2-Deoxy-D-glucose (2DG), a glycolytic inhibitor, depleted ATP dose-dependently (30-300 μM) and prevented those increases both at the protein and transcriptional levels. This was also observed in 3D spheroids upon TGF-β transient siRNA-mediated silencing or when TGF-βR1 kinase activity was inhibited by galunisertib...3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer.

P2, N=50, Active, not recruiting, Providence Health & Services | Trial completion date: Dec 2025 --> Dec 2026

In the randomized phase II H9H-MC-JBAJ trial, high baseline ANG predicted poor survival with gemcitabine alone but significant benefit from galunisertib addition. Clinically, elevated ANG correlated with systemic TNF-α, and galunisertib reduced TNF-α exclusively in ANG-high patients, with reductions associated with markedly improved survival. These findings define an ANG-EGFR-TGFβ-TNF-α axis in TAMs as a stromal driver of PDAC chemoresistance, and provide a mechanistic rationale for the development of combination strategies targeting ALK5 signaling in ANG-high PDAC patients.

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.

P2, N=6, Recruiting, Indiana University | Trial completion date: Nov 2026 --> Dec 2027 | Trial primary completion date: Feb 2026 --> Dec 2027

We evaluated indole-3-lactic acid (ILA), indole-3-acrylic acid (IAA), and indole-3-propionic acid (IPA) in comparison to tapinarof, utilizing C. acnes-stimulated human epidermal keratinocytes and a C. acnes-induced acne mouse model...Collectively, these findings establish ILA as a potent postbiotic that mitigates cutaneous inflammation through selective activation of the AHR. Future studies should prioritize the clinical translation of ILA-based topical formulations, with rigorous evaluation of their efficacy and safety in well-designed human trials, to support their development as a non-antibiotic therapeutic alternative for acne management.

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.

P3, N=180, Recruiting, Organon and Co | Not yet recruiting --> Recruiting

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.

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