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. 2012.

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. 2007.

TGFβRI -/- mice die at midgestation with severe defects in vascular development of the yolk sac

and placenta

Larsson et al. The EMBO journal. 2001.

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. 2009.

Increase of TGF-β1 expression in TGFβRI cKO SCCs increases inflammation, angiogenesis, and induces EMT

in stromal tumor cells

Bian et al. Cancer research. 2009.

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. 2009.

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. 2011.

Rb dysfunction in pancreatic adenocarcinoma is associated with autocrine TGF-β tumorigenesis

Gore et al. The Journal of clinical investigation. 2014.

SB-505124, 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. 2014.

LY2157299 (Galunisertib), a TGFβRI kinase inhibitor, is currently in early clinical trials for the treatment of advanced, metastatic cancers

Condition Intervention Phase

Unresectable Hepatocellular Carcinoma

LY2157299 in Combination With Sorafenib 1b

Advanced or Metastatic Unresectable Pancreatic

CancerLY2157299 in Combination

With Gemcitabine 1b

Advanced Hepatocellular Carcinoma

LY2157299 vs. LY2157299 - Sorafenib Combination vs.

Sorafenib2

Newly Diagnosed Malignant Glioma

LY2157299 With Standard Temozolomide-based Radiochemotherapy

1b/2a

Recurrent GlioblastomaLY2157299 vs. LY2157299 and

Lomustine vs. Lomustine Monotherapy

2

Metastatic Cancer/ Advanced or Metastatic Unresectable

Pancreatic CancerGemcitabine and LY2157299 1b/2

Recurrent Malignant GliomaDose-Escalation Study of

LY2157299 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 11.10 (2012): 790-811.• 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 1775.1 (2007): 21-62.

• Larsson, Jonas, et al. "Abnormal angiogenesis but intact hematopoietic potential in TGF‐β type I receptor deficient mice." ‐ The EMBO journal 20.7 (2001): 1663-1673.

• 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 69.14 (2009): 5918-5926.

• 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): 365-369.

• Gore, A. Jesse, et al. "Pancreatic cancer–associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation." The Journal of clinical investigation 124.1 (2014): 338.

• ClinicalTrials.gov. US National Institutes of Health. 29 Mar. 2015. https://clinicaltrials.gov/ct2/results?term=LY2157299.