TP-6379 / Sumitomo Pharma - LARVOL DELTA

Targeting TGFBR1 with the Investigational Inhibitor TP-6379 Improves Hematopoiesis in Low-Risk MDS Ex Vivo. (PubMed, Cells) - "Primary low-risk MDS bone marrow mononuclear cells (BM-MNCs) were analyzed in vitro for hematopoietic restoration by an ALK4/ALK5 inhibitor (Vactosertib), an ALK2 inhibitor (TP-0184/Itacnosertib) and an ALK5/TGFBR1-specific inhibitor (TP-6379). Similar results were obtained with K562 cells, with or without the knock-in (KI) mutation in SF3B1, with strong sensitivity to rhS100A9 that was overcome by TP-6379. Hence, directly targeting TGFBR1/ALK5 with TP-6379 restores healthy hematopoiesis in low-risk MDS preclinical models."

Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • S100A9 • SF3B1 • TGFB1 • TGFBR1

TP-6379, an investigational TGFBR1 inhibitor, shown to remodel the tumor microenvironment and enhance anti-tumorigenic immunological responses in syngeneic mouse models of cancer (AACR 2023) - "Collectively, these data suggest that TP-6379 may improve immune cell access to tumor tissue via TME remodeling and normalization of vascular networks. Thus, TP-6379 treatment may present a unique and multifactorial anti-tumor strategy, 1) as a single agent to improve anti-tumorigenic immunological responses, and 2) as a combination treatment to boost immunotherapeutic activity."

Preclinical • Tumor microenvironment • Breast Cancer • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • PTPRC • TGFB1 • TGFBR1

Improvement of hematopoiesis in primary low risk MDS with the TGFBR1 investigational inhibitor TP-6379 (AACR 2023) - "TP-6379 restores healthy hematopoiesis in low-risk MDS, which may translate into a strong therapeutic option in a disease with few clinical options. Importantly, our work also suggests a specific role for spliceosome dysfunction in bone marrow failure and a novel role for SERPINE1 in MDS and S100A9-induced suppression."

Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CD34 • S100A9 • SERPINE1 • SF3B1 • TGFBR1

Pharmacodynamic biomarkers for TGFBR1 inhibition in oncology (AACR 2023) - "Lastly, CTCs from breast cancer patients’ whole blood treated ex vivo for 24 hours with as low as 1 µM TP-6379 showed a decrease in pSMAD2 and EMT marker SNAI1 by as much as 96% and 86%, respectively, when measured by immunofluorescence.In summary, our research has shown that pSMAD2/3 and EMT marker SNAI1 are valid PD biomarkers for TP-6379 therapy. We propose that these biomarkers would be best measured clinically using PBMCs, CTCs and/or skin punches."

Biomarker • PK/PD data • Breast Cancer • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Triple Negative Breast Cancer • CTCs • SMAD3 • SMAD4 • SNAI1 • TGFBR1

TP-6379, an investigational TGFBR1 inhibitor, shows improvement in survival and enhances activity of standard of care in preclinical ovarian cancer models (AACR 2023) - "To investigate a combination effect with the standard of care in ovarian cancer, a SK-OV-3 ovarian cancer adenocarcinoma cell line was treated in vitro with TP-6379 and paclitaxel. In conclusion, our preliminary preclinical studies have shown promising activity for TP-6379 in ovarian malignancies as monotherapy and/or in combination with standard of care. TP-6379 may be a viable therapeutic option by targeting the TGF-β pathway in ovarian cancer."

Preclinical • Oncology • Ovarian Cancer • Solid Tumor • TGFB1 • TGFBR1 • TUBB3

TGFBR1 as a novel therapeutic target in adult granulosa cell tumors (AACR 2023) - "These data suggest that TGF-ß may play a significant role in the TME of AGCT. In conclusion, preclinical data shows inhibition of TGFß signaling with TP-6379 in FOXL2C134W mutant AGCT is active at blocking cell growth and may prove to be a potential therapy in this rare disease."

Clinical • Oncology • Ovarian Cancer • Solid Tumor • CD8 • FOXL2 • SMAD2 • SMAD3 • TGFBR1