Download LY2157299

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
Cancer
LY2157299 in Combination
With Gemcitabine
1b
Advanced Hepatocellular
Carcinoma
LY2157299 vs. LY2157299 Sorafenib Combination vs.
Sorafenib
2
Newly Diagnosed Malignant
Glioma
LY2157299 With Standard
Temozolomide-based
Radiochemotherapy
1b/2a
Recurrent Glioblastoma
LY2157299 vs. LY2157299 and
Lomustine vs. Lomustine
Monotherapy
2
Metastatic Cancer/ Advanced
or Metastatic Unresectable
Pancreatic Cancer
Gemcitabine and LY2157299
1b/2
Recurrent Malignant Glioma
Dose-Escalation Study of
LY2157299 monotherapy and
in combination w/Lomustine
1
References
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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.