OBSTETRICS 2 MOLECULAR ONCOLOGY

7S-7 | CEU-SOM A & B IN GYNECOLOGIC

MAYNILA E. DOMINGO, MD, DPOGS, FPSMFM, FPSUOG
CANCER

OUTLINE
I. OVERVIEW
II. IMMUNOLOGIC RESPONSE
A. Innate Immunity
B. Adaptive Immunity
i. Humoral Immunity
ii. Cellular Immunity
III. TUMOR CELL KILLING AND IMMUNOTHERAPY
A. Immunotherapy
B. Cancer Development
i. Oncogenes
ii. Tumor Suppressor Genes
iii. DNA Mismatch Repair Genes
IV. FUTURE DIRECTIONS 🔊 INNATE does not recognize a variety of foreign substances rather it
V. GYNECOLOGIC MALIGNANCIES only recognize microbial substances
VI. REFERENCES These components of innate immunity will depend their action to the
receptors in particular are the pattern recognition receptors à then it will
lead to microbial death by triggering intracellular signaling cascades
Thus, can be anti-microbial, anti-viral and anti-cancer
COURSE OBJECTIVES
But if there is a break in these series of events can lead to cancer or
Ø To understand why people develop cancer
nawawala ung pagiging anti-microbial, anti-viral and/or anti-cancer
Ø To be able to cure cancer eventually and research on it

I. OVERVIEW

Molecular Altered
cellular
Changes phenotype

Cytokines
Growth factors
Cellular receptors
🔊 Another figure describing the first diagram but with pictures
MOLECULAR CHANGES ALTERED CELLULAR
PHENOTYPE
Oncogene • Self-sufficient in growth
• Overexpression signaling
• Amplification • Insensitive to antigrowth 🔊 Complement system is
signals
• Mutation • Tissue invasion and
composed of a large group of
interacting plasma proteins
Tumor Suppressor Gene metastasis Classical pathway is activated by
• Mutation • Limitless replicative potential antigen-antibody complex
• Deletion • Sustained angiogenesis Alternative pathway is activated by
recognition of microbial surface
• Viral Infection • Evading apoptosis structures in the absence of
antibody

The activation of these pathways

II. IMMUNOLOGIC RESPONSE will eventually lead to the cleavage
INNATE IMMUNITY of these proteins to form larger
Ø Non-antigen-specific and rapid fragments that will eventually be
Ø Do not increase with repetitive exposure to a given antigen deposited on microbial surfaces
Ø Components: that will lead to complement
• Epithelial surfaces activation of C3 that will serve as
an attractant for the cellular
• Macrophages components of the innate system
• Natural Killer (NK) cells (ex: neutrophils)
• Neutrophils
• Dendritic cells
• Components of the complement system

7S-7 MOLECULAR ONCOLOGY IN GYNECOLOGIC CANCER ESTUYE • HO • JAVIER • RAMOS • ROCHA

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 ADAPTIVE IMMUNITY
1. B lymphocytes (B cells):
§ Humoral immunity
2. T lymphocytes (T cells):
§ Cell-mediated immunity

HUMORAL IMMUNITY
Ø Derived from hematopoietic stem cells
Ø Aggregate in the lymph nodes, gastrointestinal tract, or spleen
Ø B lymphocytes synthesize antibodies in response to an activated
CD8+ cell or helper T cell (Th2)
Ø C lymphocytes differentiate into plasma cells that secrete large
quantities of antibody (immunoglobulin) in response to an antigen

🔊 kelangan niya ulit ng recognition, dependent on MHC molecules

CLASS I MHC
Ø Expressed by all nucleated cells in the body
Ø Used to present intracellular peptides for surveillance to circulating
cytotoxic T lymphocytes
• Also known as CD8+ T cells
🔊 IgG is particularly important in obstetrics because it can cross the • Directly destroy cells that express foreign antigens that arise
placenta into the fetus after a viral infection or are expressed as a result of
IgM – first yan siya, early stages of immunity tumorigenesis
IgG – chronic • Considered to be primarily responsible for the antitumor
immune response

CLASS II MHC
Ø Expressed primarily by professional APCs, which present
phagocytosed and processed extracellular peptides to Th cells
Ø Th cells (which are CD4+) respond to antigens bound to class II
MHC molecules to secrete cytokines that stimulate the
proliferation and differentiation of T cells as well as other B cells
and macrophages
Ø 2 Subsets of Th Cells
• Th1 cells secrete interleukin (IL-2) and interferon-gamma
(IFN-γ) to elicit a cell-mediated inflammatory response
• Th2 cells secrete IL-4, IL-5, IL-6, and IL-10 to promote
antibody secretion and the humoral response
🔊 unrelated to oncology, example in recurrent pregnancy loss (RPL) – a
slight imbalance on the Th1 and Th2 can lead to RPL
In the same way that any imbalance in the function of these cells can lead
to unsuppressed growth à cancer
Class I ang important sa anti-tumor function

🔊 IgA is seen in the GI tract, the rest is seen in the plasma

CELLULAR IMMUNITY
Ø T cells originate in the bone marrow, differentiate in the thymus,
and then circulate in the blood or are harbored in the lymph
nodes, spleen, or Peyer patches of the intestine.
Ø Depends on direct cell-cell contact.
Ø T cells are restricted to peptide antigens and only recognize
peptide sequences in the context of membrane-bound host
proteins called MHC molecules

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TREGS
Ø Consists of CD4+ T cells that are present in the peripheral
circulation
Ø Inhibit immune responses
Ø Prevent autoimmunity
Ø Because most tumor-associated antigens are self-antigens,
recognition by immune effector cells is regulated by Tregs through
peripheral tolerance.
Ø Curiel and associates have shown that high levels of Tregs were
found to predict poor overall survival in a cohort of 70 patients with
ovarian cancer.
• Based on these data, a goal of immunotherapy is to eliminate
Tregs in the hope of enhancing innate antitumor immunity
🔊 Summary of the difference between cellular and humoral immunity
CELLULAR – intracellular, key players are APCs, helper T cells, T cell
receptor – need to be recognized to cause a cascade of events causing
release of cytokines that will eventually cause lysis or death of infected cells
HUMORAL – extracellular, causes production of immunoglobulins/antibodies
that leads to neutralization of pathogen
CYTOKINES
Ø Proteins secreted by immune cells that are produced in different
phases of the immune response to control its duration and extent
Ø During activation phase of the immune response system à
cytokines stimulate growth and differentiation of lymphocytes
Ø In the effector phase of the immune response à cytokines
activate other effector cells to help eliminate antigens and
microbes
Major classes of cytokines include:
1. Cytokines that regulate innate immunity
2. Cytokine that regulate adaptive immunity
3. Cytokines that stimulate hematopoiesis
CYTOKINES THAT REGULATE IMMUNE IMMUNITY
1. Interleukins
Ø M1 macrophages secrete IL-12, IL-18, IL-23, IFN-γ and TNF-𝑎 Ø Uses the woman’s immune system to elicit a response
and promote immune responses against tumors and
intracellular microbes
Ø M2 macrophages produce vascular endothelial growth factor
(VEGF), IL-6, IL-10 and prostaglandin E2, all of which have
immunosuppressive functions and are found selectively in
established tumors.
7S-7 MOLECULAR ONCOLOGY IN GYNECOLOGIC CANCER
2. Chemokines
Ø Inflammatory: released in response to inflammatory stimuli that
cause leukocyte recruitment
Ø Homeostatic: cause migration of leukocytes to lymphoid organs
Ø Chemokines affect tumor establishment by:
• Determining the extent and type of leukocyte infiltration
• Promoting angiogenesis
• Controlling site-specific metastasis
• Affecting tumor cell proliferation
3. Interferon
Ø Type 1 IFN (IFN- 𝑎 and IFN-β) – stimulated by intracellular TLRs
and mediate the early innate immune response to viral infections
• Increase expression of class I MHC, and promote a Th1
cell-mediated immune response by promoting T-cell
proliferation and NK cell cytolytic activity.
Ø Type 2 IFN (IFN-γ) – responsible tor macrophage activation and
the effector functions of innate and adaptive immune responses
CYTOKINES THAT MEDIATE ADAPTIVE IMMUNITY
Ø IL-2 stimulates antibody synthesis and B cells by acting as a
growth factor
Ø IL-4 promotes IgE production from B cells and stimulates the
development of Th2 cells from naïve cells
Ø IFN-γ activates the microbicidal function of macrophages,
stimulates the expression of class I and II MHC and co-
stimulatory molecules by antigen-presenting cells (APC),
promotes the maturation of cells expressing CD4 into Th1 cells,
and inhibits the Th2 cell pathway, thereby effectively promoting
a cellular immune response
Ø TGF-β inhibits the proliferation and differentiation of T cells and
contributes to immune evasion of tumor cells by inhibiting
antitumor host immune responses
CYTOKINES THAT STIMULATE HEMATOPOIESIS
Colony-Stimulating Factors
Ø IL-3 is a multilineage colony-stimulating factor that allows for the
differentiation of cells into myeloid progenitor cells,
granulocytes, monocytes and dendritic cells.
Ø Granulocyte colony-stimulating factor (G-CSF) is a cytokine
produced by macrophages, fibroblasts and endothelial cells and
promotes the mobilization of neutrophils from the bone marrow.
Ø Granulocyte-macrophage colony-stimulating factor (GM-
CSF) is produced by T cells, macrophages, endothelial cells and
fibroblasts.
• Stimulates the maturation of bone marrow cells into
dendritic cells and monocytes
III. TUMOR CELL KILLING AND IMMUNOTHERAPY
IMMUNOTHERAPY
Three Major Classes of Immunotherapy:
1. Immune Modulation
Ø Relies on nonspecific means such as the administration of IL-2,
IFNs, or bacilli Calmette-Guerin to elicit an immune response
2. Passive Therapy
Ø Transfers components of the acquired immune system to the
cancer patient (passive immunity)
3. Active Therapy
ESTUYE • HO • JAVIER • RAMOS • ROCHA
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 CANCER DEVELOPMENT TUMOR SUPPRESSOR GENES
Ø Control cell growth and cellular proliferation and aberrations in
tumor suppressor genes can cause malignancy.
Ø Retinoblastoma (Rb) gene – first tumor suppressor gene to be
identified and encodes a nuclear protein that regulates G1 phase
Tumor cell cycle arrest.
Suppressor

SPORADIC Oncogene Gene
KNUDSON’S “TWO-HIT THEORY”
Ø The first hit is the inheritance
DNA
HEREDITARY • Gene amplification (increase in the number of copies of
Mismatch
Repair the genes in the cell)
Gene • Translocation, or
• Overexpression, which refers to excessive and abnormal
protein production

CANCER

🔊 Multifactorial à that is why it is difficult to treat

Can be caused by acquired mutation or can also be inherited
In addressing it, we have to identify the different components to properly
address that specific type of cancer

ONCOGENES
Ø Refers to a set of genes that when altered are associated with the
development of a malignant cell
Ø Involved in cell proliferation, signal transduction, and
transcriptional alteration
Ø Mechanisms of alteration in oncogene function:
• Gene amplification (increase in the number of copies of
the genes in the cell)
• Translocation, or
• Overexpression, which refers to excessive and abnormal
protein production
Ø Classes of oncogenes:
• Peptide growth factors
🔊 Non-hereditary: two copies of undamaged chromosomes à an event can
• Cytoplasmic factors occur causing a change or a mutation on one of the genes à later on dapat
• Nuclear factors may another event para magcause siya ng somatic loss of the function or
mutation
Hereditary: to begin with wala siyang two normal copies, meron na talaga
siyang “first-hit”, innate yun may damaged cells na. Occurs at conception then
another event can occur than can lead to somatic mutation na which will
manifest itself as the disease

TUMOR SUPPRESSOR GENES: p53

Ø Most common tumor suppressor gene in gynecologic
malignancies
Ø Located on the short arm of chromosome 17
Ø P53 has key roles as a transcription factor and regulator of the cell
cycle and apoptosis

Table 4. Classes of Genes Involved in Growth Stimulatory Pathways

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🔊 Normally if there is DNA damage or any abnormality in the cell cycle
kunwari may periods of hypoxia may nacreate na abnormal cell, ung p53 i-
aarrest niya ung cycle na yun kasi may nadetect na may abnormality so STOP
muna then allow DNA repair before we restart the cell cycle.
For example, nadamage na ung cells so they will trigger apoptosis para hindi
na yun magproliferate.
BUT IF p53 is mutated, it cannot perform its function despite of the presence of
DNA damage or any abnormality in the cell cycle, it can no longer halt or arrest
the cell cycle and allow DNA repair or apoptosis to happen therefore
nagccontinue lang ung cell cycle. Dahil nagccontinue with a damaged cell, the
cell will become cancerous dahil hindi niya nacontrol ung pagproliferate ng
abnormal cells.
That is why very important ang p53, very common in gynecologic cancers.
TUMOR SUPPRESSOR GENES: BRCA1 and BRCA2
Ø Approximately 5% to 10% of breast and ovarian cancers arise in the
setting of a genetic predisposition
Ø Associated with germline mutations in the:
• BRCA1 gene located on chromosome 17q21
• BRCA2 gene located on chromosome 13q12.3
Ø The pattern of inheritance is autosomal dominant
Ø Occurs more frequently in Ashkenazi Jewish and French Canadian
women
🔊 In patterns of inheritance – Mendellian à Autosomal dominant – kahit one
copy magmmanifest whereas kapag recessive – dapat dalawa bago
magmanifest
That is why yung in-breeding mas nagmmanifest ung sakit
Ø The cumulative risk of developing ovarian cancer by the age of 70
years:
• 40% to 50% for BRCA1 mutation carriers
• 20% to 25% for BRCA2 mutation carriers
🔊 BRCA1 > BRCA2 risk for ovarian cancer
Ø There is equal breast cancer penetrance in BRCA1 or BRCA2
mutation carriers.
🔊 same lang ung risk for breast cancer
Ø The BRCA2 mutation is also associated with male breast cancer and
pancreatic, urinary tract and biliary tract cancers.
🔊 cumulative risk is not only dependent on the presence of gene but also we
have to correlate gene + patient’s age
🔊 In this table, in general even without mutation or inherited risk – 12% risk for
the general population but it increases to 80% with mutation and so on
BUT we have to be very careful in interpreting mutation, dahil nowadays you
can have urself tested even asymptomatic. In the risk computation and what
you do with the result, dun kelangan ng counseling may pre and post. So what
do you expect to know? What is your next step?
Depending on patient’s manifestations and concerns, dun natin tinatailor.
Male breast CA – we note that if males develop breast CA it is more advanced
and what’s responsible for that is BRCA2
Ovarian = BRCA1;
Female breast CA = both BRCA1 and BRCA2
7S-7 MOLECULAR ONCOLOGY IN GYNECOLOGIC CANCER
According to NCCN Guidelines 2015, the following women with no
personal history of cancer but with a family history as listed here
should be tested for a BRCA mutation
Ø A known mutation in a cancer susceptibility gene within the family
Ø A woman with a family history of two or more women with breast
cancer on the same side of the family
Ø A woman with greater than two breast cancer primaries in the
same individual
Ø A first- or second-degree relative with breast cancer <45 years of
age
Ø A woman with at least one family member with invasive ovarian,
fallopian tube, or primary peritoneal cancers
Ø Male breast cancer
Ø Personal or family history of three or more of the following cancers:
pancreatic cancer, prostate cancer, gastric cancer, melanoma,
brain tumors
DNA MISMATCH REPAIR GENES
Ø Hereditary nonpolyposis colorectal cancer (HNPCC), also
known as Lynch syndrome, is an autosomal dominant cancer
syndrome that predisposes an individual to colorectal,
endometrial, gastric, biliary tract, urinary tract, or ovarian cancer.
• Account for all cases of hereditary endometrial cancer
• Up to 5% of hereditary ovarian cancers
Ø Lifetime risk for endometrial cancer in HNPCC gene carriers is
40% to 60%, corresponding to a relative risk of 13 to 20
Ø Lifetime risk for ovarian cancer in HNPCC gene carriers is 6% to
20%, corresponding to a relative risk of 4 to 8
Ø Caused by germline mutations in genes responsible for
recognizing and fixing errors in the DNA helix, resulting from
incorrect pairings of nucleotides during replication or the formation
of abnormal loops of DNA.
🔊 You have to understand even if majority of cancer cases are sporadic or
isolated, we should not disregard risk on other associated organs.
Endometrial cancer on more than 60 yo with history of hypertension, DM,
PCOS – probably isolated
Pero kapag bata tapos nagkacancer sa lining ng matres, kelangan mo irule out
ung presence of HNPCC sa patient na to. Going back to Knudson’s two hit
theory, baka namana niya yun upon conception may first hit na so baka
magkaron na siya ng colorectal, gastric, biliary so you have to screen
thoroughly.
Another example, px has HNPCC gene – tell her that her lifetime risk is 40-
60% risk of endometrial cancer, next na gagawin is tatanggalin ba ung matres?
- of course not but remove other factors; obesity, DM, hypertension, high
cholesterol, irregular menses, unopposed ovulation.
Unfortunately, gene therapy is not yet well-established. What we can control as
of now is other modifiable risk factors.
Ø Most commonly mutated mismatch repair genes:
• MSH2 (MutS homologue 2) – located on chromosome
2p16
• MLH1 (MutL homologue 1) – located on chromosome
3p21
Ø Other mismatch repair genes are MSH6, MSH3, PMS1 and PMS2
Ø Cells with a defective mismatch repair system exhibit
microsatellite instability (MSI)
• Occurs as DNA mismatches cause a shortening or
lengthening of repetitive DNA sequences and these
mismatches go unchecked
ESTUYE • HO • JAVIER • RAMOS • ROCHA
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 Ø The clinical diversity of gynecologic cancers such as histologic
type, stage and outcome is probably attributable to molecular
differences among cancers.

🔊 In gynecologic cancers, aside from the stage, we also have different

histologic types so kapag high-grade tumor – poorer prognosis

ENDOMETRIAL CANCER AND TUMOR SUPPRESSOR GENES

Two types of Endometrial Cancer:
1. Type I – due to unopposed estrogen and develops in a background
of endometrial hyperplasia (madaming development = kumakapal ung
lining)
2. Type II – comprises non-endometrioid and more aggressive
cancers

Ø Inactivation of tumor suppressor gene p53 is among the most

frequent genetic events in endometrial cancer occurring in about
20% to 30% of cases.
Ø Overexpression of p53 occurs more frequently in advanced
stage endometrial cancer and has been associated with worse
survival after controlling for stage, suggesting that loss of p53
tumor suppressor function leads to a more aggressive phenotype.
Ø There is a disproportionate frequency of p53 mutations in 90% of
serous and 33% of high-grade endometrioid cancers.
Ø In uterine sarcomas, overexpression of mutant p53 occurs in the
majority of malignant mixed mesodermal tumors (MMMTs) and in
some leiomyosarcomas.
Ø PTEN gene is on chromosome 10q and encodes a phosphatase
that functions by opposing the activity of PI3K
Ø Mutations in this gene are:
🔊 WHY did we come up with these criteria? To guide us on screening of family • Deletions
members. As of now ang target natin is EARLY detection and possibly • Insertions
PREVENTION of possibly developing cancers • Nonsense mutations
Ø Loss of PTEN and p27 protein expression in obese endometrial
cancer patients is associated with a significantly better prognosis
IV. FUTURE DIRECTIONS
Ø PTEN mutation status can be used to differentiate an ovarian
metastasis from an endometrial cancer versus synchronous
primary cancers

🔊 Why is it important to know about this? For prognostication and screening of

other family members – proper counselling

ENDOMETRIAL CANCER AND ONCOGENES

Ø Fewer alterations in oncogenes have been found in endometrial
cancer.
Ø Her2/neu expressed in 3% of endometrioid and 25% of serous
carcinomas
• Associated with aggressive phenotype and poor survival in a
population-based series
Ø The levels of Her2/neu overexpression are much lower than in
breast cancer (Engelsen, 2008)
Ø KRAS mutations occur most often in type I endometrial cancers
🔊 Oncogenes promotes growth so kapag may means na tayo to target that as well as in hyperplasias à KRAS mutation is an early event in
particular oncogene, we can STOP the uncontrolled growth and proliferation the development of type I endometrial cancers
ncRNA – include ribozymes, antisense siRNA, microRNA (miRNA), and Ø BRAF mutations were found in endometrial cancers with
aptamers. mismatch repair deficiency and have different frequencies in
various populations (Feng, 2005)
4 Types of responses that trigger specific gene inactivation: Ø The beta-catenin (β-catenin) gene maps to chromosome 3p21
1. Destruction of homologous messenger RNA • Mutations in exon 3 of β-catenin occur in approximately 15%
2. Inhibition of translation to 50% of endometrial cancers and are independent of the
3. De novo methylation of genomic regions that block transcription of presence of microsatellite instability and the mutational status
target genes of PTEN and KRAS.
4. Chromosomal rearrangement • Characterizes an aggressive subset of low-grade and low-
stage endometrioid adenocarcinomas in younger women, and
V. GYNECOLOGIC MALIGNANCIES this subset of patients may warrant more aggressive
Ø Cancer is a complex multistep process that requires: therapeutic management (Liu, 2014c).
• Self-sufficient growth signals Ø The fibroblast growth factor receptor 2 (FGFR2) gene encodes
one of a family of tyrosine kinase growth factor receptors that
• Insensitivity to anti-growth signals
receive signals from a large family of ligands
• Tissue invasion and metastasis
• In approximately 10% of endometrioid cancers
• Limitless replicative potential
• Sustained angiogenesis
• Evasion of apoptosis

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 OVARIAN CANCER AND TUMOR SUPPRESSOR GENES Ø Other immunotherapy options in cervical cancer:
Ø Alteration of the p53 tumor suppressor gene is the most frequent • Checkpoint inhibitors
genetic event in ovarian cancers • Chimeric T-cell receptor antigens
Ø Evidence suggests that inactivation of Rb greatly enhances tumor
formation in ovarian cells with p53 mutations VI. REFERENCES
Ø Cyclin-dependent kinase inhibitors (CDKIs) also acts as tumor Ø Dr. Domingo’s PPT and Zoom recording
suppressors because they inhibit cell cycle progression from the
G1 to S phase
Ø The p16 gene (CDKN2A) undergoes homozygous deletion in
approximately 15% of ovarian cancers.
Ø BRCA1 and p16 may be inactivated by transcriptional silencing
because of promoter methylation rather than mutation or deletion.
Ø TCGA analysis found that only a small number of high-grade
serous ovarian cases had deletions in PTEN and Rb, but
endometrioid and clear cell ovarian cancers had higher mutation
rates in ARID1A, PI3K, PTEN and β-catenin (Cancer Genome
Atlas Research Network 2011)

OVARIAN CANCER AND ONCOGENES

Ø A minority of ovarian cancers have increased Her2/neu
expression
• The Gynecologic Oncology Group has conducted a trial to
evaluate the response rate of ovarian cancer patients to
single-agent anti-Her2/neu antibody therapy and found the
rate of response to be approximately 7%
Ø KRAS mutations are commonly found in borderline tumors of the
ovary and mucinous ovarian cancers, but not in serous ovarian
tumors
Ø In low-grade ovarian cancers, BRAF and KRAS mutations are
found and inhibitors of the MEK1/2 have been found to be active
therapeutic agents with a 63% disease control in patients with
recurrent low-grade serous carcinoma (Farley, 2013)
Ø PI3K and β-catenin are rarer mutations, but they are more likely
to be found in endometrioid and clear cell tumors of the ovary.

CERVICAL CANCER AND ONCOGENES

Ø Inactivation of the TP53 tumor suppressor gene leads to
genomic instability that results in secondary genetic alterations
that lead to the development of cervical cancer
Ø The allelic loss of possible tumor suppressor genes at loci on
chromosomes 3p, 11p, and others has been noted, but specific
tumor suppressor genes remain unidentified.
Ø RAS and MYC genes are key oncogenes in cervical carcinomas
Ø Oncogenes Hi and NRAS are up-regulated in cervical cancer
independently of HPV infection.
Ø Gene silencing caused by promoter hypermethylation may also be
involved in cervical cancer development
Ø The methylation status of the oncogene human telomerase
reverse transcriptase and the tumor suppressor genes death-
associated protein kinase and O6-methylguanine DNA
methyltransferase could be used to distinguish the progression
from normal to cervical dysplasia to invasive cancer.

🔊 Although cervical cancer is associated with a virus, meron ding mga genetic
predisposition. WHY? Not everyone exposed to the virus develops cervical
cancer. For all we know, sexual promiscuity near the age of menarche can
cause HPV but bakit hindi lahat nagkakaron? Maybe there are some that has
mutations in these particular genes.

CERVICAL CANCER AND IMMUNOTHERAPY

Ø ADXS11-001 is a live attenuated Listeria monocytogenes
bioengineered to secrete an HPV-16 E7 fusion protein targeting
HPV transformed cells.
Ø Peptide-based vaccines, which have the advantages of relative
tolerability, stability and ease of production.
• Tend to have poor immunogenicity and require adjuvants to
enhance vaccine potency
• An ongoing clinical trial is utilizing ISA101, a HPV-16 E6/E7
long peptide vaccine, at varying doses with or without
interferon alfa in combination with carboplatin and paclitaxel
in women with HPV-16 positive advanced stage, metastatic or
recurrent cervical cancer
Ø Adoptive T-cell therapy

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