.

P2, N=50, Active, not recruiting, Providence Health & Services | Trial completion date: Dec 2022 --> Dec 2025 | Trial primary completion date: Sep 2022 --> Dec 2025

Indeed, the encapsulated drug reduces collagen deposition, hepatic stellate cells (HSCs) activation, prevents fatty degeneration and restores the correct lobular architecture of the liver as well as normalizes the serum parameters and expression of the genes involved in the onset of HF. In summary, GLY-NM improved the pharmacological activity of the free TGF- β1 inhibitor in the in vivo HF treatment and thus is a candidate as a novel therapeutic strategy.

Based on the tumor-draining lymph node analysis, combination therapy results in better prognosis, including disappearance of disease-exacerbating regulatory T cells and prevention of CD8 T-cell exhaustion by downregulating MDSCs. Galunisertib synergistically potentiates the doxorubicin-mediated antitumor effect without aggravating the toxic effects and the ability to kickstart the immune system, supporting the clinical relevance of targeting TGF-βRI in combination with doxorubicin against lymphoma.

We identified CKS2 as a critical contributor to the gliomagenesis, which might provide a novel therapeutic target for inhibiting the spread and infiltration of glioma.

In silico analysis indicated that NRAS, AKT1, and HSPB1 genes can be the main oncogenes in the VEGF signaling pathway and galunisertib strongly interacts with these genes. Consequently, the use of galunisertib to overcome AAT in GBM in combination therapy can be assessed.

The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials.

GB was well tolerated with TC with no DLTs. Paired biopsies were too limited to make conclusions. However, the putative mechanism of action of galunisertib and the well tolerated nature of the combination would warrant further exploration.

Furthermore, pretreatment with the clinical stage TGF-β1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-β1 signaling improved the anti-tumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-β1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell-based immunotherapy.

Enrolled patients completed a 14-day course of galunisertib, followed by chemoradiation with continuous infusion 5-fluorouracil or capecitabine with radiation to 50.4-54Gy in 28-30 fractions...Those with complete response by physical exam, proctoscopy, and MRI, could opt for non-operative management and proceed to mFOLFOX6... The addition of TGFβ inhibition to neoadjuvant chemoradiation in locally advanced rectal cancer markedly improved response to therapy, was well tolerated, and warrants further investigation. Clinical Trial Information: NCT02688712.

Moreover, using the TGF-β receptor I antagonist, galunisertib, significantly inhibited the tumor growth and progression of the TRAMP-C1 cell line-derived subcutaneous tumor model. Finally, we confirmed that the stromal microenvironment was shaped by TGF-β in HIC1-deficient PCa and was associated with the progression of PCa.

Results from in vivo experiments further validated Galunisertib's effect on HO attenuation, by intercepting the TGF-β/Smad2/3 signaling pathway. In conclusion, our findings demonstrated Galunisertib's potential as a prophylactic drug for the treatment of traumatic HO or other related diseases triggered by over-expressed TGF-β.

To achieve that, ovarian cancer SKOV-3 cells were treated with or without sorafenib (10 µM), transforming growth factor (TGF)-β1 (10 ng/mL), sorafenib (10 µM) + TGF-β1 (10 ng/mL), and TGF-β1 (10 ng/mL) + Ly2157299 (5 µM), followed by 8-Gy radiation. Molecularly, sorafenib could inhibit the TGF-β1-mediated EMT. Future studies will assess sorafenib anti-ovarian cancer activity plus TGF-β1 inhibitors in ovarian cancer in vivo.

Additionally, core enrichment in the GSEA analysis indicated that GPR34-mediated gliomagenesis was associated with the cell cycle arrest, epithelial-mesenchymal transition (EMT), and activation of the TGF-β/Smad pathway; furthermore, inhibiting TGF-β/Smad signaling using LY2157299, a TGF-β inhibitor, reversed the oncogenic effects and malignant phenotype associated with GPR34 overexpression. GPR34 enhances the malignancy and carcinogenesis of glioma by promoting an EMT-like process, G1/S phase cell cycle transition, and TGF-β/Smad signaling. Accordingly, GPR34 likely functions as an oncogene in glioma and may represent a potential therapeutic target for this cancer.

There are several TGF-β inhibitors which are potential anticancer agents and are undergoing clinical trials in cancer, including galunisertib, dalantercept, and vigil. There is a growing body of data showing the potential therapeutic impact of targeting the TGF-β pathway in different cancer types, although further studies are still warranted to explore the value of this strategy and finding the most appropriate patients who could most benefit from therapy.