This document discusses signaling pathways that can be targeted for cancer therapy. It outlines that cancer development is a complex, multi-step genetic process involving acquired capabilities like uncontrolled growth. Key signaling targets include protein tyrosine kinases, receptor tyrosine kinases, and cytoplasmic intermediates like the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Mutations in genes that regulate these pathways are common in many cancer types. The document also notes there is signaling cross-talk between pathways, and combination drug therapies targeting multiple pathways may be more effective than single pathway inhibitors for treating aggressive cancers.

1. U
Sree parvathy.j
MSC.BT

2. INTRODUCTION
 Transformation of normal cell into
cancer cell with its full blown set of
malignant properties is in most instance
,a highly complex,multistep,genetic
event.
 Hahn and Weinberg hypothesis:the
pathogenesis of human cancers is
governed by a set of genetic and
biochemical rules that apply to most of
human tumors.

3. ……
 ACCQUIRED CAPABILITIES :The
capability of cancer cells to generate
their own mitogenic signals ,to resist
exogenous growth ,to evade
apoptosis,to proliferate with out limits.
 The crucial points in the pathways of
above procesess can be used for cancer
therapy.

4. TYPES OF SIGNALING
TARGETS.
 Protein Tyrosine Kinase(TK)
Receptor Tyrosine Kinase(RTK)
Cytoplasmic Signaling Intermediates
(a)The Ras/Raf/MAPK Pathway
(b)The P13K/AKT/mTOR pathway
 Signaling cross talk

5. Protein Tyrosine Kinase (TK)
as Therapeutic agents.
 2 types :Receptor TK(RTK),Non
receptor TK.
 RECEPTOR TK : activated when the
ligand binds to the extracellular domain.
 NON RECEPTOR TK : maintained in an
inactive stage by cellular inhibitor
proteins and lipids and through intra
molecular auto inhibition.

6. Mechanism of TK activation
1.Fusion of TK with a partner protein
2.Mutation that disrupts auto regulation of
kinase
3.Increased or aberrant expression of
receptor TK its ligand ,or both.

7. RTK
EGFR (a member of Erb B family)serves as a
genetic marker & also accounting for ⁴⁵ %
of EGFR mutations in NSCLC, this can be
used as anticancer drug targets.
EGFR kinase mutations seem to be highly
correlated with clinical characteristics that
are predictors of TK responsive disease,
where as EGFR gene amplification ,as
measured by qPCR , seems to be more
common in smoking associated cancers.

8. CYTOPLASMIC SIGNALING
INTERMEDIATES
 Ras/Raf/MAPK Pathway
 The mitogen acivated protein kinase
(MAPK) module is a key integratoin point
along the signal cascade that links divers
extracellular stimuli to proliferation
,differentiation , and survival.
 Over expression of activated Raf protiens
is associated with cell cycle arrest in rat
Schwann cells, mouse PC12 cells,human
promyelocytic leukemia HL 60 cells , small
cell lung cancer cell lines,prostate cancer
LNCaP cells,and some hematopoietic cells.

9.  The Raf/MEK/ERK cascade and Raf itslf
also have diverse effects on key
molecules involved in the prevention of
apoptosis.like BAD,Mcl1&Bim protiens.
 Amplification of Ras proto oncogenes
and activating mutations that lead to the
expression of constitutively active Ras
proteins are observed in aproximately
30%of human cancers.

10.  Mutated alleles of Raf 1 are present in therapy
-induced acute myelogenous leukemia, arising
after chemotherapy treatment for breast
cancer.
 BRAF mutations may constitute the Achille’s
heel of malignant melanoma,as wel as of other
malignancy ,
 It has been reported that a high frequency of
acute myeloid leukemias (AML) and acute
lymphocytic leukemia(ALL) displays
constitutive activation of the Raf/MEK/ERK
pathway in absence of any obvious genetic
mutation.

11.  P13K/AKT/ m TOR pathway
 Phosphoinositide 3 kinase(P13K) are a
family of proteins involved in the
regulationofcellgrowth,metabolism,prolifera
tion,glucose homeostasis, and vesicle
trafficking.
 The phosphatas and tensin homolog
deleted on chromosome#10(PTEN)was
originally discovered as a candidate tumor
suppressor mutated and lost in various
cancers.

12.  The loss and mutation of PTEN in various cancers
lead to hyperactive P13K signaling .For example
,PTEN is commonly mutated in Its phosphatase
domain : and in glioblastoma , mutations that impair
its proper membrane localization might resutl in
deficient tumor supressive activity.
 The kinase activity of P13K was first reported to be
associated with viral oncoprotein .Subsequent
studies employing mouse knockouts of both the
regulatory and ctalytic subunits of PIK3 resulted in a
number of deflicts including embryonic lethality ,B
cell defects ,liver necrosis, and colorectal cancer.

13.  Gene amplification ,deletion,and more
recently somatic missense mutation in
the PIK3CA gene have been reported in
many human cancer types including
cancers of the
colon,breast,brain,livir,stomach,and
lung.

14.  Despite a certain degree of discrepancy
in the reported P1K3CA mutation
rates,their high frequeny and discovery
of hotspot mutations have important
clinical implications diagnosis ,prognosis
and therapy.

15. SIGNALING CROSS TALK
 Treatment of human disease with drug
combinations might be exploited
therapeutically .It has recently been
demonstrated that even in aggressive
melanoma cell lines that are resistant to
single pathway MEK or P13K inhibition
,the combination of MEK with P3K
inhibitors suppresses the growth and
invasion of metastatic melanoma cell

16.  The combination of an inhibitor of MEK
½ and m TOR ,interacted synergistically
to prevent prostate cancer cell growth
both invitro and invivo.
 The combination of MEK/ERK and m
TOR inhibition may be effective in the
treatment of dvaned cancer.

17. THANK YOU