Download Cancer therapy

‫‪Cancer Biomarkers‬‬
‫)‪( Diagnosis, Treatment, Disease managements‬‬
‫‪Personalized Medicine‬‬
‫فروزنده محجوبی‬
‫متخصص سیتوژنتیک مولکولی پزشکی‬
‫دانشیار پژوهشگاه ملی مهندسی ژنتیک‬
‫مدیر عامل بنیاد ژنتیک‬
‫آزمایشگاه ژنتیک پزشکی سالله‬
Iran?
Same and different story
A cancer patient knows he/she has cancer
An apparently healthy person doesn’t have cancer
yet
(screening?/Early detection)
Cancer therapy:
 Surgery
 Chemotherapy
 Radiotherapy
 Immunotherapy
 etc
Cancer therapy
1) Success rate (survivor rate)
2) Side effect
3) Cost
The best survivor rate
so far in USA
Side effects
Side effect:
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Bone density loss
Cardiotoxicity (Heart damage)
Cognitive (mental) deficits( chemo brain)
Distress
Fatigue
Infertility
Pain
Pulmonary (lung) dysfunction
Drug resistance
Cost
Cost in Iran for breast cancer
‫معاون درمان وزیر بهداشت‪:‬‬
‫‪ ‬ساالنه در ایران ساالنه بطور مستقیم و غیرمستقیم ‪ ،‬هشت هزارو‬
‫‪ 500‬میلیارد تومان صرف هزینه های درمانی سرطان می شود‪.‬‬
‫معاون درمان وزیربهداشت‪:‬‬
‫‪ ‬سرطان سومین علت مرگ و میر در کشور به شمار می رود و یک دوم‬
‫مرگ های ناش ی ازسرطان با تشخیص به موقع و درمان مناسب‬
‫قابل پیشگیری است‪.‬‬

Cost of care
Even the USA can't afford
treating 100% to benefit 20%
Summary:

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High incidence
Medium/low survival rate
Very costly
Very bad side effects
Biomarkers and
Personalized medicine
Surgeons /Clinicians
Pathologists
Oncologist
Old Paradigm:
Personalized medicine or Precision
medicine

Precision medicine implies that diseases are defined by
underlying molecular mechanisms rather than traditional
signs and symptoms.
Lancet 378 : 1678, 2011
Toward precision medicine
US National Research Council, nov 2011
New Paradigm:
Cancer and genetics
All cancers are caused by
genetic changes
507 patients were subjected to whole-exome
sequencing, identifying 30,626 somatic mutations :
Average 60 mutations in each
breast tumor
But only small proportion
of cancers are hereditary
About 5% to 10% of breast cancers are
thought to be hereditary:
Meaning?
The genetic nature of each
tumor may be unique
Definition
Mutations:
a) Pathogenic
b) Polymorphism, normal Variant, SNP

A frameshift mutation :
original

In contrast, any insertion or deletion that is evenly divisible by three
is termed an in-frame mutation

A nonsense mutation : premature stop codon, or a nonsense codon in
the transcribed mRNA, and possibly a truncated, and often
nonfunctional protein product

Missense mutations or nonsynonymous mutations: are types of point
mutations substitution of a different amino acid.


different translation from the
A neutral mutation : results in the use of a
different, but chemically similar, amino acid.
Silent mutations : do not result in a change
to the amino acid sequence of a protein,
Different types of SNP



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Outside genes : no impact
In the genes coding sequence :
 change of base but not of amino acid (cf redundancy of
genetic code : GCA et GCC both code for alanine)
 change of amino acid : more or less impressive
modification of function (loss or gain)
In the promoter region :  or  transcription of
the gene and protein expression
In the mRNA 3’-untranslated region :  (or )
sensitivity to miRNA (that inhibit translation and
destabilize mRNA).
SNP and Personalized Medicine:

A particular SNP is more /less frequent in the affected
population
SNP A
SNP B
Investigation of C1236T polymorphism in MDR1 gene in children
with acute lymphoblastic leukemia
F. Mahjoubi et al (AMUJ) 2013; 16(79): 76- 83
SNP and Personalized Medicine:

A particular SNP changes the
affected
response to drug in the
Effect of MDR1 polymorphism on multidrug resistance expression
in breast cancer patients.
Mahjoubi F et al Genet Mol Res. 2010 Jan 12;9(1):34-40
Study of the Possible Correlation between MRP1 Gene Polymorphisms
(C2217T, G2168A,T825C, G816A, G1299, G-260C, A-275G, G2268A) and its
mRNA Expression in Acute Leukemic Patients with MDR Phenotype
Mahjoubi et al SID (2001) Vol (24);1-9
Analysis of VKORC1 and CYP2C9 reveal
variable warfarin dose response
Needs
low-dose
Needs
high-dose
Variants at these
two genes account
for ~60% of
variability in
therapeutic dose
Prospective trials
now underway
FDA has added
information about
genetics to label
Slow P450
metabolizers
Rieder, M. et al. NEJM 352: 2285-2293, 2005
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CYP2C19*2 Polymorphism is Associated 
with Increased Survival in Breast Cancer
Patients Using Tamoxifen
Rikje Pharmacogenomics. 2010;11(10):1367- 
1375
Definition (con)
Epigenetics:
Changes in gene expression (active versus
inactive genes) that does not involve
changes to the underlying DNA sequence
Epigenetic can make a gene
on ( eg oncogene) or off
( eg tumor-supressor gene)
Gene expression
Gene Expression: Gene product.
Gene Expression up/ down : cancer / changes in survival/ changes in response
Personalized medicine
Hippocrates:
it is far more important to
know what person the disease
has than what disease the
person has
National Institutes of Health (NIH), personalized medicine is "an
emerging practice of medicine that uses an
individual's
genetic profile to guide decisions made in
regard to the prevention, diagnosis, and
treatment of disease".
FDA "the best medical outcomes by choosing treatments that
work well with a person's genomic profile or
with certain characteristics in the person's
blood proteins or cell surface proteins".
Personalized medicine does not literally mean individuality.
“
"Medicine
Tailored Just for You."
Personalized medicine is "the ability to classify individuals into
subpopulations that differ in their susceptibility to a
particular disease or their response to a specific
treatment"
Biomarkers
Surgeons /Clinicians
Pathologists
Oncologist
Biomarkers
• Molecules or genes found in the body that can
provide important information about a disease
• FDA definition
• A characteristic that is measured as an
indicator of normal biology or disease or drug
response
Types of Biomarkers
Biomarkers for:
 Screening
 Diagnostic/early detection
 Staging
 Prognosis
 Predication of response to therapy
 Susceptibility to cancer
Personalized medicine
Is it a new era ?!!1
New era of personalized
medicine: targeting drugs for
each unique genetic profile
Imatinib (INN) or Gleevec (is a tyrosine-kinase inhibitor used in
the treatment of multiple cancers, most notably Philadelphia
chromosome-positive (Ph+) chronic myelogenous leukemia
Personalized medicine
New era in personalized medicine:
targeting drugs for each unique
genetic profile
Personalized Medicine
Give cancer patients the treatments that are most
likely to work on their particular cancer with
fewer harmful side effects.
Today, many patients have treatment options based on the
particular markers in their tumors. These patients can get
better, more specific treatments, which might also have fewer side
effects.
Personalized Medicine in Iran
Our goal???
Finding biomarkers suitable for Iranian
population with specificity and sensitivity with
the cost affordable for our nation
(focus on breast cancer & CRC)
Over 50 genes (expression study)
Plz refer to published papers by F.Mahjoubi et al.
Biomarker
discovery
begins by
collecting
molecular data
in in vitro
experiments
and then
patients
Step 1
Data collection
Step 2
Quality control
Step 3
Step 4
Step 5
Identification of
candidate biomarkers
Construction od
prediction model
Independent validation
of prediction
Preventative
 BRCA1 (Breast Cancer 1)
 BRCA2 (Breast Cancer 2)
 TP53 gene
 ATM gene
 etc..
Diagnosis
&
Early
biomarkers
detection
Prognostic biomarkers
Response to therapy
Some Genes Which Have Been Studing
In CRC Cancer By Our Team
M. Golalipour. F. Mahjoubi, * M Sanati, K. Alimogaddam. Gene dosage is not responsible
for the upregulation of MRP1 gene expression in adult leukemia patients. Arc Med Res
(2007). Apr;38(3):297-304

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M. Golalipour. F. Mahjoubi*, M Sanati. RNAi induced inhibition of MRP1 expression and
reversal of drug resistance in human promyelocytic HL60 cell line. Iranian Journal of
Biotechnology (2007). 38(3):297-304
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
Akbari S, Mahjoubi F*, Monatzeri M, Nazari Sh, Elahi, E. Comparison between the 
expression of MRP1 in pediatric leukemic patients with different response to chemotherapy.
J of Genetic Novin (2007) , 2; 67-73
Frouzandeh Mahjoubi*, Masoud Golalipour, Kamran Alimoghaddam. Expression of MRP1
gene in acute leukemias. Sao Paolo Med J (2008) 126 ; 172-179

Frouzandeh Mahjoubi*, Masoud Golalipour, Kamran Alimoghaddam. Expression of
MRP1 gene in acute leukemias. Sao Paolo Med J (2008) 126 ; 172-179
Frouzandeh Mahjoubi*, Soodeh Akbari, Maryam Montazeree, Farzaneh Moshyree.
MRP1 polymorphisms (T2684C, C2007T, C2012T and C2665T) are not associated
with multidrug resistance in leukemic patients. Journal of Medical Research
(2008);7(4):1369-74
Rezvani S, Montazeri M, Mahjoubi F*. Study of the effect the of MRP1 gene
polymorphisms on its mRNA expression in acute leukemic patients. Journal of
Zystshenasy (2001) Vol (24);1-9
M Tahery, F. Mahjoubi*, R Omranipour, F Feraidony. Investigation of MDR1
C3435T polymorphism in Patients with breast cancer. Tabeeb Sharg (2009) Vol 11
;9-17
Taheri M, Mahjoubi F*, Omranipour R. The effect of MDR1 
polymorphism on its expression in Breast Cancer Patients. Journal of
Medical Research. Genet Mol Res. (2010 ) 12;9(1):34-40
Sara Samanian, Bahar Mahjoubi, Frouzandeh Mahjoubi*, Rezvan Mirzaee,
Rasool Azizi. Association between MDR1 and MRP1 expression levels and
clinicopathology markers in colorectal patients. Zahedan Journal of Medical
Research,(2012) 15 (7):31-34
S. Samanian, F. Mahjoubi. Genotype and allele frequencies of MDR1
gene C3435T and C1236T polymorphisms in an Iranian population.
Journal of Genetic Novin (2012) 3:221-226


Mahjoubi F, Akbari S. Multidrug resistance-associated protein 1 predicts relapse in
Iranian childhood acute lymphoblastic leukemia.Asian Pac J Cancer Prev.
(2012);13(5):2285-9
Mohsen Taheri, Frouzandeh Mahjoubi.MRP1 but not MDR1 is associated with response to
neoadjuvant chemotherapy in breast cancer patients. Journal of Disease Marker (2013) 34 : 387–
393
M Mirakhorli, Sabariah Abdulrahman * Syahrilnizam Abdullah, Masoud Vakili, Ahad
Khoshzaban, Frouzandeh Mahjoubi. Multidrug resistance protein genetic polymorphism
colorectal cancer recurrence in patients receiving adjuvant FOLFOX-4 chemotherapy. Molecular
Medicine Reports (2013) 7: 613-617
Ramyar Molania, Frouzandeh Mahjoubi*,Rezvan Mirzaei, Saeed-Reza khatami, Bahar
Mahjoubi. A panel of cancer testis antigens (CTA) and clinical risk factors to predict metastasis
in colorectal cancer. Journal of Biomarkers (2014) 1 : 1-
N Mokhberian N, F Mahjoubi, R Pourahmad . Investigation of G2677T/A polymorphism in
MDR1 gene of childhood acute lymphoblastic leukemia Sci J Iran Blood Transfus Organ
(2014) 11(2): 103-109
Samira Shabani, Frouzandeh Mahjoubi, Bahar Mahjoubi, Rezvan Mirzaee. Investigation of
hTERT expression level and its relation with clinicopathological features and resistance to
chemotherapy in colorectal cancer patients. Journal of Pharmaceutical Sciences (2014)
Samira shabani, Sara Samanian, Rezvan Mirzaei, Bahar Mahjoubi, Frouzandeh Mahjoubi.
Correlation among MDR1, MRP and hTERT Genes Expression Level and Clinical Response
in Colorectal Cancer Patients. J Mol Biomark Diagn 2014, 3-:5
Personalized medicine
2016US budget:
$215 million
For NIH
Thank You
prognostic" and "predictive



A prognostic biomarker is related with a patient's clinical
outcome
A predictive biomarker is related to the patient's response
to a particular intervention.
In other words, a predictive biomarker enables screening of a
subset of patients that are responsive to a specific therapy
Preventative
 BRCA1 (Breast Cancer 1)
 BRCA2 (Breast Cancer 2)
 TP53 gene
 ATM gene
 etc..
Predictive

Genetically defined subgroups of patients

Oncotype DX® who would benefit from a
specific therapy
Prognosis
median survival: 4 yrs with conventional therapy (hydroxyurea,
busulfan), 6 yrs with aIFN therapy; allogeneic bone marrow
transplantation may cure the patient; otherwise, the best treatment
to date associates interferon a, hydroxyurea and cytarabine
prognostic" and "predictive
A prognostic biomarker is related with a patient's clinical outcome

.
In other words, a predictive biomarker enables 
screening of a subset of patients that are
responsive to a specific therapy
A predictive biomarker is related to the patient's response to a particular intervention

Adjuvant systemic treatment
Nodal status [ 
Tumor size 
Tumor type/grade 
Lymphatic and vascular invasion
Tumor hormone receptor 
(HER2)/neu status 
Age 
ethnicity [29-31]. 

Numerous proteins and genes exist that are 
specifically associated with breast cancer
growth, proliferation, and metastasis.
Preventative
 BRCA1 (Breast Cancer 1)
 BRCA2 (Breast Cancer 2)
 TP53 gene
 ATM gene
 Pte..
Predictive
Genetically defined subgroups of patients

Oncotype DX® who would benefit from a 
specific therapy
Participatory
patients will be more likely and willing to 
comply with their treatments.
‫‪ ‬خودت این اسالید را درست کن و‬
‫‪ ‬نشان بده که ما در مرحله‪ 3‬هستیم‬
“A surgeon who uses the wrong side of the
scalpel cuts her own fingers and not the
patient;
if the same applied to drugs they would have
been investigated very carefully a long time
ago”
Personalized Medicines Are Benefitting Patients Across Many Different
Diseases
Oncology is on the Leading Edge of Personalized Medicine
Iran
Age-standardized incidence rate of all cancers per 100 000 in male in Iran 2005–2006.
S. M. Mousavi et al. Ann Oncol 2008;20:556-563
© The Author 2008. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. All rights reserved. For permissions, please email:
[email protected]
Age-standardized incidence rate of all cancers per 100 000 in female in Iran 2005–2006.
S. M. Mousavi et al. Ann Oncol 2008;20:556-563
© The Author 2008. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. All rights reserved. For permissions, please email:
[email protected]
The age-standardized incidence rate of cancer per 100 000 population in female and male in 2003–2006.
S. M. Mousavi et al. Ann Oncol 2008;20:556-563
© The Author 2008. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. All rights reserved. For permissions, please email:
[email protected]
Pharmacogenomic examples-2011
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bcr/abl or 9:22 translocation—imatinib mesylate*
HER2-neu—trastuzumab**
C-kit mutations—imatinib mesylate**
Epidermal growth factor receptor mutations—gefitinib
Thiopurine S-methyltransferase—mercaptopurine and azathioprine*
UGT1A1-irinotecan**
CYP2D9/VKORC1-warfarin*
HLA-B*5701-abacavir *
HLA-B*1502-carbamazepine *
CYP2C19-clopidogrel
Cytochrome P-450 (CYP) 2D6—5-HT3 receptor antagonists,
antidepressants, ADHD drugs, and codeine derivatives, tamoxifen*