TGF-β Receptor I/ALK5: An Attractive Therapeutic Target in Tumor Development By Jake Bridgers

TGF-β receptor I (TGFβRI) is a transmembrane serine/threonine kinase involved in multiple pathways important in cancer development Akhurst et al. Nature reviews Drug discovery

TGF-β signaling inhibits cellular proliferation and tumor growth by promoting transcription of CDK inhibitors and inhibiting transcription of Myc and other proliferation-promoting genes. Pardali et al. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer

TGFβRI -/- mice die at midgestation with severe defects in vascular development of the yolk sac and placenta Larsson et al. The EMBO journal

Conditional knockout of TGFβRI in head and neck epithelia leads to increased risk of tumor development in presence of DMBA Bian et al. Cancer research

Increase of TGF-β1 expression in TGFβRI cKO SCCs increases inflammation, angiogenesis, and induces EMT in stromal tumor cells Bian et al. Cancer research

TGFβRI knockout in presence of additional oncogenic mutations leads to increased TGFβ-1 expression and paracrine effects in tumor stroma Bian et al. Cancer research

Multiple self-healing squamous epithelioma (MSSE) is an autosomal dominant disease caused by loss of function mutations in the receptor and kinase domains of TGFβRI Goudie et al. Nature genetics

Rb dysfunction in pancreatic adenocarcinoma is associated with autocrine TGF-β tumorigenesis Gore et al. The Journal of clinical investigation

SB , a competitive inhibitor of the ATP-binding site of TGFβRI, diminishes growth in Kras-driven pancreatic cancer cells that lack Rb Gore et al. The Journal of clinical investigation

LY (Galunisertib), a TGFβRI kinase inhibitor, is currently in early clinical trials for the treatment of advanced, metastatic cancers ConditionInterventionPhase Unresectable Hepatocellular Carcinoma LY in Combination With Sorafenib 1b Advanced or Metastatic Unresectable Pancreatic Cancer LY in Combination With Gemcitabine 1b Advanced Hepatocellular Carcinoma LY vs. LY Sorafenib Combination vs. Sorafenib 2 Newly Diagnosed Malignant Glioma LY With Standard Temozolomide-based Radiochemotherapy 1b/2a Recurrent Glioblastoma LY vs. LY and Lomustine vs. Lomustine Monotherapy 2 Metastatic Cancer/ Advanced or Metastatic Unresectable Pancreatic Cancer Gemcitabine and LY b/2 Recurrent Malignant Glioma Dose-Escalation Study of LY monotherapy and in combination w/Lomustine 1

References Akhurst, Rosemary J., and Akiko Hata. "Targeting the TGFβ signalling pathway in disease." Nature reviews Drug discovery (2012): Pardali, Katerina, and Aristidis Moustakas. "Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer." Biochimica et Biophysica Acta (BBA)- Reviews on Cancer (2007): Larsson, Jonas, et al. "Abnormal angiogenesis but intact hematopoietic potential in TGF‐β type I receptor‐deficient mice." The EMBO journal 20.7 (2001): Bian, Yansong, et al. "Progressive tumor formation in mice with conditional deletion of TGF-β signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway." Cancer research (2009): Goudie, David R., et al. "Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1." Nature genetics 43.4 (2011): Gore, A. Jesse, et al. "Pancreatic cancer–associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation." The Journal of clinical investigation (2014): 338. ClinicalTrials.gov. US National Institutes of Health. 29 Mar