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=60, Not yet recruiting, Scholar Rock, Inc.

P2/3, N=840, Recruiting, AbbVie | Active, not recruiting --> Recruiting | N=167 --> 840

P1/2, N=121, Recruiting, Avalyn Pharma Inc.

P1/2, N=30, Recruiting, Scholar Rock Inc.

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.

Here, we evaluated targeting candidates from this signature KMT5B/C and IKBKE using inhibitors A-196 and IKBKEi respectively, alongside anti-estrogen (fulvestrant) and a TGFβ blocking antibody (NIS793), both individually and in combination with αPD-L1, within this rat model. Comprehensive tumor profiling through polychromatic flow cytometry and single-cell RNA sequencing revealed that A-196 induced a luminal-to-basal shift in tumor epithelial cells, enhancing antigen presentation, whereas epithelial-to-mesenchymal transition was linked to fulvestrant resistance. Our findings underscore the value of the rat mammary tumor model for preclinical studies in ER-positive breast cancer and advocate for the further validation and potential clinical development of KMT5B/C inhibitors to enhance the efficacy and broaden the applicability of ICI therapy in cancer patients.

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.

Selective blockade of latent TGF-β1 activation represents a promising approach for treating a broad range of fibrotic diseases and cancers. By specifically targeting TGF-β1, SOF10 may offer a safer and more effective therapeutic option compared to non-selective TGF-β inhibitors. This strategy has the potential to transform the treatment paradigm for fibrosis-related conditions.

STP355 also reduced tumor weight significantly, without the toxicity observed with cisplatin, resulting in prolonged survival of mice compared with this small molecule. It increased immune cell penetration into TME and reduced metastases to the lung. STP355 was more efficacious than, and somewhat additive with, immune checkpoint inhibitory monoclonal antibodies.

P2/3, N=167, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | N=840 --> 167