Systemic Cancer Therapeutics

Assoc prof L. Miron

 The six hallmarks of cancer
Growth signal auttonomy = unlimited cell growth

Reduced sensitivity Insensitivity to

to apoptosis antigrowth signals

Cancer

Development and
maintenance of Invasion and
vasculature metastasis
(angiogenesis)

Limitless replicative potential

Adapted from Hanahan and Weinberg, et al. Cell 2000

1909 Paul Ehrlich's magic bullet concept
Primul razboi mondial – gazele toxice de lupta
Vasul SS John Harvey- 2 decembrie 1943- atacul din portul Bari
 Citotoxic chemotherapy - definitions

 Chemotherapy is the treatment of cancer by chemical agents that kill fast

growing cells.

 The term “chemotherapy” had been loosely applied to the myriad

systemic therapeutic options in cancer treatment exclusive of irradiation
and surgical approaches;
 Chimioterapia citotoxica este dependenta de ciclul
celular

Solit et al, Clin Can Res 2005; Davies A et al. CLC 7 (6): 385-388, 2006; Encyclopedia of Science Cell Biology
http://www.daviddarling.info/encyclopedia/C/cell_cycle.html
 I. Alkilating agents- mechanism of action

 Diverse group of anticancer agents with the commonality that react in a

manner such that an electrophilic alkil group can covalently bind to the
cellular nucleophilic sites.

 Alkylating agents form covalent bounds whith nucleophilic cellular

molecules such as oxigen-, nitrogen-, phosphorus-. or sulfur- ADN
containing sites, through their alkil groups, cross-links two DNA strands
 Cytotoxic chemotherapy- classification

 Alkilating agents
 Antimetabolites
 Natural products:
A. Antitumor antibiotics
B. Topoisomerase inhibitors
C. Mitotic inhibitors (Antimicrotubule agents)
 Slide 2

Presented By Jean-Charles Soria at 2014 ASCO Annual Meeting

 Alkilating agents

 Nitrogen mustards:
 Cyclophosphamide, Ifosfamide, Busulfan, Thiotepa, Chlorambucil
 Nitrosoureeas:
 Carmustine (BCNU) lomustine, streptozocin
Ethyleneimines (Thiotepa)
 Triazenes:
 Dacarbazine (DTIC), temozolamide
 Metal salts:
 Cisplatin ( C-DDP), carboplatin, oxaliplatin
Alkylating Agents
Sulfur –muştarul- Mecloretamnina
Mecanismul de acţiune al alkilanţilor
Ciclofosfamida
Clorambucil (Leukeran)
Levolfalan (Melfalan, L-PAM)
Era of Platinums

(Toulouse)
CISPLATIN
 Platinum compounds

Presented By Jean-Charles Soria at 2014 ASCO Annual Meeting

Sărurile de platină- generaţia II-a: carboplatin
Alkylating Agents: platinum salt
Generatia a III-a: Oxaliplatin
 Alkilating’s acute toxicities

 Nausea and Vomiting

 Bone Marrow Toxicity
 Renal and Bladder Toxicity
 Interstitial Pneumonitis and Pulmonary Fibrosis
 Gonadal Toxicity, Teratogenesis, and Carcinogenesis
 Alopecia
 Allergic Reactions
 Immunosuppression
 Alkilating’s cronic toxicities

 Renal and bladder toxicity

 Interstitial pneumonitis and pulmonary fibrosis
 Gonadal toxicity
 Teratogenesis and carcinogenesis
 Immunosupression
 II. Antimetabolites

Mecanism of action: antimetabolites are structurally similar to natural compunds necessary for cell
division.
 They act as competitive substrates for critical purine or pyrimidine nucleoside synthesis
pathwaays.
 As expected from their mechanism of action through disruption of DNA synthesis,
antimetabolites are most effective against tumors with a high growth fraction, and particular
during S phase.
 II. Antimetabolites- classification
have affinity to enzymes of nuclic acid byosinthesis “false binding
blocks”

A. Folate antagonists: Metotrexat (MTX), Pemetrexed (Alimta®), Ralitrexed,

Edatrexed, Piretexim.
B. Pyrimidine antagonists: 5-Fluorouracil ( 5-FU), Capecitabine (Xeloda®),
Gemcitabine, 6-Mecaptopurine and
Thioguanine, Fludarabine, Cladribine, Pentostatine
C. Purine analogs: Citozinarabinozin, 5-Azacitidine, Cladribine
D. Ureea substitutes: Hidroxiuree
 Antimetabolites

Presented By Jean-Charles Soria at 2014 ASCO Annual Meeting

Methotrexat
 Antimetabolites- folate antagonists

Inhibitory effects of methotrexate (MTX) and pemetrexed. 5-FU, 5-fluorouracil; dTDP,

deoxythymidine diphosphate; dTMP, deoxythymidine monophosphate; dTTP, deoxythymidine
triphosphate; dUMP, deoxyuridine monophosphate; THF, tetrahydrofolate; DHF, dihydrofolate; TK,
thymidine kinase.
Pemetrexed (Alimta)
 ALIMTA (pemetrexed): Multitargeted Antifolate

ALIMTA TS 5-FU, raltitrexed

(pemetrexed) dUMP dTMP DNA

5,10-CH2-THF
10-CHO-THF DHF
NADPH
PRPP GARFT DHFR
Methotrexate
THF NADP+
GAR
fGAR
AMP, GMP DNA, RNA
TS: thymidylate synthase; 5-FU: 5-fluorouracil; GARFT: glycinamide ribonucleotide formyl transferase; DHFR:
dihydrofolate reductase; DNA: deoxyribonucleic acid; RNA: ribonucleic acid

1. Kindler Cancer 2002;95:928-32. 2, Scagliotti et al. Expert Opin Pharmacother 2005;6:2855-66.

33
5-Fluorouracil (5-FU)
 Antimetabolites- Purines analogs: 5-Fluoropyrimidines

Metabolism of 5-fluorouracil (5-FU). DPD, dihydropyrimidine dehydrogenase; FUrd,

5-fluorouridine; FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridine-5′-diphosphate;
FUTP, 5-fluorouridine-5′-triphosphate; FUdR, 5-fluoro-2′-deoxyuridine; FdUMP, 5-Fluoro-2′-
deoxyuridine-5′-O-monophosphate; FdUTP, 5-fluoro-2′-deoxyuridine-5′-triphosphate; dUMP,
deoxyuridine monophosphate; TS, thymidylate synthase; dTMP, deoxythymidine monophosphate;
THF, tetrahydrofolate; DHF, dihydrofolate.
 5-FU for 40 Years (1957-1995), the single drug !
 5-FU bolus
 5-FU infusion
 24 hrs

 48 hrs

 46 hrs

 120 hrs

 ∞ hrs

 LV + 5-FU
 5-FU + LV
 5-FU + Lev
 5-FU + everything
Patented in 1957, 5-FU remains “arguably the single best drug we have in CRC” ( Saltz L)
“Virtually every drug since then have been a relative failure in terms of its intention to replace 5-FU”
 Capecitabina (Xeloda®)

 Capecitabine Doza= 1250mgm2 x 14

zile la 21 de zile
 In the UK, capecitabine is approved by
the National Institute for Health and
Clinical Excellence (NICE) for colon
and colorectal cancer, and locally
advanced or metastatic breast cancer:
Gemcitabina (Gem)
 Antimetabolite’s toxicyty

 ACUTE: diareea, hand-food syndrome

myelosupression: neutropenic fever,
mucositis,
alopecia
acute elevation in hepatic enzymes level
 CRONIC: renal toxicity ( Methotrexate)
 III. Natural products

 Antitumoral antibiotics and related synthetic compunds

 Topoisomerase inhibitors -interacting agents

 Antimicrotubule agents
A. Antitumor antibiotics and related synthetic compunds
generate free radicals through redox cycles

 I. Anthracyclines: Doxorubicin ( Adriamicin), Epirubicin (Farmorubicin), Daunorubicin,

Idarubicin
A.- DNA intercalation (alkilant – like).
B. – inhibit topoisomerase II enzyme: anthrcycline form a ternary “ clevable complex” with
DNA-topoisomerase II which then “ traps” the DNA strands passage intermediates.
C. - reactions generate free radicals and other reactive species, oxidant species tha damage
intracellular macromolecules, generate free radicals through redox cycles.
II. Non-antharacyclines: Mythomicin C, Mitoxantrone (Novantrone), Actinomycine D (
Dactinomycin), Bleomycine .
Doxorubicin (Adriamicin)
 Anthracyclines

Anthracyclines:
doxorubicin,
epirubicin
Anthracyclines -Mechanism of action
 Anthracyclines: toxicities

 Myelosuppression is universal and usually dose-limiting with each

individual cycle
 Diarrhea and stomatitis are common but usually mild
 Alopecia, rash, hyperpigmentation are common.
 Cardiotoxicities is common and can be dose-limiting; cumulative
cardiomyopathy is expected when total dose exceeds 400 to 500mg/m2
( 1-2%).
 Delayed occurrence of acute myeloid leukemia
(AML) 0.5% cases .
Anthracycline’s- side effects
Bleomicina
 Slide 8

Presented By Mark Kris at 2014 ASCO Annual Meeting

 Actinomicin D (Dactynomicin, Cosmegen)

 Actinomicina D (Dactinomycin, Cosmegen) este un antibiotic pentapeptid ce

conţine fenoxazină, izolat din Streptomyces parvullus. Poate fi utilizat ca
agent unic sau în asociaţie; determină rate înalte de răspuns în coriocarcinom
şi nefroblastom (tumora Wilms). Dozele uzuale sunt de 0,5mg/zi I.V. x 5 zile
consecutiv. Dactinomicina este foarte caustică pe ţesuturile moi şi
extravazarea sa trebuie cu grijă evitată. Se excretă prin bilă nemodificată şi
semiviaţa sa este de 36 ore; nu traversează bariera hematoencefalică.
Mitoxantrone (Novantrone)
 B. Drugs targeting topoisomerase
interfere with DNA transcription and replication

 A. DNA topoisomerase I- targeting agents:

Camptotecin (CPT 11)
Topotecan
Irinotecan

DNA topoisomerase I is a ubiquitous nuclear enzyme that relaxes the torsional

DNA strain by catalyzing a transient single-strand nick in the DNA; this results
in a covalent linkage of the enzymes of the 3’-terminus of the cleaved DNA.
Topoisomerase- I. Agents:
Camptotecin

Topoisomerase I mechanism of
action and replication fork collision
model for camptothecin
cytotoxicity. A: Top1 (blue)
normally relaxes supercoiled DNA
by forming a covalent interaction
between tyrosine-723 and the 3′ end
of the nicked DNA. B: Addition of
camptothecin (yellow) results in
the formation of the ternary
complex and prevents religation of
DNA. C: Collision of the advancing
replication fork with the ternary
complex leads to DNA damage
and cell death.
 Topoisomerase I inhibitors

Presented By Jean-Charles Soria at 2014 ASCO Annual Meeting

2. Camthoteca acuminata- derivaţii de Campto
a. Topoisomerase I -Interacting Agents
 Topo II inhibitors

DNA topoisomerase II inhibitors:

n Etoposide (VP16)
n Tenoposide ( VM26) and
n Anthracyclines (Doxorubicin, Epirubicin)
DNA topoisomerase II release the torsional DNA by actively insertting stable
DNA strands through the other in the helix and then reanealing DNA the
strand break. It can create double-stranded DNA gaps orchestrate concerted
strand passage, and then catalyse “ unknotting” or decattenation of interwinted
DNA attesting to its role in the mitosis.
Podophillum peltatum- epipodofilotoxinele

 Etoposid
Topoisomerase II mechanism of action and model for drug cytotoxicity. A Top2 (blue)
homodimer binds to DNA, forming a double-strand DNA break in which the proteins are
covalently bound to the 5′ end of broken DNA strands to form the Top2 cleavable complex. A
second DNA double-helix strand (red) can then pass through this “gate” in an energy-dependent
fashion. Finally, the broken DNA is relegated. In the presence of Top2 poisons (yellow) DNA is
unable to religate, leading to double-strand DNA breaks and cell death.
b. Topoisomerase II-Interacting Agents-
Epipodophylotoxines
 Topoisomerase inhibitors toxicity

 ACUTE: nausea, vomiting ( moderate)

diareea – acute colinergyc effect by inhibition
of acetylcholinesterase and mucosal toxiciity.

 CRONIC: leukemia ( mielomonocytic- FAB M4)

Inhibitors of mitosis -anti microtutubules
agents
- Drugs thar affect the mitotic apparatus-
Drugs affecting microtubule depolymerisation- Vinca
rosea- Derivaţii de Vinca
Dinamica microtubulilor fusului de diviziune
 C. Microtubule –tageting drugs (I)
inhibitors of mitosis: VINCA

Microtubules are integral components of the mitotic spindle apparatus during

metaphase in dividing cells.

I. Vinca alkaloids:
Vincristine,
Vinblastine,
Vinorelbine,
Vindesine
- cytotoxicity of vinca alkaloides is principally related to the microtubular
depolymerisation by inhibing microtubule assembly resulting in metaphases arest in
G2 and M cell-cycle phases in dividing cells.
Vinorelbine (Navelbine®)
 VINCA ALKALOID AND TAXANE’s TOXICITY

 ACUTE: neurotoxicity ( polyneurophaty)- neuritic pain

confusion, mental status changes, halucinations,
agitations, insomnia.
constipation, abdominal cramps, paralytic ileus,
urinary retention.
neutropenia
alopecia reversible
major hipersensytivity reaction
cardiac rhytm dsturbance
 CRONIC: hepatotoxicity
pulmonary tocitity
Taxus brecvifolia- Taxanii: taxol, taxotere şi cabazitaxel
Paclitaxel (Taxol®)
Drugs affecting microtubule polymerisation:
Taxanes
Docetaxel (Taxotere®)
 Microtubule-targeting drugs (II)
inhibitors of mitosis TAXANES

II. Taxanes:
 Paclitaxel (Taxol) ,

 Docetaxel (Taxotere)

- affect microtubules through a mechanism of action

unique from the Vinca alkaloids.
- shift the dynamic equilibrium toward microtubule
assembly prevent, inhibit depolymerisation of
tubulin, and therefore suppress microtubular
reorganisation.
 Taxanes: toxicities

 Myelosuppression, predominantly neutropenia is expected and is

dose-limiting.
 Peripheral neuropathy is common, usually common and increase
with cumulative with cumulative dose.
 Mucositis is also very common , particularly with longer infusion.
 Cardiovascular side effect include: hypertension, hypotension,
premature contraction and bradyarrhytmias.
 Hipersensitivity reactions to paclitaxel includes: urticaria,
wheezing, chest pain, dyspnea, and hypotension - premedication
with corticosteroids and histamine 1 and histamine 2
antihistamines.
Antimicrotubule Agents
Acţiunea paclitaxel pe ciclul celular
PACLITAXEL (Taxol)
Categories of chemotherapeutic drugs by their activities in cell
cycle

I. Phase non specific:

a. Cycle- non specific drugs – kill nondividing cells ( ex. antibiotics exept
Bleomycin)
b. Cycle- specific, phase-non specific drugs are effective only if the cell
proced through the generation cycle ( ex. Alkilating agents)
Cycle –non specific and cyclo-specific have a liniar dose-response
curve: greater the dose, the greater the fraction of cell killed.
II. Phase specific:
a. Cycle-specific, phase-specific drugs are effective only if present
during a particular phase of cell cycle.
Their effect is a function of both time and concentration- further
increase in drug dose DO NOT result in more cell killing. If drug
concentration is maintening over a period of time, more cell enter in the
specific lethal phase of the cell cycle and are killed.
 I. Phase non specific:
a. Cycle- non specific drugs – kill nondividing cells ( ex. antibiotics exept Bleomycin)
b. Cycle- specific, phase-non specific drugs are effective only if the cell proced through the
generation cycle ( ex. Alkilating agents)II.
II.Phase specific:
a. Cycle-specific, phase-specific drugs are effective only if present during a particular phase of
cell cycle
 Indications of cytotoxic chemotherapy

Indications: chemotherapy is used in the following circumstances:

 1. to cure certain malignancies
 2. to palliate symptoms in patients with disseminated cancer when potential
benefits of treatment exeed the side effects of treatment.
 3. to treat asymptomatic patients in the following circumstances:
- when the cancer is agresive and tratable
- when treatment has been proven to decrease the rate of relapse and
increase the disease-free interval or increase the absolute survival
4. to allow less-mutilating surgery by trating first with chemotherapy alone or
in combination wit RT ( sarcomas and carcinomas of anus, breast, oesophagus).
 Contraindications

Chemotherapeutic agents are relatively or absoulutley contraindicated in the

following situations:
 1. When facilities are inadequate to evaluate the patient’s response to therapy
and to monitor and manage toxic reactions.
 2. When the patient is not likely to survival longer even if tumor shrinkage could
be accomplished
 3. When the patient is not likely to survive long enough to obtain benefits from
the drugs ( ex. severlly debilitated patient)
 4. When the patient is asymptomatic with slow-growing, incurable tumors, in
which case chemotherapy should be postponed until symptoms require
palliation.
 Requirements for chemotherapy

 1. Biopsy- proven residual or metastatic disease

 2. Indicator lesion ( target)
 3. Satisfactory performance score and nutrition
 4. Patient capable or informed consent
 5. Minimal bone marrow, renal, and hepatic function (occasionally,
pulmonary or cardiac function important)
 6. Avaible monitoring and support function
 Route of chemotherapy administration

 Intravenous ( i.v.)
 Oral (per os)
 Intraperitoneal therapy
 Intratecal and intraventricular therapy
 Intra-arterial therapy
 Prolonged intravenous infusion chemotherapy
 Other routes of administration: intrapleurally
 Chemoherapy treatment modalities

 Adjuvant chemotherpy- is used to treat patients known to be at high risk of

reccurence after initial local therapy (surgery or radiation) has
removed all evidence of disease
 Neoadjuvant chemotherapy- called also induction chemotherapy is given after
a histologic diagnosis is has been established, but before definitive treatment.
 Primary chemotherapy – chemotherapy use only single treatment to treat
curative or palliative cancer.
 Direct instillation into sanctuary sites or by site-directed perfusion of specific
regions of the body directly affected by the cancer.
 Adjuvant chemotherapy- management approach

1. Effective chemotherapy must be avaible.

2. Known tumor should be removed by surgery.

3. Chemotherapy should be started as soon as possible postoperatively.

4. Chemotherapy should be given in maximally tolerated doses.

5. Chemotherapy should be continue a limited time period

6. Chemotherapy should be intermitent, when possible to minimize

immunosupresion.
Cancers with established or probable benefit
from adjuvant chemotherapy

 Breast cancer
 Colorectal cancer
 Osteosarcoma
 Wilms’ tumor
 Stage II-III gastrc cancer
 Stage II-III non small cell lung cancer
 Stage III melanoma
Adjuvant chemotherapy is indicated in high risk patients

 Tumor size and regional lymph node involvement are consistently

associated with distant relapse.
 The involvement of regional lymph nodes is often, but not always, a
harbinger for increased risk of distant metastasis.
 When tumor cells appear to have aggressive traits on microscopic
analysis, this often translates into increased risk for distant disease.
 (1) Tumor grade

 (2) Depth of invasion beyond normal tissue compartmental

boundaries.
 (3) Lymphovascular invasion.
 Cancers that are curable or occasionally
curable with chemotherapy alone

Cancer that are curable with chemotherapy alone:

 Gestational choriocarcinoma
 Hodgkin’s disease
 Germ cell of the testis
 Acute lymphid leukemia
 Non- hodgkin’s lymphoma ( some subtypes)
 Hairy cell leukemia ( probable)
Cancer that are occasionally cured with chemotherapy:
 Acute myeloid leukemia
 Ovarian cancer
 Small cell lung cancer ( localised , with RT)
 Cancers without response to clasical chemotherapy

 Renal cell carcinoma

 Malignant nelanoma
Adjuvant chemotherapy is indicated in high risk patients

 Tumor size and regional lymph node involvement are consistently

associated with distant relapse.
 The involvement of regional lymph nodes is often, but not always, a
harbinger for increased risk of distant metastasis.
 When tumor cells appear to have aggressive traits on microscopic
analysis, this often translates into increased risk for distant disease.
 (1) Tumor grade

 (2) Depth of invasion beyond normal tissue compartmental

boundaries.
 (3) Lymphovascular invasion.
 Neoadjuvant chemotherapy

 Neoadjuvant (induction) is given after a histologic diagnosis has been

established, but before definitive surgical therapy.
 The rationale for neoadjuvant is:
1. the immediate exposure of local and posssible distant disease to
effective chemotherapy avoiding the delay introduced by surgery and
recovery;
2. immediate in vivo assesment of chemotherapy responsiveness of
the primary tumor, and therefore, of possible nodal or distant
micrometastaic disease;
3. bulk reduction of local disease to allow for subsequent less
anatomically destructive surgical procedure.
 Cancers with established benefit from neoadjuvant
chemotherapy

Locally advanced breast cancer:

________________________________________
 Laharinx cancer
 Esophageal cancer
 Bladder cancer
 Anal cancer
 Osteosarcoma
 Soft tissue sarcoma
 Association chemotherapy + radiotherapy

 Sequencial
 Concurrent
Cancers: Rectal cancer
Cervix cancer
Head and neck tumors ( larinx)
Chemotherapeutic rugs with radiation sensisittizer proprieties:
- 5-Fluorouracil
- Gemcitabine
- Cisplatin, carboplatin
- Paclitaxel
- CPT-11 ( Irinotecan), topotecan
 Mechanism responsible for differential response of tumor vs.
normal cells

_______________________________________________________
 Increased proliferative fraction and shortened cell cycle
 Inefficiency or inactivation of cellular checkpoints
 Defects in DNA repair
 Altered apoptosis
 Dependence on ‘cancer pathways’
________________________________________________________
Mecanisms of drug resistence
 Mecanisms of drug resistence

The pharmacological resistence can be due to:

 Decarsed drug activating enzymes

 Increased drug-inactivating enzymes
 Increased DNA repair
 Mutations in drug targets
 Excretion of drug out of the cells
 Strategies to overcome resistance

Strategies to overcome resistance due to cell kinetics include the

following:

 Reducing tumor bulk with surgery or radiotherapy

 Using combinations to include drugs that affect resting

populations (with many G0 cells)

 Scheduling of drugs to prevent phase escape or to synchronize

cell populations and increase cell kill
 Selection of drugs for combination regimens

Combination chemotherapy accomplishes three important objectives

not possible with single-agent therapy:

(1) It provides maximum cell kill within the range of toxicity

tolerated by the host for each drug;
(2) it offers a broader range of coverage of resistant cell
lines in a heterogeneous tumor population;
(3) it prevents or slows the development of new drug-
resistant cell lines.
Principles for combination chemotherapeutic regimens

 1. All drugs must have single-agent activity

 2. Drugs should have nonoverlapping toxicity
 3. Drugs should have different mechanisms of action
 4. Drugs should have different mechanisms or pattern of
ressistence
 5. Drugs should be given in an optimum dose and shedule
to optimize dose intensity/ dose density
 6. Drugs schould be individually titrated in individual
patients to end-organ toxicity to optimize adherence to
schedule
 General mechanisms of resistance to chemotherapy

Presented By Jean-Charles Soria at 2014 ASCO Annual Meeting

Hipócrates din Cos-
Ἱπποκράτης ὁ Κῷος

“Primum non
nocere… deinde
vindecare “
 II. MOLECULAR TARGETED THERAPY

 The term target agents has come to refer to an emerging class of drugs
that target pathways specifically and differentially activated in cancer
cells as compared with their normal countparts on molecular level
including gene expression, growth regulation, cell cycle control,
apoptosis, and angiogenesis.

 Molecuar targeted therapy is a broad term encompassing several classes of

agents, including tyrosine kinase inhibitors and monoclonal antibody
Cytotoxic chemotherapy versus molecular targeted therapy
CONFIDENTIAL NOT FOR DISTRIBUTION.
 Cancer Targets

From National Cancer Institute, US National Institutes of Health.

108
 Targeted Therapy For Lung Cancer

Presented By Martin Edelman at 2014 ASCO Annual Meeting

DRUGS AFFECTING GROWTH FACTORS
AND GROWTH FACTOR RECEPTORS
Caile de semnal biologic
 Classification of targeted agents

 Signaling cellular pathways:

- tyrosine-kinase inhibitors ( TKI)
- monoclonal antibody
- cell cycle proteins ( ciclina D1)
- signaling pathwaays ( PKC, PKA MAPK);
- COX-2
 Apoptosis:
 Mdm2
 Bcl-2
 Genes transcription:
 Decetilarea histonelor
 ADN- metiltransferaza
 Angiogenesis:
 Factorii agiogenetici şi receptorii acestora ( VEGF, vascular endotelial groth factor, VEGFR-
vascular endotelial groth factor receptor).
 Proliferarea celulelor ndoteliale;
 Metalloproteinaze (MMP).
 Epidermal Growth Factor Receptor Familiy

Citri and Yarden (2006) Nature Rev. Mol. Cell Biol. 7, 505-516
 [TITLE]

Presented By S. Gail Eckhardt, MD at 2011 ASCO Annual Meeting

 Anticorpii monoclonali

• au o molecula > decat inhibitorii de TK

• sant produsi prin inginerie genetica
• sant Atc identici caci sant produsi de un singur tip de celule imune: LB,
au un singur parinte
• Au afinitate monovalenta doar pt un singur site (epitop)
• se administreaza doar IV
• actioneaza prin multe mecanisme dar de cele mai multe ori ataca
receptorii de suprafata

117
 The Development of Human Monoclonal Antibodies

Mouse Chimeric Humanized Fully Human

100% ~34% ~10% 100%

Mouse Protein Mouse Protein Mouse Protein Human Protein
cetuximab bevacizumab panitumuma
rituximab b
cetuximab† rituximab* bevacizumab panitumumab†

antihistamine + corticosteroid (mandatory for glucocorticoids

Premedication1 none none
first, recommended for subsequent infusions) (recommended generally)
Infusion reactions
All grades 20% >50% <3% 3%
Severe 5%2 10%1 <1%3,4 <1% 1

Yang XD, et al. Crit Rev Oncol Hematol 2001;38:17-23. 1. Erbitux®, MabThera®, Avastin®, Vectibix® European Public Assessment Reports as of Apr 2010.
2. Erbitux® US Package Insert as of Apr 2010, http://packageinserts.bms.com/pi/pi_erbitux.pdf. 3. Avastin® US Prescribing Information as of Apr 2010. 4.
Kang and Saif. J Support Oncol 2007; 5:451-7.* Non-Hodgkins’s lymphoma. † Monotherapy in mCRC. Data are not from comparative studies.
Monoclonal Antibodies
 Blocantii EGFR (Her-1)

 Anticorpii monoclonali (MoAb) anti regiunii extracelulare a EGFR:

1. Trastuzumab (Herceptin)
2. Cetuximab (Erbitux)
3. Panitumumab (Vectibix)
4. Pertuzumab (Perjeta)
 Trastuzumab: 1 tinta
4 mecanise de actiune

Activarea ADCC
Prevenirea formarii p95HER2

Inhibarea angiogenezei reglate pe cale

Inhibarea proliferarii celulare HER2
Trastuzumab (Herceptin®) has transformed the course
of HER2-positive MBC

HER2-positive status no longer dictates probability of survival

1.0 HER2-normal
HER2-positive without trastuzumab
0.8 HER2-positive with trastuzumab
OS

0.6

0.4

0.2

0
0 12 24 36 48 60
Time (months from diagnosis)

Dawood et al. JCO 2010;28:92-98

 Monoclonal antybody: trastuzumab

 Trastuzumab (Herceptin)
 genetic humanized mouse monoclonal antibody directed
against te her2/neu growth factor receptor that is
overexpressed in many invasive breast cancer.
 Indications: Her2/neu overexpressing metastatic or
locally advanced breast cancer.
 Toxicities:
 Common: acute fever, chills, nausea, vomiting, and
headache.
 Worsens leukopenia, anemia, and diarrhea when given
with chemotherapy compared to chemotherapy alone.
 Uncommon: acute cardiotoxicity, which add to more
common anthracycline-induced cardiotoxicity.
Cetuximab
Activarea EGFR poate implica acivarea căilor de semnal în amonte
care includ Kras
 Panitumumab Inhibits Ligand Binding to EGFR and
Dimerisation

EGF, TGFα or other Inhibition of EGF

ligands binding to EGFR binding to EGFR

Panitumumab

Affinity
This may lead to:
• KD Panitumumab (0.05 nM1,2) > Cetuximab (0.4 nM2) > EGF (natural ligand; 3-7 nM3)  Cell proliferation
Panitumumab and cetuximab  Cell survival
• can inhibit receptor activation of all known EGFR ligands  Angiogenesis
 Metastatic spread
• bind to surface-exposed amino acids in the ligand-binding domain L2 of EGFR2

1 Yang XD et al. Cancer Res 1999;59:1236-43.

2 Freeman D et al. J Clin Oncol 2008 26:14536 and Poster. 3 Gill GN et al. J Biol Chem 1984;259:7755-60.
KRAS is Important in Growth and Cell Division – Mutations Can
Cause Cancer

Inactive Wild-type Ras  Ras proteins are GTPases

Ras  Ras family members include: KRAS, NRAS,
GDP Normal: and HRAS
• Growth
Active • Proliferation  Normal cycle occurs between a GDP-bound
• Differentiation
(inactive) and a GTP-bound (active) form of
Ras
Ras
GTP
 Specific mutations* in the KRAS gene result

Inactive Mutant Ras*

in a constitutively active protein
Ras*  Reported incidence of mutations in KRAS in

GDP Abnormal: CRC: ~40%

• Growth
Active • Proliferation
• Differentiation
Ras*
GTP

Schubbert S, et al. Nat Rev Cancer 2007;7:295-308.

Andreyev HJ et al. J Natl Cancer Inst. 1998 May 6;90(9):675-84.
Acneiform skin rash in a patient treated with
cetuximab

Left : Typical V-shaped localization on the

upper trunk
Above: picture details
 Pertuzumab and Trastuzumab Bind to Distinct
Extracellular HER2 Epitopes

Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex

Pertuzumab
I I Dimerization domain
I I
II I II I
I I Trastuzumab
IV IV

 Inhibits HER2 dimerization with other HER  Activates ADCC

family receptors (particularly HER3)
 Inhibits HER-mediated signaling pathways
 Activates ADCC
 Prevents HER2 domain cleavage
 Inhibits multiple HER-mediated signaling
pathways
Hubbard SR. Cancer Cell. 2005;7:287-288.
 Ado Trastuzumab Emtansine (T-DM1)

Presented By Mark Kris at 2014 ASCO Annual Meeting

 T-DM1: the first-in-class HER2-targeted
antibody-drug conjugate
 Trastuzumab: A monoclonal
antibody that recognizes and
selectively binds to HER2 antigens
on the surface of tumor cells, where
it exhibits anti-HER2 activity5,6
 Cytotoxic agent DM1: A derivative
of the potent antimitotic drug
maytansine that inhibits tubulin
polymerization.1,5,6 In preclinical
studies, maytansinoids were shown
to be 24- to 270-fold more potent
than paclitaxel and 2 to 3 orders of
magnitude more potent than
doxorubicin5
 Linker: A nonreducible thioether
linker that is designed to remain
stable in circulation prior to entering
HER2-overexpressing cells6
 Slide 44

Presented By Mark Kris at 2014 ASCO Annual Meeting

 Slide 44

Presented By Mark Kris at 2014 ASCO Annual Meeting

INHIBITORII KINAZICI
 EGFR ocupă un loc important (“driver”) in căile de
semnalizare din interiorul celulelor tumorale

1. Dimerizarea receptorilor
care au fixat ligandul

2. Fosforilarea domeniului
tirozin-kinazic P P

Calea Calea RAS-RAF-

PI3K-AKT-mTOR MEK-MAPK
3. Activarea a doua
cai majore de
semnalizare
intracelulara

Proliferare/ Metastazare
4. Raspuns Supravietuire/
celular la maturizare
Angiogeneza anti-apoptoza
semnalizare celulara
Activarea semnalizarii intracelulare prin intermediul
EGFR

P P

Calea Calea RAS-RAF-

PI3K-AKT-mTOR MEK-MAPK
ATP
ATP

Proliferare/ Metastazare Supravietuire/

maturizare
Angiogeneza anti-apoptoza
celulara
Efectele blocarii semnalizarii pe calea EGFR
utilizand un inhibitor de tirozinkinaza

Calea Calea
PI3K-AKT MAPK
ATP
ATP
EGFR TKI blocheaza fixarea
ATP si impiedica activarea
domeniului TK

Proliferare / Inhibarea
Metastazare Supravietuire/
maturizare semnalizarii anti-apoptoza
celulara Angiogeneza
intracelulare
 Inhibitorii tirozinkinazici (TKI)

Molecule mici TKI (“ib”):

 Imatinib (Glivec): leucemie mieloidă cronică

 Erlotinib (Tarceva): cancr bronho-pulmonar şi pancreatic
 Gefitinib ( Iressa): cancrul bronho-pulmonar
 Lapatinib- cancerul mamar rezistent la terapiile antiHEr2
 Pazopanib- cancer mamar, cancer renal
 Axitinib- cancee renal
 Cryzotinib- cancere bronho-pulmonare non microcelulare
 Imatinib: Background

 A selective tyrosine kinase inhibitor of

 c-KIT
 BCR-ABL
 PDGFRα and PDGFRβ

C29H31N7O•CH4SO3
MW 589.7 kDa

Druker BJ et al. Nat Med. 1996;2:561-566.

Consecinţele activarii Bcr-Abl
Supravieţuirea pacienţilor cu LMC
Gastric mucosa
 Inhibition of KIT Signaling by Imatinib

• The ATP binding

pocket of the KIT
kinase domain is
occupied by imatinib
• Substrate
phosphorylation is
prevented and Kinase
signaling is inhibited domains
• With signaling
inhibited, proliferation
and survival are P
interrupted ATP
P P P
Imatinib
mesylate
Savage et al. N Engl J Med. 2002;346:683-693. SIGNALING
Scheijen et al. Oncogene. 2002;21:3314-3333.
Gefitinib (Iressa)
Erlotinib (Tarceva)
LAPATINIB (Tykerb)
 Lapatinib este primul inhibitor TK oral cu legare intracelulara

Bevacizumab
Ertumaxomab
VEGF
Pertuzumab

Trastuzumab

ErbB3 ErbB2 IGF-IR VEGFR

ErbB1 ErbB2 PDGFR

Pazopanib Sunitinib

Lapatinib
PI3K

Tanespimycin
Akt HSP90 Alvespimycin
HDAC

Vorinostat Temsirolimus
mTOR
Everolimus
HDAC=histone deacetylase
The target: angiogenesis
Antiangiogenic Therapy for Cancer:
Origins of the Concept

 The era of antiangiogenic drug

development began with the
publication in 1971 of a landmark
hypothesis article in the New England
Journal of Medicine by
M. Judah Folkman
 Antiangiogenetic therapy
Neovascularisation is a crucial component of cancer cell growth and progression.
I. Anti- VEGF antibodies:
1. BEVACIZUMAB ( Avastin®) – a recombinant humanised monoclonal anti-VEGF
antibody.- colon, breast, and lung cancers.

II. Small molecule tyrosine kinase inhibitors- these compunds act directly on VEGF
tyrosine kinase to block VEGF signalimg:
 SUNITINIB ( Sutent®) is a small molecule, multitargeted kinase inhibitor, wicch act acts as
an inhibitor of VEGFR, PDGFR, c-kit, FLT-3 and RET
renal cell carcinoma,
gastro-intestinal stromal tumours ( GIST).
2. SORAFENIB ( Nexavar®) inhibits phosphorilation of MAP kinase pathway ( mainly Raf), can
inhibit proangiogenetic TKR such as VEGFR-2,3, PDGFR beta, c-Kit, FLT-3 and FGFR-1.
hepatocellular carcinoma
GIST
3. PAZOPANIB – small molecule, multi-targeted kinase inhibitor, which act as an inhibitor of
VEGR-1, -2, -3, PDGFR alpha& beta and c-Kit
Breast cancer
Antiangiogenesis Agents
 Bevacizumab: first anti-angiogenic that directly inhibits
VEGF

 Avastin (Bevacizumab):
monoclonal antibody, not a
cytotoxic agent
synergistic with existing therapies
inhibits angiogenesis via novel
mechanism of action

X
Growth
Proliferation
Migration
Survival
VEGF: central to the angiogenic switch in tumours
Hypoxia PDGF
IGF-1
EGF

IL-8
Binding and activation
VEGF release of VEGFR
bFGF

COX-2
Nitric oxide
Oncogenes

Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
Survival Proliferation Migration
Permeability
ANGIOGENESI
S
Ferrara, et al. Endocr Rev 1997
Kerbel, et al. Nat Rev Cancer 2002
 Vascular endothelial cell growth factor (VEGF) family of ligands and receptors. There are several members of the VEGF
family. VEGF-A (also called VEGF) is the major stimulator of physiologic and pathologic angiogenesis, including tumor
angiogenesis. The major signaling receptor for VEGF-mediated angiogenesis is VEGFR-2 (KDR in humans, and flk-1 in
mice). VEGF-C is the major mediator of lymphangiogenesis, mediated through VEGFR-2 signaling. Placental growth
factor (PlGF), which signals through VEGFR-1, has also been implicated in angiogenesis, but its relative contribution to
tumor angiogenesis remains uncertain at this time. Functions of other VEGF family members are also not so well defined
with respect to tumor angiogenesis.
 Inhibition of VEGF: significant reductions in
tumour vascular volume and density

Antibodies inhibiting Anti-VEGF antibodies Soluble VEGF

VEGF receptors (e.g. Avastin) receptors

VEGF
VEGFR-2

Small molecule VEGFR

inhibitors (TKIs)

Ribozymes
Molcular targeted therapy
 Anti-VEGF antibody therapy causes
regression of vasculature
Preclinical evidence Clinical evidence
• Reduced size of • Tumour shrinkage
micrometastases in a
• Symptom improvement
mouse model1
– improvement of dyspnoea

28.09.07 27.12.07

Anti-VEGF MAb Control MAb

Tumour
1Warren, et al. J Clin Invest 1995 Courtesy of Martin Reck
 Gastrointestinal Symptoms: Oral Changes

 Characteristics
 dysgeusia, dysphagia, sensitivity and
sores (including cheilitis)
 oral changes (‘functional mucositis’) do
not have the appearance and severity of
chemotherapy-induced mucositis
 usually resolve after
1 week off treatment
 gel containing tetracain-hydrochloride,
camomile, sage, arnica, zinc

Creel T, et al. ISNCC 2006; Wood LS. Community Oncology 2006;3:558–562

Grade 2 Rash

 Prominent on trunk

 Small erythema

 Tendency for confluence

Example of Grade 3 Hand–Foot Syndrome with TKI
Treatment

 Erythema and desquamation over the entire

surface of the sole

 Pain

 Complete loss of function

 Antiangiogenetic therapy
Neovascularisation is a crucial component of cancer cell growth and progression.
I. Anti- VEGF antibodies:
1. BEVACIZUMAB ( Avastin®) – a recombinant humanised monoclonal anti-VEGF
antibody.- colon, breast, and lung cancers.

II. Small molecule tyrosine kinase inhibitors- these compunds act directly on VEGF
tyrosine kinase to block VEGF signalimg:
 SUNITINIB ( Sutent®) is a small molecule, multitargeted kinase inhibitor, wicch act acts as
an inhibitor of VEGFR, PDGFR, c-kit, FLT-3 and RET
renal cell carcinoma,
gastro-intestinal stromal tumours ( GIST).
2. SORAFENIB ( Nexavar®) inhibits phosphorilation of MAP kinase pathway ( mainly Raf), can
inhibit proangiogenetic TKR such as VEGFR-2,3, PDGFR beta, c-Kit, FLT-3 and FGFR-1.
hepatocellular carcinoma
GIST
3. PAZOPANIB – small molecule, multi-targeted kinase inhibitor, which act as an inhibitor of
VEGR-1, -2, -3, PDGFR alpha& beta and c-Kit
Breast cancer
Sunitinib (Sutent)
Sorafenib ( Nexavar)
 A wealth of molecular-targeted agents
under investigation in cancers

EGFR/HER Angiogenesis
Phase II
inhibitors Vatalanib inhibitors
Lapatinib
Matuzumab Sorafenib
Panitumumab Phase III Sunitinib
Cetuximab Motesanib
Tarceva Vandetanib
Neratinib Gefitinib Avastin
AS1404 Cediranib
Approved Aflibercept
Talabostat Bexarotene
CP-751871 Celecoxib
Bortezomib
Approved Tipifarnib ABT-751
First-line AZD6244
Second/third-line Everolimus Other molecular-
targeted therapies
Heat schok protein
Preventive Cancer Vaccines
 HORMONOTERAPIA

MOLECULE CARE TINTESC RECEPTORII FACTORILOR DE

CRESTERE STEROIDIENI- RECEPTORII HORMONALI

Terapia hormonala reprezita tratamentul sistemic al tumorilor

hormonosensibile prin suprimare surselor de hormoni sau blocarea
actiunii acestora la nivel celular.
Caile de snteza ale estrogenilor si testosteronului
The gonadal –hypotalamic axis
 Hormonal therapy = endocrine manipulation

 Supressive (ablative( hormonotherapy-

Ablation of endocrine glands- castration- ovarectomie ( breast cancer), orhiectomie
(prostate cancer)

 Additive hormonotherapy :
A. Competitive:
a) Selective Estrogen-Receptor Modulators ( SERM)- TAMOXIFEN,
TOREMIFEN, RALOXIFEN
b) Antiandrogens: FLUTAMID, BICALUTAMID, NILUTAMID
c) Progestives: MEDROXIPROGESTEROL CETAT, MEGESTROL
c) Estrogens: DIETILSTILBESTROL, ESTRADURIN, CLORTRIANISEN
d) Androgens: METILTESTOSTERON, FLUOXIMESTERON
B. Privative:
a) Inhibitory hypofisar function: Gn-RH inhibitors: goserlelin,b userlelin, triptorelin,
leuprolid acetat
b. Aromatase inhibitors (AI): AMNOGLUTETIMID (gen I), ANASTROZOL,
LETROZOL (gen III, nonsteroidal), FORMESTAN (steroidal, EXEMESTAN>
 Inhibitory
Tiroidian hormons
Somatostatins analogs: octreotid, lanreotid, pasitreotid
 Terapia hormonală a cancerului mamar

Gonadotropi Estrogeni
(FSH + LH) Progesteron
Premenopauza
Ovar

Prolactina Tamoxifen
RE +
Glanda hipofiza Corticosteroizi
LHRH Fulvestrant
Pre/post- Corticosuprarenala
(hipotalamus)menopauza
Goserelin Androgeni EstrogenI
Hormonul
adenocorticotrop Progesteron
(ACTH)
Conversie periferica
Inhibitorii de
aromataza
Prostate cancer hormonosensitive
Androgeni

ACTH Celula prostatica

Suprarenala
DHT
LHRH
Hipotalamus
Alte celule tinta

Glanda pituitara DHT Receptor

androgenic
Testicul
LH

Testosteron circulant
Control feed back negativ

LHRH - hormonul eliberator de gonadotropine

LH - hormonul luteinizant
DHT - dihidrotestosteron
ACTH - adrenocorticotrop hipofizar
 Hormones and hormones antagonists
 Androgen: FLUOXIMESTERON and others
 Androgen antagonist: BICALUTAMIDE, FLUTAMIDE,
NILUTAMIDE
 Aromatase inhibitor: AMINOGLUTHETIMIDE, ANASTROZOLE,
LETROZOLE, EXEMESTANE
 Estrogens: DIETHYLSTILBESTROL
 Estrogen antagonist: FULVESTRANT, RALOXIFENE,
TAMOXIFEN, TOREMIFENE
 Corticosteroid : DEXAMETHAXONE, PREDNISONE
 Luteinizing hormone- releasng hormone antagonist: GOSERELIN,
( LH-RH antagonist) LEUPROLIDE, TRIPTORELIN
 Progestin: MEGESTROL ACETATE,
MEDROXIPROGESTERONE ACETATE
 Thyroid hormones: LEVOTHYROXINE, LITHYRONINE
Blocarea receptorului estrogen - Fulvestrant
 DRUGS THAT TARGET THE IMMUNE SYSTEM

Immunotherapy refers to antitumor treatment utilizing the actions of

natural host-defense mechanisms and/or mammalian-derived substances
 Imunoterapia -strategii

Astăzi, strategiile imunoterapice în tratamentul cancerelor se concentrează

pe 2 directii:
A. stimularea elementelor efectorii deficitare ( cel T, cel dendritice, NK)

B. inhibarea factorilor supresivi natutrali (T reg, cel DC imature, self

antigene, citokine supresive :IL-10).

Modalitati practice:
1. Vaccinurile anticanceroase
2. Utilizarea citokinelor pentru stimularea imunităţii
3. Anticorpii monoclonali
4. Terapia adaptativă cu celule T: CTL-4, PD-1
1. Anticancers vaccines
 2. Antitumoral cytokines

 Cytokines are signalling molecules that can enhance or

suppress the immune response1

 They have a vital role in the recognition and elimination of

tumour cells1

 Examples of immunotherapeutic use of cytokines include the

administration of IL-2 and IFN-α in renal cancer and
malignant melanoma respectively1,2

IL-2=Interleukin-2; IFN-α=Interferon-α
1Kim-Schulze SB et al. Surg Oncol Clin N Am 2007; 16(4): 793-818, viii; 2Kirkwood JM et al. J Clin Oncol 1996; 14(1): 7-17.
Interferons
Antitumoral cytokines: Interferons
 3. Monoclonal antibodies

 Monoclonal antibodies raised against individual tumour cell targets can

trigger immune mechanisms that affect tumour cell survival or
proliferation

 Rituximab is one such antibody that is used to treat non-Hodgkin's

lymphoma.1 It acts by:
 Complement-mediated CD-20+ B-cell lysis1
 Antibody-dependent cell-mediated cytotoxicity1

1Maloney DG et al. Blood 1997; 90(6): 2188-95.

 THE DESIRED T-CELL RESPONSE TO
TUMOURS
Steps 1 and 2

APC T-cells

T-cell

1 - T-cell activation 2 - T-cell proliferation

APC=Antigen presenting cell

190
 THE DESIRED T-CELL RESPONSE TO
TUMOURS
Steps 3 and 4

T-cells T-cells

Tumour
Destroyed tumour cells

3 - Infiltration of tumour site 4 - Tumour cell destruction

However – tumours have the ability to evade the immune system,

and
T-cell activation is under regulatory control. Immunotherapeutic
strategies aim to enhance this natural response
 CTLA-4 CYTOTOXIC T-LYMPHOCYTE ASSOCIATED
ANTIGEN-4

 CTLA-4, a TCR, is a naturally occurring negative regulator of the immune system. It

has a role in the prevention of autoimmune disease and it has an important role in
immunosuppression during tumourigenesis1

 Features of CTLA-42
 Receptor expressed on activated helper T-cells and CTLs
 Inhibits T-cell activation and proliferation
 Binds to the B7 molecule on the APC’s surface with higher affinity
than CD-28
 Puts a brake on T-cell proliferation

 Blockading the CTLA-4 receptor may suppress the inhibition of

T-cell activation and proliferation and hence may potentially improve the ability of T-
cells to destroy tumour cells1

TCR=T-cell receptor; CTL=Cytotoxic T-lymphocyte

1GabrielEM & Lattime EC. Clin Cancer Res 2007; 13 (3): 785-788; 2Sharpe AH & Abbas AK. N Engl J Med
2006; 355(10): 973-975. 196
 Slide 40

Presented By Michael Atkins at 2014 ASCO Annual Meeting

 Slide 2

Presented By Drew Pardoll at 2014 ASCO Annual Meeting

Activarea limfocitelor Inhibarea limfocitelor
 Ipilimumab: Mecanism de acţiune
T-cell T-cell T-cell
activation inhibition potentiation
CTLA4

T cell T cell T cell

CD28 CD28 CTLA4

CTLA4
TCR TCR TCR
B7 IPILIMUMAB
MHC B7 MHC MHC B7 blocks
CTLA-4
APC APC APC

O‘Day S et al. ASCO 2010 plenary session (#4)

[TITLE]
 [TITLE]

Presented By David R. Spigel, MD at 2013 ASCO Annual Meeting

 7 Companies Developing PD-1 checkpoint inhibitors!

Presented By Laura Chow at 2014 ASCO Annual Meeting

Blocanţii CTL-4: Ipilimumab ( Iervoy)- melanomul
malign metastazat

Blocanţii PD-1/ PDL1: Nivolumab (BMS)

Lambrolizumab (MK3575)
MDL 3280A
Pambroluzimab
IMMUNE TARGETED THERAPY

Adapted from Hodi FS, et al.

N Engl J Med. 2010
Aug 19;363(8):711-23.

Hodi et al.
Abstract #3008
ASCO 2008
 Slide 40

Presented By Mark Kris at 2014 ASCO Annual Meeting

[TITLE]
 GENE THERAPY (I)

 Gene-therapy encompassses a wide range of treatment type that all use

genetic material to modify cells in the treatment of cancer.
 This may be insertion of genes into the cells or by use of nucleic acid ( either
DNA or RNA) to influence protein formation. In the theory, it is possible to
transform either somatic or germline cells by gene therapy, and gene therapy can
be performed ex vivo ( modificaton of cells outside the body) or in vivo ( in the
body) treatment of cancer.
 Gene thrapy can be used to:
- restore mutated genes
- induce activities such as increased immunosuprssion
- suppress the expression of certain genes.
 GENE THERAPY (II)

Some ways in which anti-cancer gene therapy might be used

 Replacing faulty genes: inserting new normal genes into the cells to

replace the abnormal cancerous genes.

 Boosting immunity: altering the cancer genes to make their cells more

vulnerable to the body’s immune system.

 Increasing sensitivity to treatment: altering the cancer genes to make

their cells either more vulnerable to other treatments, or to stop them

developing resistance to those treatments.
 Reducing the sensitivity of normal cells to treatment: selectively

targeting normal genes to make their cells more resistant to the

effects of treatment, so that higher doses of drugs or radiation may
be given.
 Suicide genes: introducing genes into cancer cells which are designed

to destroy the abnormal oncogenes or tumour suppressor genes.

 Anti-angiogenesis genes: introducing genes into cancer cells that will

stop them from developing the new blood vessels essential for the support of tumour growth
[TITLE]
Descifrarea fiecărui genom al cancerului ‹›

Celule
canceroase Gene canceroase

Alterații ale genelor

Furnizarea și integrarea informațiilor moleculare complete în tratamentul

cancerului
215 CONFIDENTIAL
 Molecular Profiling:
the next revolution in medicine

• early disease diagnosis

• individualized therapy tailored to patients and their disease
• response prediction (thereby reducing costs)
• reduced side effects from therapy
 Tumor-Tissue Samples

Tissue Bank Pathology Lab Biomarker

The New Family of Diseases Perception / Molecular Portraits
EXACT chemosensitivity testing Ergebnis
 Slide 10

Presented By Roman Thomas at 2014 ASCO Annual Meeting

Secvențierea de ultimă generație poate fi utilizată pentru a identifica
toate modificările prezente în genele cancerului ‹›

Fluxul de lucru al genomului de cancer profilat

14-21 zile

221
 ‹›

222 CONFIDENTIAL
Number of altered cases Number of altered cases Number of altered cases

0
50
100
150
200

0
50
100
150
200
TP53 TP53

PIK3CA EGFR

MYC KRAS

CCND1 CDKN2A

ERBB2 CDKN2B

MCL1 RB1

FGFR1 STK11

PTEN PIK3CA

RB1 MCL1

NF1 MDM2

CDH1 MYC

BRCA2 ARID1A

KRAS ERBB2

MDM2 RICTOR

CCNE1 NF1

BRCA1 LRP1B

AKT1 CDK4

ESR1 PTPRD

EGFR SMARCA4

RPTOR PTEN

CDKN2A SOX2

AURKA NKX2_1

AKT2 ALK

CDKN2B CCND1

FGFR2 SMAD4

MAP2K4 CCNE1

PIK3R1 DNMT3A

ARID1A APC

CDK4 BRCA2

NOTCH1 ATM

RUNX1 CTNNB1

IGF1R AKT2

PTPRD FGFR1

CDK6 RET

BRAF BRAF

CCND3 RPTOR

CCND2 BAP1

RAF1 MET

SRC TET2

APC NOTCH1

ATM CCND3

SOX2 CCND2

MDM4 BRCA1

JAK2 NRAS

DNMT3A NF2
LUNG CANCER 310/342 (85.2%) of specimens harbored ≥1 actionable alteration

FGFR3 MSH6
BREAST CANCER 246/273 (86.9%) of specimens harbored ≥1 actionable alteration

BAP1 GNAS

NKX2_1 IDH1
ERBB3
COLORECTAL CANCER 103/133 (88.1%) of specimens harbored ≥1 actionable alteration

VHL
JUN MSH2

IRS2 KDM6A
Genele cele mai frecvent modificate în funcție de tipuri de tumori

AKT3 FGFR3

ARFRP1 CDK6

SMAD4 PDGFRA

STK11 KIT

RICTOR PTCH1

LRP1B KDR

KDM6A MEN1

TET2 IRS2

TSC2 SMARCB1

MEN1 HOXA3

FLT3 PTPN11
Probele de cercetare cu acționabilitate– Malignități
Heme

©2013 Foundation Medicine, Inc. | Confidential 224

Cancer Treatment: Individualized Therapy
A group of patients all have lung cancer
The tumor of each patient is tested using proteomics technology

Therapy is tailored to the molecular circuitry of the individual patient’s tumor

The Outcome:
• The correct therapy is given to the correct patient
• Higher treatment success rate
• Patients are spared unnecessary toxicity
Tumor Shrinks Tumor Shrinks

Treatment A Treatment B
Individualized Medicine in the Treatment
of Cancer

Predicted poor or no Increased likelihood of Predicted good response

response to drug toxicity of drug to drug
FIRST WE HAVE TO FIND OUT WHICH PATIENT
SHOULD GET WHICH TARGETED MEDICINE
 Actionable genomic aberations, increased knowledge
….and many new therapeutic classes and agents

IGR available drugs/clinical trials

CELL CYCLE/DIVISION INHIBITORS
APOPTOSIS MODULATORS

• Bcl-2 inh • flavopiridol

• Survivin • CDKs inh
• PARP inh • Aurora/Polo Kinases inh
• Apo/TRAIL agonists, • Kinesin/Microtubules inh
•TRAIL-R mAb

SIGNAL TRANSDUCTION
ANTI-ANGIOGENIC INHIBITORS
• Kit - PDGFR inh
• VEGF/VEGFR inh • HER Family inh
• Angiopoietins inh • Ras inh.
• Integrin antagonists •farnesyl transferase inh
• Vascular Disrupting Agents • RAF/MEK inh
• PKC inh
• Pi3K/AKT/mTOR inh

CELL REPLICATION/
EPIGENETIC REGULATION INHIBITORS
• Anti-telomerase agents
• Telomere interacting agents
• HDAC inh
• HSP90, proteasome inh
ANTI-INVASIVE AGENTS
IMMUNOMODULATORS
• Metaloproteinases-MMP inh.
• anti-CTLA4, anti-PD1/1L mAbs • Chemokines/R modulators
• TLRs agonists • Src inhibitors
• tumor vaccines
Hanahan & Weinberg, Cell 144, March 4, 2011
 Summary

 Cytototoxic chemotherapy is used to cure certain malignancies, to

palliate symptoms in advanced cancer patients
 Molecular targeted cancer therapies (also called molecular targeted
therapies) are drugs or other substances that block the growth and spread
of cancer by interfering with specific molecules involved in tumor growth
and progression or in blood vessel development, rather than interfering
with rapidly dividing cells
 The hormones and hormone antagonists that are clinically active against
cancer include steroid estrogens, progestins, androgens, corticoids and
their synthetic derivatives, nonsteroidal synthetic compounds with steroid
or steroid-antagonist activity, hypothalamic pituitary analogs, and thyroid
hormones
 Parcurs didactic

Conferențiar
92-95 Kg
Șef lucrări
79-85 kg

Student
60Kg