1.
* Cancer is a condition where cells in a specific part of
the body grow and reproduce uncontrollably.
The cancerous cells can invade and destroy surrounding
healthy tissue, including organs.
Cancer
◾The term cancer encompasses more than 200 diseases
all characterized by the uncontrolled proliferation of cells.
◾When a normal cells have lost the usual control over their
division, differentiation and apoptosis (programmed cell
death),they become tumor cells.
A tumor(Neoplasm) is the result of an abnormal
proliferation of cells.

2.
Cancer.....
• When cancer cells break away from the main tumor and enter the bloodstream or lymphatic system. These systems
carry fluids around the body. This means that the cancer cells can travel far from the original tumor and form new
tumors when they settle and grow in a different part of the body. This is referred to as Metastasis.
• Tumors formed from cells that have spread are called secondary tumors. The cancer may have spread to areas near
the primary site, called regional metastasis, or to parts of the body that are farther away, called distant metastasis.
• Cancer can spread to the skin, muscle, or other organs in the body. Cancer cells can also spread to the lining around
the lungs called the pleural cavity. It can also spread to the space around the belly called the peritoneal cavity. When
these cancer cells cause fluid to build up in these areas, it is called malignant pleural effusion and malignant ascites.
Tumor Progression and Metastasis

3.
Tumor can be either Benign or Malignant.
Benign and Malignant
Benign Tumors
• Tumor cells remain clustered together in a single mass.
• Grow slowly and have distinct borders.
• Do not invade surrounding tissue.
• Do not invade other parts of the body(absence of metastasis).
• Benign are harmless.
Malignant Tumors
• Can grow quickly and have irregular borders.
• Often invade surrounding tissue.
• Can spread to other parts of the body through the process
Metastasis.

4.
Cancer Types.......
• Cancers are classified according to the tissue and
cell type from which they arise.
◾Carcinomas,◾ Sarcomas, ◾ Haematopoietic Cancer
(Leukemia, Myeloma, Lymphoma).

5.
1. CARCINOMA
• Carcinomas are cancers arising from epithelial cells.
• Start in skin or the tissue that line other organs.
• Epithelial tissue are the most likely to be exposed to the various
forms of Physical and Chemical damage that favor the
development of cancer.
• Carcinoma fall into two categories- a) Squamous cell carcinoma
(protective cell layer epithelia. b)Adenocarcinoma(secretory
epithelia).
• Most common in Humans.
Carcinoma Cancer, Skin

6.
2. SARCOMA
• Cancer of Mesenchymal
(Embryonic connective
tissue) origin.
• Cancer of connective
tissue such as bones,
muscles, cartilages and
blood vessels.
• There are 50 different
types of sarcoma but
broadly they can be
groups into soft tissue
sarcoma and bone
sarcoma or
Osteosarcoma.
Sarcoma sites...

7.
3. HAEMATOPOIETIC CANCERS
• Cancer that begins in blood-forming tissue, such as the bone marrow, or in the cells of
the immune system.
• Examples of Haematopoietic cancer are leukemia, lymphoma, and multiple myeloma.
Also called blood cancer.

8.
LEUKEMIA • It is a cancer of bone marrow,which make the blood cells.
• It is a cancer of blood cells caused by rise of White Blood Cells in
the body.
• Leukemia happens when body makes more WBC than it needs.
• Two main types of WBC in our body: Lymphoid and Myeloid,
Leukemia can happen in either type.
• Leukemia cells can't fight infection,the way normal WBC do &
because of there large number, they start to affect the major
organ work. Eventually there are not enough RBC to supply O2,
enough platelets to clot the blood or no enough WBC to fight
infection.

9.
MYELOMA Cancer of the plasma cells is Myeloma.

10.
LYMPHOMA
• Cancers of the lymphatic organs, especially the lymph the lymph
nodes.
• Also spleen, thymus gland and bone marrow.
• The main types of lymphoma are Hodgkin's lymphoma and non-
Hodgkin's lymphoma.
Lymphoma, Translational perspective

11.
Clonal Evolution
• A tumor
developes
through
repeated round
of Genetic
changes and
proliferation.
• Development of
cancer requires
a gradual
accumulation of
genetic and
epigenetic
changes in a
number of
different genes.
• These changes
enhance cell
proliferation.
• Initiation involves
genetic changes. Change
in the gene affect the
processes associated with
cellular proliferation,
survival and
differentiation.
Promotion is associated with
increased proliferation of the
initiated cell. It lengthy and
reversible process where
preneoplastic cell
accumulate.
Progression is final stage of
neoplastic transformation.
Genetic and Epigenetic
changes within cells of tumor
population. Epigenetic
changes become dominant
within tumor population
(clonal selection).

12.
Cancer cell, Properties...
• Cancer cells are immortal and can grow indefinitely.
• Proliferation of cancer cells is not sensitive to density dependent
inhibition.
• Invasiveness refers to ability of tumor cells to invade
neighbouring tissue.
• Metastasis
• Cancer cell also secrete growth factors that promote formation
of new blood vessels (Angiogenesis).
• Autocrine stimulation drives the proliferation of tumor cells
continuously.
• Fail to undergo apoptosis, exhibit increased life spans.

13.
Molecular Basis and Genetics
◾Cellular functions are controlled
by proteins, and because these
proteins are encoded by DNA
organized into genes, molecular
studies shown that cancer is a
paradigm of acquired genetic
disease.
Tumor Suppressor
Gene
Proto-oncogene
Oncogene
Carcinogen
Point Mutation
Chromosomal Translocation
Benign versus Malignant

14.
Proto-oncogene; Oncogene
• There are trillions of living cells in the body that grow, divide, and die in an orderly
fashion. This process is tightly regulated by the genes within a cell’s nucleus. These
genes code for proteins that help regulate cell growth. These important genes are
called proto-oncogenes.
• A change or Mutation in the DNA sequence of the proto-oncogene gives rise to an
oncogene, which produces a different protein and interferes with normal cell
regulation.
• A mutated or defective version of a proto-oncogene (oncogene) increases the
production of these proteins, thereby leading to unregulated cell division, a slower
rate of cell differentiation and increased inhibition of cell death.
• Together, these features define cells that have become cancerous.
◾Several genetic mechanisms that cause a proto-oncogene to become an oncogene.
• Point mutations, insertions or deletions that give rise to an overactive gene product.
• Point mutations, insertions or deletions that lead to an increase in transcription
• Gene amplification leading to additional copies of a proto-oncogene
• Chromosomal translocation that causes a proto-oncogene to move to a different
chromosomal site associated with increased expression
• Chromosomal translocations that cause a proto-oncogene to fuse with another gene to
produce a protein that has oncogenic activity.

15.
Point Mutation
• When a mutation occurs in a proto-oncogene, it becomes
permanently turned on (activated).
• The gene will then start to make too much of the proteins that
code for cell growth. Cell growth occurs uncontrollably.
• This alteration may be the deletion of a base, insertion.
• It can increase gene function or can interrupt gene function.
Converting proto-oncogene to oncogene
An oncogene is a
dominantly
expressed mutated
gene that renders a
cell advantageous
towards survival.
Oncogenes act in a
dominant
manner,gain of
mutation in a single
copy of the cancer
critical gene can
drive a cell toward
cancer.
RAS proto-oncogene.
HER2 gene. This gene
codes for a
transmembrane tyrosine
kinase receptor called
human epidermal growth
factor receptor 2

16.
Chromosomal Translocation
• Chromosomal translocations are favored in neighboring
chromosomes or genes in spatial proximity within the
nucleus.
• Chromosomal translocations leading to cancer are generally
via two ways, formation of oncogenic fusion protein or
oncogene activation by a new promoter or enhancer.
• Burkittt's Lymphoma (Translocation induced overexpression of
Proto-oncogene).
• MYC Containing segment of Chromosome-8 translocate to
Chromosome-14.
• Translocation places MYC gene close to Ig heavy chain gene.
• Translocated MYC gene regulated by Ig gene enhancer and cell to
become cancerous.
• MYC proto-oncogene protein act as a Transcription factor.
• MYC family consists 3 related human gene; c-myc(MYC), l-
myc(MYCL), n-myc(MYCN).
Burkittt's Lymphoma Translocation

17.
Translocation cont.....
• Chronic myelogenous leukemia(chronic myeloid leukemia or chronic granulocytic leukemia) occurs when
something goes awry in the genes of your bone marrow cells.
• People with chronic myelogenous leukemia, the chromosomes in the blood cells swap sections with each other.
• A section of chromosome 9 switches places with a section of chromosome 22, creating an extra-short chromosome
22 and an extra-long chromosome 9.
• Abnormal Philadelphia chromosome (ph1) result of balanced reciprocal 9;22 Translocation.
• Genes from chromosome 9 combine with genes from chromosome 22 to create a new gene called BCR-ABL.
• The BCR-ABL gene contains instructions that tell the abnormal blood cell to produce too much of a protein called
tyrosine kinase.
• Tyrosine kinase promotes cancer by allowing certain blood cells to grow out of control.
Generation of BCR-ABL gene by Translocation

18.
Oncogenic Chromosomal Translocation
• Chronic
myelogenous
Leukemia ➡️
Chromosomal
Translocation
(9;22)
• Acute
myelogenous
Leukemia ➡️
Translocation
(8;21)
• Retinoblastom
a ➡️ Deletion
(13q)

19.
Activation of MYC oncogene by Insertion
• Expression of MYC gene is elevated after the insertion of a non defective retrovirus in the
vicinity of the gene.
• ALV(Avian leukosis virus) retrovirus doesn't carry any viral oncogenes,yet able to transform
B cell into lymphomas.
• ALV integrate within MYC proto-oncogene,which contains 3 exons.
• Exon-1 has an unknown function; Exon-2 and 3 encode with MYC protein.
• Insertion of ALV between exon 1 & 2 allow the provirus promoter to increase transcription
of exons 2 & 3, resulting increased synthesis of MYC protein.

20.
Tumor Suppressor Gene
• Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die
(a process known as apoptosis or programmed cell death).
• When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer.
• An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the
activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated
(turned off).
• Tumor suppressor genes are also known as antioncogenes or loss-of-function genes.
• Most tumor suppressor gene mutations are acquired, not inherited.
• Example of some tumor suppressor genes:-
• p53 gene: The p53 gene (TP53) creates protein p53 which regulates gene repair in cells. Mutations in
this gene are implicated in around 50 percent of cancers. Inherited mutations in the p53 gene are
much less common than acquired mutations and result in the hereditary condition known as Li
Fraumeni syndrome. The p53 codes for proteins that tell cells to die if they are damaged beyond repair,
a process referred to as apoptosis.
• BRCA1/BRCA2 genes: These genes are responsible for around 5 percent to 10 percent of breast
cancers.
• APC gene: These genes are associated with an increased risk of colon cancer in people with familial
adenomatous polyposis.
• PTEN gene: The PTEN gene is one of the non-BRCA genes that can increase the risk of a woman
developing breast cancer (up to an 85 percent lifetime risk). It is associated with both PTEN hamartoma
tumor syndrome and Cowden syndrome.
• RB1:- cell cycle check point.
• hMLH1 gene :- DNA mismatch repair.
• NF1 gene:- GTPase

21.
Tumor Suppressor Gene
• Genes that regulate or inhibit cell
cycle progression.(RB1)
• Genes that encode receptors or
developmental signals that inhibit
cell proliferation (Hedgehog
receptor).
• Genes encoding checkpoint-control
proteins that arrest cell cycle if DNA
is damaged (TP53).
• Genes that promote Apoptosis.
• Genes that encode enzymes that
participate in DNA repair.
• Mutations in Tumor Suppressor
Gene generally act in a recessive
manner.
• Function of both alleles of the
cancer critical gene drive a cell
toward cancer.
• Mutation of some tumor suppressor
genes can have an effect even when
only one of the two gene copies is
damaged.

22.
TP53 Gene
• The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53).
• This protein acts as a tumor suppressor, which means that it regulates cell division by
keeping cells from growing and dividing too fast or in an uncontrolled way.
• When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or
UVrays from sunlight, this protein plays a critical role in determining whether the DNA will
be repaired or the damaged cell will self-destruct .
• If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot
be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis.
By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the
development of tumors.
• It is also known as the "guardian of the genome."
• Mutation in TP53 Gene are associated with more than 50% human cancer.
• Loss of P53 abolishes the DNA damage checkpoint.
• Cells with functional p53 become arrested in G1 when exposed to DNA damaging
irradiation, whereas cells lacking functional p53 do not.This permits the cells to repair the
DNA damage prior to stages of it fixation and propagation, which leads tumor formation.

23.
p53 Mutation
• In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer
cells. Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells
with growth and survival advantages.
• Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation,
thus contributing differentially to tumor initiation, promotion, aggressiveness, and metastasis.
• The importance of p53 as a cardinal player in protecting against cancer development is further emphasized by Li-Fraumeni syndrome
(LFS), a rare type of cancer predisposition syndrome associated with germline TP53 mutations.
• The TP53 gene in human tumors is often found to undergo missense mutations, in which a single nucleotide is substituted by another.
• APC gene mutation and beta-catenin accumulation preceded the loss of chromosome 17p,.
• The aberrant accumulation of beta-catenin in tumors results from p53 inactivation.
• A mutation in TP53 at an early stage of cancer progression can occur due to exposure to a carcinogen.
• Aflatoxin B1 induces a G:C to T:A transversion in codon 249 of the TP53.Aflatoxin B1 was also found to be enzymatically activated in
human hepatocytes and to bind to the third base of codon 249.The expression of the 249 serine mutation was further shown to inhibit
p53-dependent apoptosis and transcription and enhance liver cell growth in vitro.This mutation was also found in nontumorous liver in
correlation with aflatoxin B1 intake, highlighting the notion that this mutation can occur early in the process of malignant
transformation.
• Loss of function mutations in other tumor suppressor gene are recessive because the encoded protein function as monomers and
Mutation of a single allele has little functional consequence effect.

24.
p53 Mutation.....cont.
Mutant p53 as a guardian of the
cancer cell.
Mutant p53 in Cancer

25.
RB Gene and it's
genetic mechanism
• RB Gene is missing in several common types
of sporadic cancer (lung,breast, bladder).
• RB Gene encodes the RB protein, which is
universal regulator of the cell cycle.
• Mutations in the RB1 gene are responsible
for most cases of retinoblastoma.
• The RB/E2F pathway regulates apoptosis,
G1-S phase transition and RB inhibition of
apoptosis is an important mechanism of
tumor suppression whereby cells deficient
for RB function can be eliminated by
apoptosis.
• One manner through which RB can inhibit
apoptosis is through its binding to RNA
processing factors.
• Cyclin D1-CDK4 complex phosphorylates RB,
leading to dissociation from the RB-E2F
complex, which frees E2F for activation of
cyclin D1 and S phase gene transcription.
• Positive feedback loop among RB, E2F, and
cyclin D1 allows for cell cycle progression
through G1/S and S phase.
• Deregulation of RB pathways occur in most
cancer and is mediated either by loss of
function mutation of negative players
including RB and CDK inhibitors
(CKIs,p15,p21 etc ) or by amplification or
overexpression of cyclin D1.

26.
RB Gene...
Mechanism of RB inactivation
The Genetic mechanisms that cause Retinoblastoma
• All cells in the lack one of the normal 2
functional copy of Rb tumor suppressor gene,
tumor occur where the remaining copy is lost
or inactivated by mutation or epigenetic
silencing.
• In nonhereditary form all cells initially contain
2 functional copies of the gene.And tumor
because both copy are lost or inactivated.

27.
BRCA1 & BRCA2
• BReast-CAncer susceptibility gene1 and 2 are tumor
suppressor gene.
• The two genes most responsible for breast cancer and
ovarian cancer.
• Mutations to the BRCA1 and BRCA2 genes are inherited,
either from a person's mother or father (or both), and
these are linked to an increased risk for cancer.
• Maintain genome stability through repair of DNA double
strand breaks by homologous recombination, cell growth
regulation and control of cell division.
• Individuals carrying germline pathogenic mutation in
BRCA1 or BRCA2 are at highly risk of breast or ovarian
cancer.
BRCA Mutation

28.
• The number of mutations required for neoplastic transformation may vary, all
tumors are reliant on two critical mechanisms for their development; the
activation of oncogenes that promote proliferation and survival of cancer cells,
as well as the inactivation of tumor suppressor genes that normally repress
development and growth of tumors.
• Oncogenes can be activated via multiple mechanisms, including chromosomal
translocations, deletions or insertions, as well as point mutations.
• Tumor suppressor genes can be inactivated through multiple mechanisms,
including large-scale chromosomal alterations or point mutations.
• Anti-apoptopic genes such as BCL-2 behave as Proto-oncogenes because
overproduction of their encoded proteins prevent normal apoptosis.
• Apoptopic genes whose protein products stimulate apoptosis behave as tumor
suppressors.
Points to
Remember

29.
CARCINOGEN
• A carcinogen is a specific chemical or physical agent that has the ability to cause
cancer in individuals exposed to that agent.
• Initiate or promote tumor formation.
• Three classes of Carcinogen a) Physical (UV-ray, gamma-ray) b) Chemical
(benzopyrene, benzene) c) Biological (oncovirus)
• There are two types of chemical carcinogen- 1) Direct acting (act directly without
any metabolic activation) and 2) Indirect acting(require metabolic activation).
• Chemical carcinogens are mostly Tumor Initiators,cause cancer by inducing
Mutation.
• Some are Tumor Promoter.
• Phorbol esters stimulate cell proliferation by activating protein kinase C.
• Aflatoxin (a myotoxin)-
Indirect acting
Carcinogen.
• Activated into aflatoxin-
2,3, epoxide by the action
of intracellular enzymes
which is associated with
mutation of the p53 gene.
• Aflatoxin is produced by
the fungus Aspergillus
flavus and Aspergillus
parasitics.
• Aflatoxin consists of a
difurofuran ring system
fused to a substituted
coumarin moiety with a
methoxy group attach at
the corresponding
benzene ring.
• After chemical
modification by liver
enzymes aflatoxin
becomes linked to G-
residues in DNA and
induces G-T transversion.
• Other chemical carcinogen associated with human cancer is-
• Benzene (Leukemia), Arsenic (lung and skin), Cadmium (prostate), Radon
(lung), Asbestos (lung,GI tract) Vinyl Chloride (Angiosercoma,Liver).

30.
Chemical Carcinogen and their effect on genome;

31.
Oncovirus
Onco= Relating to tumor
Virus= Infectious agent
• Oncovirus- a virus that can cause cancer. This Viruses infect healthy
cells and transform them to infected one, creating tumor producing
potential in the cells.
• This virus can contain DNA or RNA or both as their genetic material
and basically responsible for tumor or cancer cause.
• The vast majority of human and animal virus do not cause cancer
most probably because of longstanding co-evolution of host and
virus.
• Most of the cancer that occurs because of these viruses can be
prevented if vaccination is taken on proper time.
• Diagnosis can be done through simple blood tests and can be treated
with non-toxic antiviral compound also.
• It is difficult to detect the virus until it infect the host.

32.
Types of Oncovirus
DNA Oncogenic Virus RNA Oncogenic Virus
• Oncogenic DNA viruses include EBV, hepatitis B virus (HBV), human papillomavirus (HPV), human
herpesvirus-8 (HHV-8), and Merkel cell polyomavirus (MCPyV). Oncogenic RNA viruses include,
hepatitis C virus (HCV) and human T-cell lymphotropic virus-1 (HTLV-1).
• The Epstein-Barr virus has been linked to Burkitt’s lymphoma. This virus infects B cells of the immune
system and epithelial cells.
• The hepatitis B virus has been linked to liver cancer in people with chronic infections.
• Human papilloma viruses have been linked to cervical cancer. They also cause warts and benign
papillomas. This virus uses 2 viral proteins, E6 and E7 to sequester the host cells p53 and Rb
respectively.
• E1A and E1B proteins of adenovirus inactivate the RB and p53 tumor suppressor protein with E1A
binding to RB and E1B binding to p53.
• Human herpes virus-8 has been linked to the development of Kaposi sarcoma.
• DNA tumor viruses have two life-styles. In permissive cells, all parts of the viral genome are expressed.
This leads to viral replication, cell lysis and cell death. In cells that are non-permissive for replication,
viral DNA is usually, but not always, integrated into the cell chromosomes at random sites. Only part of
the viral genome is expressed.
DNA Contain Oncovirus

33.
• Viral oncogene first reported in Rous Sarcoma virus by Peyton Rous, which transforms chicken embryo
fibroblasts in culture and induces Sarcoma.
• The first oncogene found in Rous Sarcoma virus, designated as src oncogene.
• Oncogenic RNA viruses include, hepatitis C virus (HCV) and human T-cell lymphotropic virus-1 (HTLV-1),
HTLV-2(Hairy cell Leukemia).
• Viral cancers do not arise acutely after infection, but instead develop 15–40 years later.
• Hepatitis C virus is an enveloped RNA virus capable of causing acute and chronic hepatitis in humans by
infecting liver cells. It is estimated 3% of the world’s population are carriers. Chronic infection with
hepatitis C virus results in cirrhosis, which in turn can lead to liver cancer.
• Hepatitis viruses includes hepatitis B and hepatitis C have been linked to hepatocellular carcinoma.
• Simian virus 40,SV40 (Non-Hodgkin's lymphoma).
Retroviral Oncogene:-
• Normal chicken cells contain genes that are closely related to retroviral src
oncogene (codes for Src protein kinase) of Rous Sarcoma virus (H. Varmous & M.
Bishop).
• The oncogene in the virus did not represent true viral gene,but was a normal
cellular gene, which the virus acquired during replication in host cell.
• src related sequences also found in normal DNA of a wide range of vertebrate
(including human).
• The normal genes from which the retroviral oncogene originate are called proto-
oncogene.
• Mutations or genetic rearrangement of Proto-oncogenes by Carcinogen or viruses
alter the normally regulated function of these genes.
• v-viral Oncogene and c-cellular Oncogene.
• Oncogene carried by Rous sarcoma is called v-src and proto-oncogene related to it
in cellular genomes is called v-src.
RNA Containing Oncovirus

34.
V
I
R
A
L
vs
C
E
L
L
U
L
A
R
O
N
C
O
G
E
N
E

35.
Therapeutic Interventions
Supportive care services describe a broad range of therapies designed to combat
side effects and maintain well-being. Treating cancer requires focusing on more
than the disease alone; it must also address the pain, fatigue, depression and other
side effects that come with it.
• Nutrition therapy to help prevent
malnutrition and reduce side effects
• Naturopathic support to use natural
remedies to boost energy and reduce
side effects
• Oncology rehabilitation to rebuild
strength and overcome some of the
physical effects of treatment
• Mind-body medicine to improve
emotional well-being through counseling,
stress management techniques and
support groups
• Treatment options depend on the type of
cancer, its stage, if the cancer has spread
and your general health. The goal of
treatment is to kill as many cancerous
cells while reducing damage to normal
cells nearby. Advances in technology
make this possible.
• The three main treatments are:
• Surgery: directly removing the tumor
• Chemotherapy: using chemicals to kill
cancer cells
• Radiation therapy: using X-rays to kill
cancer cells.

36.
Treatment...
• Cell-lethal combination with some lesion that is present in the cancer cells,but
harmless to cells where this lesion is absent (synthetic lethal);it kills only in
partnership with the cancer-specific mutation.
• PARP Inhibitors kill cancer cells that have Defects in Brca1 or Brca2 genes.
• Design of small molecules to inhibit specific Oncogenic protein. eg-Chimeric Bcr-Abl
protein can inhibit by drug molecules imatinib, blocks Bcr-Abl by inhibit the activity
of tyrosine kinase.
• The MAP kinase (MAPK) pathway has emerged as the crucial route between
membrane-bound Ras and the nucleus. The MAPK pathway encompasses a cascade
of phosphorylation events involving three key kinases, namely Raf, MEK (MAP kinase
kinase) and ERK (MAP kinase). This kinase cascade presents novel opportunities for
the development of new cancer therapies designed to be less toxic than
conventional chemotherapeutic drugs.
• Furthermore, as a signal transduction-based approach to cancer treatment,
inhibition of any one of these targets has the potential for translational
pharmacodynamic evaluation of target suppression.

37.
• The Ras-MAPK (Mitogen Activated Protein
Kinase) pathway begins with growth factor
binding to transmembrane Receptor Tyrosine
Kinases (RTKs).
• Growth factor binding initiates
homodimerization and auto-phosphorylation in
trans at specific tyrosines of the RTKs.
• Growth factor receptor-bound protein 2 (Grb2)
is then recruited to the cytosolic portion of the
RTKs via a Src homology 2 (SH2) domain which
binds to phosphotyrosines. Grb2 then recruits a
guanine exchange factor, Son of Sevenless
(SOS), via an SH3 domain and the GTPase Ras.
• Ras, a protein that was originally identified as
the transforming component in oncogenic
viruses, is then post- translationally modified
with an isoprenyl group that localizes it to the
plasma membrane.
• The GTPase activity of Ras is enhanced by the
GTPase Activating Protein (GAP).
• Ras recruits and activates the MAPK kinase
kinase (MAPKKK) Raf which initiates a
phosphorylation cascade from Raf to MEK
(MAPKK) which finally phosphorylates ERK
(MAPK, Extracellar Regulated Kinase).
• Phosphorylated ERK then translocates to the
nucleus where it phosphorylates transcription
factors important for proliferation and
differentiation.
• Oncogene activation of the ERK MAPK cascade. Mutationally
activated B-Raf, Ras and mutationally activated (by missense
mutations in the cytoplasmic kinase domain in NSCLC or by
extracellular domain truncations (e.g., VIII) in glioblastomas)
and/or overexpressed EGFR causes persistent activation of the
ERK MAPK cascade in human cancers.
• Activated ERKs translocate to the nucleus, where they
phosphorylate and regulate various transcription factors
leading to changes in gene expression.
• In particular, ERK-mediated transcription can result in the
upregulation of EGFR ligands, such as TGFα, thus creating an
autocrine feedback loop that is critical for Ras-mediated
transformation and Raf-mediated gene expression changes

38.
Immunotherapy
• Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer.
This can be done in a couple of ways:
• Stimulating, or boosting, the natural defenses of your immune system so it works harder or smarter to find and
attack cancer cells
• Making substances in a lab that are just like immune system components and using them to help restore or improve
how your immune system works to find and attack cancer cells.
• Checkpoint inhibitors: These drugs basically take the ‘brakes’ off the immune system, which helps it recognize and
attack cancer cells.
• Chimeric antigen receptor (CAR) T-cell therapy: This therapy takes some T-cells from a patient's blood, mixes them
with a special virus that makes the T-cells learn how to attach to tumor cells, and then gives the cells back to the
patient so they can find, attach to, and kill the cancer.
• Cytokines: This treatment uses cytokines (small proteins that carry messages between cells) to stimulate the immune
cells to attack cancer.
• Immunomodulators: This group of drugs generally boosts parts of the immune system to treat certain types of
cancer.
• Cancer vaccines: Vaccines are substances put into the body to start an immune response against certain diseases. We
usually think of them as being given to healthy people to help prevent infections. But some vaccines can help prevent
or treat cancer.
• Monoclonal antibodies (mAbs or MoAbs): These are man-made versions of immune system proteins. mAbs can be
very useful in treating cancer because they can be designed to attack a very specific part of a cancer cell.
• Oncolytic viruses: This treatment uses viruses that have been modified in a lab to infect and kill certain tumor cells.
• A monoclonal antibody called trastuzumab that binds to Her2 and inhibits it's functions slows the growth of breast
tumors in humans that overexpress Her2,it is now an approved therapy.