STRATEGY OF NOTCH SIGNALING PATHWAY AS NOVEL CANCER THERAPEUTIC TARGET

1. STRATEGY OF NOTCH SIGNALING PATHWAY
AS NOVEL CANCER THERAPEUTIC TARGET
ANKUSH BISWAS*, ROHAN PAL, PRITHWISH BASU,
ABHIJIT DE
BENGAL SCHOOL OF TECHNOLOGY, CHINSURAH, HOOGHLY
ABSTRACT
NOTCH activation plays a role in the onset and progression
of many human malignancies. The prevailing new strategy for
rationally targeted cancer treatment is aimed at the
development of target selective “ smart ” drugs on the basis
of characterized mechanisms of
action. Notch signaling promotes tumorigenesis and
the NOTCH pathway has tremendous potential
for novel targeting strategies in cancer treatment. This review
describes the mechanisms of signal transduction of the
NOTCH signaling pathway and provides emerging evidence
in support of its role in the development of human
malignancies.
INTRODUCTION
 In 1914, John S. Dexter noticed the appearance of a
notch in the wings of the fruit fly Drosophila melanogaster.
The alleles of the gene were identified in 1917 by Thomas
Hunt Morgan. Its molecular analysis and sequencing was
independently undertaken in the 1980s by Spyros Artavanis-
Tsakonas and Michael W. Young. Alleles of the two C.
elegans Notch genes were identified based on
developmental phenotypes: lin-12 and glp-1.
 The Notch signaling pathway is a short-range
communication transducer that is involved in regulating many
cellular processes (proliferation, stem cell and stem cell niche
maintenance, cell fate specification, differentiation, and cell
death) during development and renewal of adult tissues.
 CLASSIFICATION:
PATHOGENICITY OF NOTCH
SIGNALING IN CANCER
CONCLUSION
Notch signaling is a conserved cell fate determining factor in
embryo development. However, the deregulation of Notch
signaling is frequently observed in many cancers through
mutations and amplification of the components of the Notch
signaling pathway. In addition, transgenic mice with liver-specific
activation of Notch2 are sufficient to induce HCC formation and
biliary hyperplasia. This provides an opportunity for the
development of targeted therapy. Ample evidence has
demonstrated that inhibition of Notch induces tumor growth
arrest. Moreover, combined therapy of chemotherapy or
radiotherapy with Notch inhibitors also results in a synergistic
effect, suggesting Notch inhibitors may improve chemotherapy
response. Finally, based on the stratification of patients by Notch
activating mutation and amplification, Notch inhibitors combined
with chemotherapy or radiotherapy hold great promise for
cancer control.
ACKNOWLEDGEMENT
I would like to thankful MR. ABHIJIT DE, Assistant Professor of
Bengal school of technology & my friend ROHAN PAL, for their
most appropiated help in data collection and the invaluable
guidence they have given me throughout this experience.
REFERENCES
 P. Ranganathan, K.L.Weaver, A.J. Capobianco, Notch
signalling in solid tumours: a little bit of everything but not all
the time, Nat. Rev. Cancer 11 (2011) 338–351.
 X. Yuan, H.Wu, N. Han, H. Xu, Q. Chu, S. Yu, et al.,
Notch signaling and EMT in non-small cell lung cancer:
biological significance and therapeutic application, J.
Hematol. Oncol. 7 (2014) 87.
 Z. Wang, T.G. Da Silva, K. Jin, X. Han, P. Ranganathan,
X. Zhu, et al., Notch signaling drives stemness and
tumorigenicity of esophageal adenocarcinoma, Cancer
Res. 74 (2014) 6364–6374.
 R.C.D. Angelo, M. Ouzounova, A. Davis, D. Choi, S.M.
Tchuenkam, G. Kim, et al., Notch reporter activity in
breast cancer cell lines identifies a subset of cells with
stem cell activity, Mol. Cancer Ther. 14 (2015) 779–787.
NOTCH SIGNALING PATHWAY
NOTCH INHIBITORS & THEIR
CURRENT DEVELOPMENT STAGE:
TYPES OF
CANCER
ROLE OF NOTCH
T-CELL LEUKEMIA
The high prevalence of
activating NOTCH1 mutations highlights
the critical role of NOTCH signaling in
the pathogenesis of this disease and
has prompted the development of
therapeutic approaches targeting the
NOTCH signaling pathway. Small
molecule gamma secretase inhibitors
(GSIs) can effectively inhibit oncogenic
NOTCH1 and are in clinical testing for
the treatment of T-ALL.
BREAST CANCER
Breast cancer initiating populations can
be enriched using cell surface makers
CD44+/CD24- and have upregulated
genes which include Notch. Notch
signalling has been highlighted as a
pathway involved in the development of
the breast and is frequently dysregulated
in invasive breast cancer. The role of
Notch in a pre-invasive breast lesion,
ductal carcinoma in situ (DCIS), and
have found that aberrant activation of
Notch signalling is an early event in
breast cancer.
PROSTATE CANCER
A role of Notch signaling in prostate
stromal homeostasis. Major Notch
downstream target genes and regulatory
components of the Notch pathway are
also widely expressed in prostate
epithelial cells.
COLORECTAL
CANCER
Notch signaling is overexpressed or
constitutively activated in many cancers
including colorectal cancer (CRC). The
activation of Notch signaling is
implicated in tumorigenesis in the colon
due to the induction of pro-survival
signaling in colonic epithelial cells.
inhibition of Notch is an attractive target
for CRC and several groups are working
to identify small molecules or
monoclonal antibodies that inhibit Notch
or its downstream events.
LUNG CANCER
Notch receptors and ligands control
critical cell fate decisions both in
compartments that are undergoing
differentiation and in pluripotent
progenitor cells. Notch signaling can be
exploited as a therapeutic target in
NSCLC and represents a promising
complement to the current arsenal
utilized to combat this malignancy.
PANCREATIC
CANCER
Notch1 suppresses PanIN (Pancreatic
Intraepithelial Neoplasias). Reactivation
of Notch signaling is observed in early
PC pathogenesis and persists
throughout the progression of the
disease. Notch plays important
oncogenic roles in pancreatic
tumorigenesis.
ORAL CANCER
The role of Notch signaling related
genes in human OSCC using a meta-
analysis of Gene Expression Omnibus
database and to examine the role of
Notch signaling in OSCC behaviors.
Notch signaling inhibition by a γ-
secretase inhibitor significantly
decreased OSCC cell proliferation in
vitro. corresponding with a decrease in
C-FOS mRNA expression.