galunisertib (LY2157299)

In vivo in orthotopic tumors formed by FC1199 cells GAL decreased CD9+-NK frequency, promoted M1-macrophage polarization, and activated NK and CD8+T-cells, together with a significant reduction of tumor weight, fibrosis and inhibition of angiogenesis. Our study identifies CD9+NKs as a novel cell subset expanded in PDAC and underscores the role of TGF-β1/TGF-βR1 signalling in promoting a pro-tumoral NKs GAL-treatment emerges as immunomodulator able in re-educating pro-tumor NKs cells in PDAC.

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.

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.

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.

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.

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.

P2, N=60, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: May 2026 --> Dec 2026

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.

Although these targeted therapies show potential to overcome resistance and improve patient outcomes, challenges remain due to the complex regulation of EMP. Future directions focus on refining combination strategies and advancing personalized approaches to enhance efficacy across multiple cancer types.

The formulation co-delivered NMS-873 (NM), a VCP/p97 inhibitor, to induce endoplasmic reticulum stress (ERS) and proteostasis collapse, together with bispecific PD-L1/CTLA-4 aptamers (P1C4) for dual checkpoint blockade. A complementary SLN formulation encapsulating galunisertib (G) and DNase (DN) degraded neutrophil extracellular traps (NETs) and suppressed tumor-associated neutrophils (TANs), thereby reshaping the immunosuppressive TME...In vivo PET/MRI imaging and immunohistopathological analyses confirmed selective tumor accumulation and effective tumor regression. This peptide-guided, TME-tailored SLN strategy achieves coordinated immune reprogramming, ERS induction, EMT/CSC reversal, NET disruption, and dual checkpoint blockade, offering a clinically translatable platform to overcome chemoimmunotherapy resistance in EGFR/PD-L1/CTLA-4-driven CRC.

Moreover, inhibition of TGF-β/SMAD signaling through treatment with galunisertib achieved synergistic efficacy with cisplatin. The above findings demonstrate that BCAR3 is a positive regulator of TGF-β/SMAD signaling-mediated intrinsic cisplatin resistance. Targeting the BCAR3/TGF-β/SMAD axis might be a promising therapeutic strategy for overcoming cisplatin resistance in HNSCC.

TGF-β receptor I kinase plays a significant role in cancer biology and is a well-established target for cancer drug development, as evidenced by active molecules like Galunisertib (LY2157229)...Molecular Dynamics simulation study indicated that specific aminoacid residue interaction with TGF-β receptor I kinase. Additionally, DFT calculations were conducted on the active molecules to gain deeper insights into their electronic properties, supporting their potential as effective anticancer agents.