Syrian Arab Republic

Ministry of Higher Education and

Scientific Research
Al-Sham Private University
Faculty of Pharmacy

PERSONALISED MEDICINE

By

Leen Al-Ayoubi
Lara Kamal
Layal Alsaleh

Supervised By

DR.NADWA HAMADEH

SEP 2021
 ‫كلمة شكر‪:‬‬
‫بعض المناصب ترفع من شأن أصحابها و بعض األشخاص يزيدون من أهمية تلك المناصب بوجودهم‬
‫بها‪.‬‬
‫إلى رئيس جامعة الشام الخاصة ‪ :‬األستاذ الدكتور شريف األشقر‬

‫إلى من نهلنا من علومه و أفكاره فكانت نبعا ال ينضب من العطاء‪.‬‬

‫إلى العميدة أ‪.‬د‪.‬فايزة القبيلي‬

‫إلى من قدموا لنا المساعدات و المعلومات و غمرونا بلطف عطائهم‪.‬‬

‫أ‪.‬د‪.‬أنطون اللحام‬ ‫د‪.‬مزنى الخاني‬

‫عندما فكرنا ماذا يمكن أن نقول في نهاية مشوارنا الدراسي هذا ألساتذتنا‪.....‬لكل من تعب و‬
‫أعطانا من وقته و جهده الكثير‪......‬إحترنا‪.......‬لكن لم نجد سوى كلمة شكرا من القلب‪......‬لعلها‬
‫تكفي؟؟؟‪...‬‬
‫و نخص بالشكر و العرفان‪:‬‬

‫األستاذة الدكتورة المشرفة‪:‬‬

‫ندوه حماده‬
‫التي تفضلت باإلشراف على مشروعنا هذا‬

‫‪II‬‬
:CONTENTS
1 INTRODUCTION:..........................................................................................................................1

1.1 DEFINITION...................................................................................................................................1
1.2 HISTORY AND LANDSCAPE...........................................................................................................1
1.3 BACKGROUND:............................................................................................................................2

2 METHOD........................................................................................................................................3

3 DELIVERING PERSONALISED MEDICINE.............................................................................3

4 PERSONALISED MEDICINE RESPONSIBILITIES:.................................................................3

4.1 SHIFT THE EMPHASIS IN MEDICINE FROM REACTION TO PREVENTION:........................................4

4.2 DIRECT THE SELECTION OF OPTIMAL THERAPY AND REDUCE TRIAL-AND-ERROR PRESCRIBING: 5
4.3 HELP AVOID ADVERSE DRUG REACTIONS:...................................................................................7
4.4 INCREASE PATIENT ADHERENCE TO TREATMENT:.......................................................................9
4.5 IMPROVE QUALITY OF LIFE:........................................................................................................9
4.6 REVEAL ADDITIONAL OR ALTERNATIVE USES FOR MEDICINES AND DRUG CANDIDATES:.............9
4.7 HELP CONTROL THE OVERALL COST OF HEALTH CARE:............................................................10

5 APPLICATIONS:.........................................................................................................................11

5.1 DIAGNOSIS:..................................................................................................................................11
5.2 THERAPY:..................................................................................................................................11
5.2.1 CANCER THERAPY:.......................................................................................................................11
5.2.2 EXAMPLE OF PERSONAL CANCER THERAPY:...............................................................................13
5.2.2.1 Breast and ovarian cancer:......................................................................................................13
5.2.2.2 Lung cancer:.............................................................................................................................16
5.2.2.2.1 Prostate cancer:......................................................................................................................17
5.2.2.2.2 Lymphoma and Leukemia:.....................................................................................................18
5.2.3 DIABETES THERAPY:.....................................................................................................................20
5.2.3.1 Applications of Personalised Medicine for Diabetes:.............................................................21
5.2.3.1.1 Prevention:.............................................................................................................................21
5.2.3.1.2 Diagnosis:...............................................................................................................................21
5.2.3.1.3 Treatment:.............................................................................................................................22
5.2.3.1.4 Monitoring:............................................................................................................................23

III
5.2.4 CARDIOVASCULAR DISEASE:........................................................................................................24

6 PRECISION VERSUS PERSONALIZED MEDICINE:..............................................................26

7 FUTURE CONSIDERATIONS....................................................................................................27

8 CHALLENGES IN PRECISION MEDICINE:............................................................................28

9 REFERENCES:..................................................................................................................................32

IV
LISIT OF FIGURES
FIGURE.1 THAT PRESENTS PERSONLISED 1
MEDICINE DEFINITION AND
RESPONSIBILITIES

FIGURE.2 THAT PRESENTS THE PERCENTAGE 6

OF THE PATIENT POPULATION FOR WHICH A
PARTICULAR DRUG IN A CLASS IS
INEFFECTIVE
FIGURE.3 12
THAT PRESENT HOW THE PERSONLISED
MEDICINE CAN HELP CANCER PATIENTS TO
FIND THE THERAPY BY ANALYZING AND
MODELING PEOPLE GENES TO CHOOSE THE
BEST MEDICINE FOR EACH ONE

FIGURE.4 25
THAT PRESENTS A PRECISION MEDICINE
APPROACH TO PHENOTYPING
FIGURE.5 29
THAT PRESENTS THE CHALLENGES OF
PERSONLISED MEDICINE

V
PM PERSONLISED MEDICINE
GWAS GENOME-WIDE ASSOCIATION STUDY
ATMPs ADVANCED THERABY MEDICINAL PRODUCT
CAR CHIMERIC ANTIGEN
NTRK NEUROTROPHIC TROPOMYOSIN-RELATED KINASE
ADRs ADVERS DRUG REACTIONS
HIV HUMAN IMMUNODEFICIENCY VIRUS
IL28B INTERFERON LAMDA 28 B
ALK ANAPLASTIC LYMPHOMA KINASE
NSCLC NON SMALL CELLS LUNG CANCER
SCLC SMALL CELLS LUNG CANCER
EGFR ESTIMATED GLOMERULAR FILTRATION RATE
MET METABOLIC EQUIVALENT OF TASK
CBL CASE BASED LEARNING
SNPs SINGLE NUCLEOTIDE POLYMORPHISM
PSA PROSTATE-SPECIFIC ANTIGEN
PML-RARA PROMYELOCYTIC LEUKEMIA/RETINOIC ACID RECEPTOR ALPHA
LADA LATENT AUTOIMMUNE DIABETES IN ADULTS
MODY MATURITY-ONSET DIABETES OF THE YOUNG
LQTS LONG QT SYNDROME
IT INFORMATION TECHNOLOGY
Abbreviation

VI
LIST OF TABLES
TABLE .1 SPECIFIC ISSUES IN 19
PERSONALIZED MEDICINE AND CANCER
TABLE.2 Applications of Personalised 21
Medicine for Diabetes

VII
 Abstract:
Researchers have discovered hundreds of genes that harbor variations
contributing to human illness, identified genetic variability in patients’
responses to different of treatments, and from there begun to target the
genes as molecular causes of diseases. In addition, scientists are
developing and using diagnostic tests based on genetics or other
molecular mechanisms to better predict patients’ responses to targeted
therapy.
And personalised medicine seeks to use advances in knowledge about
genetic factors and biological mechanisms of disease coupled with
unique considerations of an individual’s patient care needs to make
healthcare more safe and effective. As a result of these contributions to
improvement in the quality of care, personalised medicine represents a
key strategy of healthcare reform.

VIII
 ‫‪:‬الخالصة‬

‫اكتشف الباحثون مئات الجينات التي تحتوي على اختالفات‬

‫تساهم في‬
‫اإلصابة باألمراض البشرية‪ ،‬وحددوا التباين الجيني في‬
‫استجابات المرضى للعالجات المختلفة‪ ،‬ومن هناك بدأوا‬
‫في استهداف الجينات كأسباب جزيئية لألمراض‪ .‬باإلضافة‬
‫إلى ذلك ‪ ،‬يعمل العلماء على تطوير واستخدام االختبارات‬
‫التشخيصية القائمة على الجينات أو اآلليات الجزيئية‬
‫األخرى للتنبؤ بشكل أفضل باستجابات المرضى للعالج‬
‫‪.‬الموجه‬
‫ويسعى الطب المخصص إلى استخدام التطورات في‬
‫المعرفة حول العوامل الوراثية واآلليات البيولوجية للمرض‬
‫إلى جانب اعتبارات فريدة الحتياجات رعاية المريض‬
‫الفردية لجعل الرعاية الصحية أكثر أمانًا وفعالية‪ .‬نتيجة‬
‫لهذه المساهمات في تحسين جودة الرعاية‪ ،‬يمثل الطب‬
‫الشخصي استراتيجية رئيسية إلصالح الرعاية الصحية‬

‫‪IX‬‬
X
1 Introduction:
1.1 Definition
Personalised medicine or precision medicine, is a
medical model that separates people into different
groups—with medical decisions, practices,
interventions and/or drugs being tailored to the
individual patient based on their predicted response or
danger of disease as it is shown in figure.1 [1]
1.2 History and landscape
For more than two thousand years, medicine has not
wavered from its aspiration of being personalised. In
ancient times, Hippocrates combined an assessment of
the four humors: blood, phlegm, yellow bile, and
black bile to determine the best course of treatment for
each patient.
Nowadays, the sequence of the four chemical
building blocks that comprise DNA, coupled with
telltale proteins in the blood, enable more accurate
medical predictions.
These include whether an individual is developing an
illness now or will develop it many years later, will
respond positively to treatment, or will suffer a serious
reaction to a drug. But what is different about
medicine today, and the reason the word
“personalised” has been added for emphasis, is that
technology has brought us much closer to exquisite
precision in disease diagnosis and treatment.

Figure.1 that presents personlised medicine definition and responsibilities[128

1
Afterward, over the past six decades, much evidence has emerged indicating that a
substantial portion of variability in drug response is genetically determined, with
age, nutrition, health status, environmental exposure, epigenetic factors, and
concurrent therapy playing important contributory roles. Achievement of
individual drug therapy with a reasonably predictive

outcome, one must further account for different patterns of drug response among
geographically and ethnically distinct populations.

These observations of highly variable drug response, which began in the early
1950s, led to the birth of a new scientific discipline arising from the confluence of
genetics, biochemistry, and pharmacology known as pharmacogenetics.
Advances in molecular medicine have breeded the newer field of
pharmacogenomics, which seeks further understanding all of the molecular
underpinnings of drug response.
Commercialization of this research application is now known as personalised
medicine (PM).
Demonstrated success is emerging for several conditions and treatments, but
whether PM will achieve widespread benefits for all remedies as yet not realized.
1.3 Background:
Disease risk assessment:
Multiple genes collectively influence the likelihood of developing many common
and complex diseases.
Personalised medicine can also be used to predict a person's risk for a particular
disease, based on one or even several genes.
This approach uses the same sequencing technology to focus on the evaluation of
disease risk, allowing the physician to initiate preventive treatment before the
disease presents itself in their patient.
For example, if it is found that a DNA mutation increases a person's risk of
developing Type 2 Diabetes, this individual can begin lifestyle changes that will
lessen their chances of developing Type 2 Diabetes later in life [2]
2 Method
In order for physicians to know if a mutation is connected to a certain disease,
researchers often do a study called a “genome-wide association study” (GWAS).
A GWAS study will look at one disease, and then sequence the genome of many
patients with that particular disease to look for shared mutations in the genome. [3]

3 Delivering personalised medicine

Personalised medicine may include treatments that fall into the following
categories:
• Gene therapies and advanced therapeutic medicinal products (ATMPs), eg CAR-
T therapy
•Targeted treatment where access is based on a genomic test result, eg targeted
Chemotherapy
• Histology-independent or tumour-agnostic products, a new class of cancer
therapies for tumours that express a genomic alteration, regardless of where in the
body the cancer originated, eg. neurotrophic tropomyosin-related kinase (NTRK)
inhibitors
• pharmacogenomic test guided therapy, eg abacavir

3
4 personalised medicine responsibilities:
Advances in personalised medicine will create a more unified treatment approach
specific to the individual and their genome.
Personalised medicine may provide better diagnoses with earlier intervention, and
more efficient drug development and more targeted therapies.
Personalised medicine can:
• Shift the emphasis in medicine from reaction to prevention
• Direct the selection of optimal therapy and reduce trial-and-error prescribing
• Help avoid adverse drug reactions
• Increase patient adherence to treatment
• Improve quality of life
• Reveal additional or alternative uses for medicines and drug candidates
• Help control the overall cost of health care [4]

4.1 Shift the emphasis in medicine from reaction to prevention:

Personalised medicine introduces the ability to use molecular markers that signal
disease risk or presence before clinical signs and symptoms appear, and it offers
the opportunity to focus on prevention and early intervention rather than on
reaction at advanced stages of disease.
In many areas, the clinical interventions can be life-saving.
For example, women with certain BRCA1 or BRCA2 gene variations have up to
an 85 percent lifetime chance of developing breast cancer, compared with a 13
percent chance among the general female population. [5] [6]

4
4.2 Direct the selection of optimal therapy and reduce trial-and-error
prescribing:

Reduce trial-and-error prescribing by directing the selection of appropriate

therapy.
Many individuals may not respond well to the initial medicine prescribed for
them.
For example, 38% of patients with depression, 50% of arthritis patients, 40% of
asthma patients, and 43% of diabetes patients will not react to early treatment.
As it is shown in Figure.2 [7]
Different genes that code for drug-metabolizing enzymes, drug transporters, or
pharmacological targets have been associated to variances in response in
studies. [8]
The enzymes that metabolize half of the most regularly given drugs contain at
least one DNA-based variant in the majority of people the use of genetic and
other forms of molecular screening allows the physician to select an optimal
therapy the first time, thus avoiding the frustrating and costly practice of trial-
and error prescribing [9]

5
 Figure.2 that presents the percentage of the patient population for which a
particular drug in a class is ineffective [129]

Outside oncology, (clopidogrel), antiplatelet aggregation drug designed to

prevent blood clots, presents another case for using genetic testing to select the
best course of treatment and it can have a different impact on protecting stent
patients from thrombosis depending on patients’ genetic variance within
CYP2C19, which encodes an enzyme that converts the drug from an inactive to
an active state. About 25 to 30 percent of stent patients have a three-fold risk of
stent thrombosis when using it in comparison to other patients.[10]
An inexpensive genetic test can reveal the risk and allow physicians to craft an
alternative course of treatment, such as the administration of the drug
(prasugrel), is an another anti platelet drug which helps prevent stroke or blood
clots in patients who have undergone cardiac surgery, have had a heart attack, or
have an implanted stent.
But clopidogrel is just one example outside of oncology.
Complex individualized diagnostic tests are being used in the field of
transplantations and cardiovascular disease—AlloMap) non-invasive blood test(
6
 is an 11-gene blood RNA signature for monitoring rejection after cardiac
transplant and Corus CAD is a 23-gene blood RNA signature used to screen for
obstructive coronary artery disease. [11]
In 2014, a dental insurance company introduced risk-based dental preventive
care that incorporates a reimbursed IL-1 genetic test (PerioPredict) plus two other
risk factors to guide the frequency of care to prevent periodontitis, one of the most
common chronic inflammatory diseases.[12]
Many more treatments that use molecular markers to aid in clinical decision-
making care in development.
A 2010 [12] survey found that at least 50 percent of clinical trials are collecting
DNA from study participants to aid in the discovery of drug-related safety and
efficacy biomarkers, and 30 percent of the companies surveyed require all
compounds in development to have a biomarker (a biological molecule found in
blood, other body fluids, or tissues that is a sign of a normal or abnormal
process, or of a condition or disease). [12]
4.3 Help avoid adverse drug reactions:
The life sciences community strives to improve the safety and efficacy of its
products, however, much more work remains to be done.
Progress in developing and adopting diagnostics to identify which medicines
work best for which patients, thus reducing adverse events, has been slow.
In fact, between 2000 and 2011, the number of adverse events recorded by the
FDA nearly tripled.
According to several studies, about 5.3 percent of all hospital admissions are
associated with adverse drug reactions (ADRs). [13]
Many ADRs result from variations in genes that code for drug-metabolizing
enzymes, such as cytochrome P450 (CYP450). [14]
These variants cause drugs to be metabolized either faster or slower than
normal. As a result, some individuals have trouble inactivating a drug and
eliminating it from their bodies, leading to “overdose toxicity;” others eliminate
the drug too rapidly before it has had a chance to work.
If these genetic variations are not considered when dosing, the consequences
can range from unpleasant to fatal.

7
Panel-based tests that can detect dozens of variations in CYP450 genes are
available at several laboratories.
These genes, linked to the metabolism of about 25 percent of all drugs
prescribed, can improve care for large population segments. [15]
Follow-on multiplex assays—tests that are especially useful for comprehensive
polypharmacy management and prevalent in the elderly and seriously ill—also
are available.
Administration of the drug warfarin, used to prevent blood clots, is complicated
by genetic variations in a drug-metabolizing enzyme (CYP2C9) and an enzyme
that activates vitamin K .
Dosing is typically adjusted for the individual patient through multiple rounds of
trial-and-error, during which the patient may be at risk of excessive bleeding or
further blood clots. The FDA now recommends genotyping for all patients
before warfarin treatment, which allows for more precise dosing. Although the
data are still evolving, early evidence suggests that this helps patients avoid
serious and possibly fatal adverse effects. [16]
Infectious disease has seen advances in personalised treatments.
About five to eight percent of HIV patients treated with (abacavir) can
experience multi-organ system hypersensitivity to the drug, which in some cases
can be fatal. This adverse reaction is strongly associated with the HLA-B*5701
gene, easily identified through genetic testing.
Nearly all patients receiving the drug are tested for the gene, significantly
improving the safety of its administration. And in chronic hepatitis C infection,
the IL28B genotype test for response to pegylated interferon/ribavirin therapy
has seen widespread adoption. [17]
The use of genetic markers to facilitate safer and more effective drug dosing and
selection takes on added significance at the population level. For example,
adverse reactions to the HIV drugs eg: (efavirenz) can occur at standard dosing
due to the presence of the CYP2B6*6 allele. This results in slower metabolism
of the drug and is found significantly more often in African- than in European-
based populations. [18]
Lowering the drug dose in individuals with this allele can help reduce adverse
effects and increase treatment compliance.
8
4.4 Increase patient adherence to treatment:
Noncompliance with therapy by patients has negative health consequences and
raises overall health-care expenses.
Patients may be more likely to stick to their treatment plan if tailored medicines
are more successful or have fewer adverse effects The biggest impact could be in
the treatment of chronic diseases like asthma and diabetes, where non-
compliance frequently worsens the condition. Inherited forms of
hypercholesterolemia (high cholesterol), for example, can raise the risk of
myocardial infarction by more than 50 times in males and 125 times in women
before the age of 40.
Patients who are aware of a genetic tendency to hypercholesterolemia are more
motivated to undertake lifestyle adjustments and control their illness. After two
years, patients with a genetic diagnosis adhered to their treatment program at a
rate of more than 86 percent, compared to 38 percent before testing [19]
4.5 Improve quality of life:
In cardio vascular disease invasive and unpleasant tissue biopsies could be
replaced by a molecular diagnostic test that just takes a blood sample ( Allomap)
a multi-gene expression test, determines whether a heart transplant recipient's
immune system is rejecting the new organ.
Around 25% of heart transplant recipients will undergo rejection, which can be
deadly.
Endomyocardial biopsies are performed as frequently as once a week following
the transplant to monitor for rejection, and then every few months for several
years after that. A tube is inserted into a vein in the neck and threaded to the
heart to get the biopsy in this invasive operation
According to a recent study, individuals who are followed for rejection using
Allomap and those who have endomyocardial biopsies, which are considered
medically required by some major health insurance carriers, may have similar
outcomes [20]
4.6 Reveal additional or alternative uses for medicines and drug candidates:
A medicine that may show weaker efficacy in a more generalized patient
population may show greater benefits when its use is limited to genetically
defined patient populations.

9
 The lung cancer drug (gefitinib) did not demonstrate a survival advantage in a
general population of patients in clinical trials, and was withdrawn from the
market after initially being granted accel- erated approval.
However, the sponsoring company has been using pharmacogenetics to
demonstrate benefit in about 10 percent of patients who test positive for
epidermal growth factor mutations, and it has won approval as a first-line
treatment for that patient population in the United Kingdom. [21]
4.7 Help control the overall cost of health care:
Help control the overall cost of health care because Health care today is in crisis
as it is expensive, reactive, inefficient, and focused largely on one-size-fits-all
treatments for events of late stage disease.
Personalized medical care has the potential to reduce health care costs
worldwide, an effect particularly marked to the United States, where the cost of
health care is on an unsustainable upward climb.
Incorporating personalized medicine into the fabric of the health care system
can help resolve many embedded inefficiencies, such as trial-and-error dosing,
hospitalizations due to adverse drug reactions, late diagnoses, and reactive
treatment.
As such, it can also play an important role in the implementa- tion of
Accountable Care Organizations to coordinate patient care and reduce costs.
Research demonstrated that genetic testing to target dosing of the blood thinner
drug warfarin resulted in percent fewer hospitalizations overall for patients and
up to 48 percent fewer hospitalizations for bleeding or thromboembolism. [22]
Hospitalization rates for heart patients were reduced by about 30 percent when
genetic information was available to doctors prescribing the drug. [23]
An economic analysis of the Oncotype test looked at the real costs of treating
women with breast cancer in a health plan with two million members. [24]

10
5 Applications:
5.1 diagnosis:
There are almost 15,000 tests available for over 2,800 genes. These tests can detect
genetic susceptibility to a variety of illnesses, including hearing loss and sudden
cardiac arrest. [25]
Some tests has predictive power, which means they can detect disease before
symptoms arise. Although not every test leads to a treatment choice, a genetic
diagnosis frequently does.
It can also help to eliminate the need for more expensive and/or time-consuming
procedures.
Diagnostic testing that is intrusive To avoid the danger of premature mortality, a
patient who finds he or she has hereditary cardiomyopathy, for example, can
benefit from advised lifestyle changes and disease-monitoring choices to avoid the
risk of sudden death [26]
5.2 therapy:
An aspect of this is pharmacogenomics, which uses an individual's genome to
provide a more informed and tailored drug prescription like cancer therapy as it is
shown in figure.3 . [27]
Often, drugs are prescribed with the idea that it will work relatively the same for
everyone, but in the application of drugs, there are a number of factors that must be
considered.
The detailed account of genetic information from the individual will help prevent
adverse events, allow for appropriate dosages, and create maximum efficacy with
drug prescriptions. [28]
Example physicians can use patients’ gene profile to prescribe optimum doses of
warfarin to prevent side effects such as major bleeding and to allow sooner and
better therapeutic efficacy. [29]

5.2.1 Cancer therapy:

Cancer genetics is a specialized field of medical genetics that is concerned with
hereditary cancer risk.

11
 Currently, there are a small number of cancer predisposition syndromes in which
an allele segregates in an autosomal dominant fashion, leading to significantly
elevated risk for certain cancers.
It is estimated that familial cancer accounts for about 5-10% of all cancers.
However, other genetic variants with more subtle effects on individual cancer risk
may enable more precise cancer risk assessment in individuals without a strong
family history [30]

Figure.3 [130]
that present how the personlised medicine can help cancer patients to find the
therapy by analyzing and modeling people genes to choose the best medicine
for each one

12
5.2.2 Example of personal cancer therapy:

5.2.2.1 Breast and ovarian cancer:

One of the most common applications of this practice has been for women with
breast cancer. About 30 percent of breast cancer cases are characterized by
overexpressionof a cell surface protein called human epidermal growth factor
receptor 2 (HER2).
For women with this form of the disease an antibody drug: (trastuzumab) can
reduce the recurrence of a tumor by 52 percent when used in combination with
chemotherapy, in comparison to chemotherapy alone. [31]
Molecular diagnostic tests for HER2 are used to identify the patients who will
benefit from receiving trastuzumab and other drugs that target HER2, such as
(lapatinib).
Two complex diagnostic tests, Oncotype and MammaPrint, for example, use
genetic information to help physicians chart the best course of treatment for breast
cancer patients.
Oncotype DX can determine whether women with certain types of breast cancer
are likely to benefit from chemotherapy. [32]
MammaPrint can detect which early-stage breast cancer patients are at risk of
distant recurrence following surgery.
Both tests place patients into risk categories that inform physicians and patients of
whether the cancer may be treated successfully with hormone therapy alone,
avoiding the expense and toxic effects of chemotherapy, or whether a more
aggressive treatment is needed.
OVA1, another example of a new diagnostic that can inform the right treatment, is
a five-protein test that can assess whether a woman’s ovarian mass is malignant
and requires surgery. [33]
A growing number of drugs are now available to treat colon cancer, and a genetic
test can be used to evaluate which drugs may be the best (or worst) candidates. For
example, approximately 40 percent of patients with metastatic colon cancer are
unlikely to respond to (cetuximab) and (panitumumab) because their tumors have
a mutated form of the KRAS gene. [34]

13
 Current practice guidelines recommend that only patients with the normal (wild-
type) form of the KRAS gene should be treated with these drugs in conjunction
with chemotherapy. [35]
Meanwhile, targeted therapies paired with genetic tests are giving fresh hope to
late-stage cancer patients and their families.
Approved in August 2011, (vemurafenib) treats melanoma that cannot be
surgically removed in patients who have the BRAF V600E gene mutation.
(crizotinib), indicated for the treatment of non-small cell lung cancer, is only
effectivefor patients who express the abnormal anaplastic lymphoma kinase (ALK)
gene. Both BRAF and ALK mutations can be detected by commercially available
tests, as well as by laboratory-developed tests.
In April 2014, the FDA approved (ceritinib) for the treatment of patients with
ALK+ metastatic non-small cell lung cancer who have progressed on or are
intolerant to crizotinib.
Interestingly, genome sequencing of tumors has identified the existence of
identical mutations in different cancer types; the FDA has expanded the indication
for these already-approved drugs.
BRAF V600 mutations are common in melanoma and also have been widely
observed in other cancers, especially hairy cell leukemia, leading to the expanded
use of and the production of more clinical studies supporting the use of
vemurafenib as an effective treatment option for refractory hairy cell leukemia.
[36],[37],[38]
Similarly, early studies indicate that crizotinib, targeting non–small cell lung
cancers, is effective against other types of tumors containing ALK alterations, such
as aggressive forms of pediatric neuroblastoma and anaplastic large cell
lymphoma. [39]
Genomic analysis of tumors has led to an evolution in the way they are classified
With an increasing body of knowledge about the underlying genomic alterations,
tumor classification is shifting away from tissue of origin and toward molecular
taxonomy, which is having a profound effect on the way that oncology treatment
decisions are made. Sequencing is illuminating the analysis of resistant tumors. For
example, non-small cell lung cancer patients treated with crizotinib often relapse,

14
leading researchers to develop the next generation of ALK inhibitors to overcome
this resistance and use combinations of targeted therapies to fight it. [40]

Testing for disease-causing mutations in the BRCA1 and BRCA2 genes, which are
implicated in familial breast and ovarian cancer syndromes. Discovery of a
disease-causing mutation in a family can inform “at-risk” individuals as to whether
they are at higher risk for cancer and may prompt individualized prophylactic
therapy including mastectomy and removal of the ovaries.
This testing involves complicated personal decisions and is undertaken in the
context of detailed genetic counseling .
More detailed molecular stratification of breast tumors may pave the way for
future tailored treatment [41]

15
5.2.2.2 Lung cancer:
Lung cancer is divided into two types: non-small cell lung cancer (NSCLC) and
small cell lung cancer (SCCLC) (SCLC).
Small cell lung cancer accounts for roughly 20% of all lung cancer cases. Mixed
small cell/large cell cancer is a form of cancer that includes both types. Metastatic
cancer to the lungs occurs when cancer spreads from another part of the body to
the lungs.
Lung cancer is exceedingly tough to cure due to the heterogeneity of cells. Lung
cancer has traditionally been treated using standard therapeutic methods, mostly
surgery and chemotherapy.
EGFR, K-ras, ALK, MET, CBL, and COX2 are being exploited as therapeutic
targets [42],[43].based on recent research and understanding of the genetic basis of
lung cancer.Crizotinib has recently been shown to be effective in the treatment of
NSCLC.
Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has shown to be
effective.
Crizotinib for lung cancer treatment has also been found to be beneficial by other
researchers [44],[45]
Clinical findings for erlotinib and EGFR-mutated lung cancer have also been
promising [46]
FLEX trial has also demonstrated promising results .
Data from histopathological examination and the patient’s history also is
considered in evaluating the state of the disease and its aggressiveness. [47]
studied association between SNPs and acute interstitial lung disease in Japanese
population undergoing treatment with gefitinib.
This research provided basis for further research. In Chinese population, ABCC1
polymorphism was found to be associated with lung cancer susceptibility in
patients undergoing chemotherapy [48] .
Genomic variations in EGFR and ERCC1 have also been correlated with drug
response in small cell lung cancer patients [49]

16
5.2.2.2.1 Prostate cancer:
Prostate cancer is the leading cancer in men and the second leading cause of death
due to cancer.
High rates of this cancer are observed in older people. The main screening
procedures used to detect prostate cancer are the digital rectal exam and prostate
specific antigen (PSA) test.
Because this cancer does not cause pain and takes several years to develop,
physicians and patients are faced with the challenge of identifying optimal
treatment strategies for localized prostate cancer, biochemicallyrecurrent prostate
cancer, and later-stage cancer.
Three treatments are very common: chemotherapy and hormonal therapy, surgery,
and radiation.
Age-related changes, including metastatic disease, may affect all of these therapies
and shift the risk-benefit ratio of these treatments [50]
. New tools, such as the Comprehensive Geriatric Assessment, are being developed
to better predict who will respond to therapy.
Such tools also may help in estimating the remaining life expectancy of a specific
prostate cancer patient. [51]
In another study for the scientist Audet-Walsh in 2011 BCL2 polymorphism was
found to be associated with adverse outcome in prostate carcinoma patients [52]

17
5.2.2.2.2 Lymphoma and Leukemia:
Lymphoma is a cancer in the lymphatic cells of the immune system. It is present as
a solid tumor of lymphoid cells.
Research is being conducted to utilize the clinical characterization of lymphoma
and integration of genomic information to identify patients who will benefit from
the treatment.
Lymphoma comprises mainly Hodgkin lymphoma and non-Hodgkin lymphoma,
although at least 60 subtypes of lymphoma have been reported to date [53]
This cancer originates from lymph nodes but can affect other organs such as the
bowel, bone, brain, and skin. Risk-stratification for all clinically identified
subtypes has not been completed yet.
Approaches for the stratification of lymphoma subtypes include refining clinical
prognostic models for better risk stratification, use of high-throughput technology
to identify biologic subtypes within pathologically similar diseases, “response-
adapted” changes in therapy and anti-idiotype vaccines.
Lymphoma treatment is accomplished by chemotherapy, radiation therapy, and
bone marrow transplantation.
An effective treatment for acute promyelocytic leukemia consists of identifying
and developing the PML-RARA fusion gene and applying all-trans retinoic acid
(ATRA) [54]
This investigation has led to the discovery of the bcr-abl fusion gene in chronic
myelogenous leukemia and development of imatinib [55]
Genetics-based drug therapy does not always work efficiently. Erlotinib and
crizotinib are other genetics-based drugs with minimum efficacy in different
cancers [56].
The mechanism of action of these medications is based on apoptosis.
The reason for developing apoptosis-based therapies is the advantage of killing
cancer cells specifically with low or minimal toxicity.
These drugs were not effective because the differentiation and proliferation
pathways were not affected by these drugs.
In an ideal situation, the drug should inhibit all of these pathways and stop the
signaling steps. To attack the final steps in the apoptosis pathway and achieve
18
better efficacy, human recombinant DNAse I-based drugs are being developed
[57]Polymorphisms in mismatch repair genes influence response to treatment and
survival in large B cell lymphoma [58] identified presence of numerous genetic
variants that may have accounted for subacute methotrexate neurotoxicity in acute
lymphoblastic leukemia.

It is timely and important to ask: Are we at the point of being able to treat each
patient uniquely based on the complete DNA structure of their cancer?
The answer is no, we are not there yet. However, the field is evolving, and
personalized medicine has much to offer toward improving cancer treatment for
today and tomorrow.

19
5.2.3 Diabetes therapy:
Not every patient with diabetes with the same age, duration of disease, body
mass index, and Hemoglobin A1c will respond the same way to a given
treatment. Some patients respond to a treatment whereas others do not.
The reason may be a genetic propensity to respond or not respond to a drug.
The physician must assess every patient and then attempt to guess which
treatment will work best.
If the physician could be armed with specific personalized information
about that patient, including information about their genetic makeup, then
treatments could be tailored for each individual patient.
This approach would then lead to better outcomes without wasting time on
ineffective therapy.
Outcome statistics, which indicate that a certain percentage of patients will
respond to a specific treatment, are not always meaningful for a given
individual. For some diseases and treatments if one treatment is used, then
100% will respond and if another treatment is used then 0% will respond and
for other patients a different treatment might be 100% effective.
The problem is that physicians do not know which treatment is likely to be
effective in any given patient, so the treatment that works most often for the
greatest number of patients is usually selected first, even though this
treatment will not be effective for some patients. [59]

The potential benefit of a personalized medicine approach to diabetes is the

possibility of earlier interventions to prevent or treat the disease by using
screening genetic tests. Patients who are at high risk for a chronic disease
such as diabetes usually experience a prolonged asymptomatic period before
the onset of the disease.
Patients who are identified by genetic testing to be at high risk for diabetes
can be directed to preventative measures, such as lifestyle modifications or
medications, in order to delay or prevent the disease. [60]
Genetic tests and biomarkers can be utilized for predicting the diagnosis and
for monitoring the course of diabetes.
Greater efficiency in drug development is possible if genetically [61] or
nutritionally [62] determined drug targets are identified in subpopulations of
patients with diabetes.
Genetically determined polymorphisms of receptors, transporters, and
metabolizing enzymes contribute to variable responses to drugs.

20
 Personalised medicine allows for personalized drug prescribing with less
trial and error and less time wasted with an inadequate response or with side
effects. [63]
The result of such a ersonalized medicine approach would be a better
outcome for the disease being treated, such as diabetes or obesity.
Table 2:
5.2.3.1 Applications of Personalised Medicine for Diabetes:
5.2.3.1.1 Prevention:

 Input:  Response:

1. Genetic studies identifying 1. Immune therapy for preventing

people at high risk for type 1 onset of type 1 diabetes [68]
diabetes [64]

2. Genetic studies identifying 2. Vaccine to prevent type1 [69]

people at high risk for type 2
diabetes [65]

3. Genetic studies identifying 3. Drug therapy to prevent

people at high risk for diabetic nephropathy [70]
nephropathy [66]

4. Genetic studies identifying 4. Lifestyle modification to prevent

people at high risk of obesity type 2 diabetes [71] and drug
[67] therapy to prevent type 2
diabetes—multicenter trials
sponsored by industry [72]

5.2.3.1.2 Diagnosis:
 Input  Response
1. Neuropathy and NH2-terminal 1. Early diagnosis of diabetic
fragment of the brain natriuretic neuropathy—tight control of
peptide [73] DM [74]

21
5.2.3.1.3 Treatment:
 Input:  Response:
1. Genetic studies demonstrating 1. Type 1: Early initiation of early
subgroups within type1 [75] treatment to avoid
complications, such as intensive
insulin therapy, [86] immune
therapy,[87] or gene therapy [88]

2. Abnormal insulin molecule [76] 2. Type 2: Early initiation of

thiazolidinediones [89] or insulin
[90] to preserve islet function
[91]

3. Abnormal release (LADA) [77] 3. LADA: Early initiation of

insulin to maintain euglycemia
in patients with this diagnosis
[92]

4. Clinical classification of new- 4.  Ketosis-prone diabetes therapy

onset, ketosis-prone patients into depends on classification [93]
subgroups [78]

5. Classification of autoimmune 5. MODY—sulfonylurea therapy

diabetes into late-onset type and and focus on specific vascular
type 1 diabetes [79] risks [94]

22
 6. Genetic studies demonstrating
subgroups within type2 [80]
Mechanisms of the cause of type
2 must be understood and
presented [81]
7. Genetic variations in response to
common diabetes drugs, e.g.,
metformin [73] and
sulfonylureas [82]
8. Distinction of MODY from type
2 DM [83]
Genetic studies of neonatal
diabetes [84]
Nutrigenomic studies of food
impact [85]
5.2.3.1.4 Monitoring:
 Input:
1. Type 1: Biomarkers of
autoimmunity—
autoantibodies [98] and
antigens [99] cytokine levels
[100] and inflammatory
serum markers [101]
2. Type 2: Lipids [102] C-
reactive protein: [103]
cytokines [104] retinol-
binding protein [105] and
other inflammatory markers
[106]
23
6. Neonatal diabetes: switch from
insulin to sulfonylureas [95]
7.  Dietary therapy of type 2
diabetes [96]
8. Exercise therapy of type 2
diabetes [97]
 Response:
1. Type 1: Immune intervention
[107] Technology:
continuous glucose
monitoring [108] insulin
pump therapy[109] and
artificial pancreas [110]
2. Type 2: Anti-inflammatory
therapy with
thiazoldinediones or statins
[111] Treatments of elevated
levels of C-reactive protein
[112]
5.2.4 Cardiovascular disease:
LQTS is used for risk prediction, clinically.
LQTS is an autosomal dominant disease, and variation in disease phenotype is
found to be associated with mutations in 12 different LQTS susceptibility genes,
warranting genetically testing of patients for these mutations. [117]
Betablockers are an effective treatment for patients with LQTS1 (KCNQ1), but not
for patients with LQTS2 (KCNH2) or LQTS3 (SCN5A). [118]
Metabolomics and proteomics applied to distinguish between the acute coronary
syndrome state of acute myocardial infarction and unstable angina. [119]
Platelet proteome in patients with and without nonST segment elevation showed
differences in platelet activation, especially, elevated levels of the secreted protein
acidic and rich in cysteine protein. [120]
Corus CAD test severity on based evidence that peripheral blood gene expression
has been associated with CAD severity.
Peripheral blood mononuclear cell gene expression profiling is used to monitor the
status of graft after solid organ transplantation, like cardiac transplantation. [121]
This test is available as AlloMap [122] classified four major pharmacotherapeutic
drugs within vascular medicine;
antiplatelet therapy
antihypertensive therapy
lipid-lowering therapy
and antithrombotic therapy
In fact, warfarin therapy is an important traditional example of pharmacogenomics.
[123]
Warfarin is an anticoagulant widely used to prevent blood clots, which has a
narrow range between efficacy and toxicity, and a large variation in the dose (up to
10-fold) is required to achieve therapeutic anticoagulation.
CYP2C9 is the enzyme responsible for the metabolism of warfarin, [124]
24
 It is complicated by genetic variations in a drug metabolizing enzyme (those
homozygous for the 2 and 3 alleles). [125]
Dosing is typically adjusted for the individual patient through multiple rounds of
trial and error, throughout the first year of treatment, during which time the patient
may be at risk for excessive bleeding or further blood clots.
The need to get warfarin dosing right the first time to avoid adverse effects led the
FDA to recommend genotyping for all patients before receiving treatment with
warfarin. [126]

Figure.4
That presents a precision medicine approach to phenotyping

Individuals may have a similar endophenotype but be biologically distinct and

have different disease profiles. Using a precision medicine approach, individuals
undergo deep phenotyping with data analysis performed using network analysis.
25
This analytical strategy clusters individuals into groups that are different from
those based on endophenotype alone. This methodology can be used to optimize
medication and behavioral changes to improve health, predict and prognosticate
disease, identify biomarkers for disease, enrich clinical trial enrollment, and
optimally tailor exposures.

6 Precision versus personalized medicine:

Although the terms precision medicine and personalized medicine have been used
interchangeably, they are not identical but, rather, related and overlapping
disciplines. Precision medicine identifies the unique aspects of an individual
related to health and disease to select appropriate and effective therapy.
Personalised medicine may refer to implementation of these data into a person-
specific treatment plan or, simply, the creation of a treatment plan for an individual
based on a known biomarker(s).
Personalised medicine is not, however, meant to suggest that results from detailed
phenotyping will be used to create new drug or other therapies.

Precision medicine is increasingly considered as the art and science of creating

individualized assessments of health and disease that are derived from established
clinical and pathological indices integrated with state-of-the-art panomic (i.e.,
genomic, transcriptomic, metabolomic, and proteomic) profiling. [127]
Thus, precision medicine aims to drive the field away from the implementation of
the same pharmacotherapy, lifestyle intervention, or behavioral modification to a
group of individuals presumed to share the same phenotype and towards
personalizing treatments that are aimed at prevention, promotion of health, and
amelioration of disease. While this concept has been embraced with success in the
field of oncology, the issue of patient adherence with a personalized therapy
identified using precision medicine remains a concern [128]

26
 Estimates indicate that approximately half of all medications are not taken as
prescribed and that patients with chronic conditions such as cardiovascular disease
only take 50%–60% of the medications prescribed [129]
. While this is a valid point and developments in precision and personalised
medicine must be matched by patient education and acceptance of these strategies,
it is also plausible that poor adherence rates are the result of imprecise medication
use leading to limited efficacy and/or increased side effect risk in a given
individual. This issue will clearly require further study.

7 Future considerations
Precision medicine is poised to become the next great revolution in the practice of
medicine, as well as in the maintenance of cardiovascular health and the prevention
and cure of cancer, diabetes , cardiovascular disease.
Precision medicine disrupts standard practice and draws from clinical testing,
electronic health records, panomics profiling, big datasets, and novel analytical
methods, such as systems biology and network science, to create a person-specific
phenotype that can then be used to identify an optimal intervention with minimal
risk.
The obvious benefits of this approach to patients, clinicians, and researchers are
numerous and include:
individual phenotype specificity, identification of individuals with a similar
molecular phenotype, selection of best drugs or therapies with maximal efficacy
and no or limited adverse reactions, efficient selection and enrichment of clinical
trial participants, potential to improve adherence and reduce costs, and creating a
paradigm shift in how cardiovascular care is delivered.
To accomplish this laudable goal, the medical community at large and other
stakeholders will need to overcome barriers to implementation that range from
technical to sociopolitical. At the very least, precision medicine will need to
demonstrate that phenotype-based person-specific interventions are superior to the
current standard of care and, ultimately, have a population effect by moving the
mean on the disease spectrum towards health.
Other barriers are related to large dataset collection and focuses on methods to
ensure data accuracy, computational power, security and privacy of datasets,
27
renewal of accruing data, and continuous development and refinement of analytical
methods.
Finally, education, affordability, and public acceptance of the strategy all play key
roles in its ultimate implementation [130]
Despite a clear path forward toward mainstream application of precision medicine,
there continues to be debate about whether a precision medicine approach will
have a global impact on cancer, diabetes, cardiovascular disease prevention and
treatment, or will only serve a small group of patients and be relegated to a highly
selected niche role.
This skepticism has arisen, in part, based on progress in the field to date and
perceived challenges in maintaining the physician-patient relationship [131].
While these concerns are valid points, they are not insurmountable and are
currently being addressed in visions as how best to implement precision medicine
in the practice of cardiovascular medicine.
The nascent field of precision medicine fully embraces Paul Ehrlich’s concept that
imprecision leads to failure, and harnesses our most precise technologies and
methodologies to improve cardiovascular health and treat cancer and diabetes.

8 Challenges in precision medicine:

Precision medicine relies on integration and dynamic adaptability of panomic
analysis, overall data analysis and data management; and acceptance by the public,
medical, research, big pharma, and policy-maker stakeholders. As it is shown in
figure.5

28
 Figure.5
That presents the challenges of personlised medicine

29
 Conclusion:

By decreasing healthcare expenses, medication development costs, and time, PM

has the ability to meet the need to enhance health outcomes.
This healthcare revolution will only be achieved with the equal participation of
patients in clinical trials, as well as the development of smart tools, the analysis of
genetic data by entrepreneurs, innovators and Physicians to comprehend disease at
the molecular level, academic researchers to accompany creative research to
unearth new insights at the molecular foundation of disease and promote target-
based medication development, IT sector to provide novel electronic tools by
investigating new business models, novel diagnostics tools, target therapy, and
other individualized treatment procedures to collect patient information,
stakeholders, payers, and policymakers.
PM has the potential to be beneficial to the healthcare system. The tailored strategy
will be used in the future. Each person will obtain their complete genomic
information on the day of their birth, which will be entered into an individual
medical record.
Doctors would be able to use this information to develop more effective healthcare
strategies based on patient exposure to various diseases.

30
 ‫‪:‬الدواء المشخصن‬
‫هو عبارة عن تصميم دواء مناسب لمواصفات كل مريض على حدة مأخوذا بعين‬
‫‪.‬االعتبار الخصائص الجينية و الجزيئية التي تميز كل شخص عن االخر‬
‫و بهذا يمكننا التنبؤ بالعالج الشخصي األمثل من حيث الفعالية و األمان بعيدا عن‬
‫النهج التقليدي إذ أصبح بإمكان األطباء بواسطة استخدام أدوات أكثر دقة اختيار خطة‬
‫العالج المناسبة مستندين إلى الصفات الجزيئية للمريض بهدف تقليل االثار الجانبية‬
‫‪.‬الخطيرة و ضمان نتيجة أكثر فعالية و أمان‬
‫‪:‬و تندرج استعماالت الطب الشخصي تحت‬
‫تحويل التركيز في الطب من رد الفعل العالجي إلى الوقاية‬ ‫‪‬‬
‫اختيار العالج األمثل و تقليل الخطأ في الوصفات الطبية‬ ‫‪‬‬
‫تجنب التفاعالت الدوائية الضارة‬ ‫‪‬‬
‫زيادة التزام المريض بالعالج‬ ‫‪‬‬
‫تحسين نوعية الحياة‬ ‫‪‬‬
‫الكشف عن االستخدامات اإلضافية أو البديلة لألدوية‬ ‫‪‬‬
‫التحكم بالتكلفة االجمالية للرعاية الصحية‬ ‫‪‬‬
‫تطبيقات الدواء المشخصن‪:‬‬
‫التشخيص‬ ‫‪‬‬
‫العالج‪ :‬عالج السرطان‪ ,‬عالج داء السكري‪ ,‬عالج األمراض القلبية‬ ‫‪‬‬
‫الطب الدقيق مقابل الطب الشخصي‪:‬‬
‫على الرغم من استخدام مصطلحي الطب الدقيق و الطب الشخصي بالتبادل اال‬
‫انهما ليسا متطابقين فالطب الدقيق يحدد الجوانب الفردية لكل فرد على حدة فيما‬
‫يتعلق بالصحة و المرض الختيار العالج المناسب و الفعال‪.‬‬
‫أما الطب الشخصي فيشير إلى تنفيذ هذه البيانات في خطة عالج خاصة بالشخص‬
‫اعتبارات المستقبل‪:‬‬
‫الدواء المشخصن مهيأ ألن يصبح ثورة عظيمة قادمة في ممارسات الطب و كذلك‬
‫في الحفاظ على صحة القلب و األوعية الدموية و الوقاية و العالج من السرطان و‬
‫السكري‪.‬‬
‫يعطل الدواء المشخصن الممارسات المعيارية و يستمد من االختبارات السريرية و‬
‫السجالت الصحية االلكترونية و تنميط البانومكس و مجموعات البيانات الكبيرة و‬
‫الطرق التحليلية الجديدة مثل بيولوجيا األنظمة و علوم الشبكات إلنشاء نمط ظاهري‬
‫‪31‬‬
 ‫خاص بالشخص الستخدامه فيما بعد لتحديد أفضل تدخل مع الحد األدنى من‬
.‫المخاطر‬

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