Spring 2020, Dept. of Pharmacology
Cancer epidemiology - incidence and mortality
in the Czech Republic
0
20
40
60
80
100
120
140
1977197919811983198519871989199119931995199719992001200320052007
Početna100000žen
Rok
ZN prsu (C50) u žen
0
10
20
30
40
50
60
70
80
90
1977197919811983198519871989199119931995199719992001200320052007
Početna100000osob
Rok
ZN kolorekta (C18-C21)
0
10
20
30
40
50
60
70
1977197919811983198519871989199119931995199719992001200320052007
Početna100000osob
Rok
ZN plic (C34)
0
20
40
60
80
100
120
1977197919811983198519871989199119931995199719992001200320052007
Početna100000mužů
Rok
ZN prostaty (C61)
0
5
10
15
20
25
30
1977197919811983198519871989199119931995199719992001200320052007
Početna100000osob
Rok
ZN ledviny (C64)
0
2
4
6
8
10
12
14
16
18
20
1977197919811983198519871989199119931995199719992001200320052007
Početna100000osob
Rok
ZN slinivky břišní (C25)
incidence mortalita
Breast Ca Colorectal Ca NSCLC
Prostatic Ca Renal ca Pancreatic Ca
Czech Cancer Care in Numbers 2015
Complex Cancer Treatment
̶ Surgery
̶ Radiotherapy
̶ Pharmacoterapy
̶ Psychotherapy, physiotherapy, nutrition care
Pharmacotherapy
̶ cytostatic agents
‒classification according to the mechanism of action
̶ endocrine (hormonal) therapy
̶ targeted therapy
‒monoclonal antibodies targeting extracellular part of receptors
‒tyrosine kinase inhibitors / intracellular signaling cascades inhibitors
̶ pain management, supportive care
̶ route of administration:
̶ parenterally (i.v. bolus, infusion, intrathecally, intravesically…)
̶ orally
̶ posology: dose in mg/m2 or mg/kg
̶ monotherapy and combination regimens
̶ repeated administration in cycles
pause = patient‘s recovery, prevention of severe AE
+ „waking“ dormant cells in G0 phase
Cytostatic drugs
Different efficacy according to the cell cycle phase:
̶ Cell cycle non-specific cytostatics (e.g., busulfan)
̶ Cell cycle specific cytostatics:
−Phase-nonspecific (e.g., some of alkylating agents)
−Phase-specific (e.g., antimetabolites, taxanes)
http://csls-text3.c.u-tokyo.ac.jp/active/13_01.html
Cytostatic drugs
Cytostatics according to their MoA
1. Drugs that damage the structure of DNA
a) Alkylating agents
b) Platinum derivatives
c) Intercalating agents
d) Bleomycin
2. Drugs that inhibit key enzymes of DNA metabolism
a) Antimetabolites:
i. Purine analogues
ii. Pyrimidine analogues
iii.Folic acid analogues
iv.Hydroxyurea
b) Topoisomerase inhibitors:
i. Inhibitors of topoisomerase I – camptothecins
ii. Inhibitors of topoisomerase II – podophyllotoxins
3. Drugs that alter microtubules
a) Inhibitors of tubulin polymerization – Vinca alkaloids
b) Inhibitors of tubulin depolymerization – taxanes
4. Others
a) Drugs that inhibit protein synthesis – L-asparaginase
Drug groups overview
1. Drugs that damage the structure of DNA
a) Alkylating agents
b) Platinum derivatives
c) Intercalating agents
d) Bleomycin
2. Drugs that inhibit key enzymes of DNA metabolism
a) Antimetabolites:
i. Purine analogues
ii. Pyrimidine analogues
iii.Folic acid analogues
iv.Hydroxyurea
b) Topoisomerase inhibitors:
i. Inhibitors of topoisomerase I – camptothecins
ii. Inhibitors of topoisomerase II – podophyllotoxins
3. Drugs that alter microtubules
a) Inhibitors of tubulin polymerization – Vinca alkaloids
b) Inhibitors of tubulin depolymerization – taxanes
4. Others
a) Drugs that inhibit protein synthesis – L-asparaginase
Cytostatics according to their MoA
A
C
T
G
syntesis
THF
DHF
DNA structure
alkylating agents
1a) Alkylating agents
• MoA: transfer of the alkyl group on nitrogen in nucleobases, covalent bond
between two guanines of one or two DNA strands
– Inhibition of replication, cell cycle arrest
• 50s: first derivatives of sulphur mustard in the clinical practice
• AE – typical toxicity: secondary malignancies – hematological
1a) Alkylating agents
ALKYLATING AGENTS
Nitrosourea derivatives:
CYCLOPHOSPHAMIDE
LOMUSTINE
MITOMYCIN CBUSULFANTEMOZOLOMIDE
DACARBAZINE
IFOSFAMIDECHLORAMBUCIL
MELPHALANE CARMUSTINE
1a) Alkylating agents – main drugs
Melphalane
• i.v., p.o. administration
• treatment of hematological malignancies and solid tumors
Cyclophosphamide
• i.v., p.o. administration
• prodrugs → CYP450 → cytotoxic metabolites
• AE: urotoxicity, emetogenity
• low doses – immunosuppressant
• hematological malignancies and solid tumors
Lomustine
• p.o. administration
• lipophilic, crosses BBB → treatment of brain tumors
1a) Alkylating agents
Temozolomide
− 100% bioavailability after oral administration
− crosses BBB → treatment of brain tumors
Busulfan
− i.v., p.o. administration
− bone marrow transplantation
− treatment of hematological malignancies
1a) Alkylating agents
A
C
T
G
syntesis
THF
DHF
DNA structure
platinum derivatives
1b) platinum derivates
• MoA: binding on DNA, cross-linking of DNA strands, inhibition
of topoisomerases
• AE – most important: emetogenity, nephrotoxicity
– AE are dose-dependent
– prevention of nephrotoxicity: i.v. hydration, forced diuresis
• cisplatin – high nephrotoxicity
– treatment of solid tumors
• others:
– carboplatin
– oxaliplatin – typical neurotoxicity
1b) platinum derivates
A
C
T
G
syntesis
THF
DHF
DNA structure
intercalating agents
1c) intercalating agents
Anthracyclines
• MoA: intercalation = insertion between base pairs, binding
of DNA strands
• AE – typical toxicity: acute and chronic cardiotoxicity
• cardioprotective cumulative dose = restraint of therapy
(e.g., doxorubicin 550 mg/m2)
• i.v., intravesical administration
• doxorubicin
– treatment of hematological malignancies and solid tumors
– modern dosage form (PEGylated liposomes) – higher
cumulative dose (860 mg/m2)
• others: epirubicin…
1c) intercalating agents
– MoA: intercalation between base pairs
+ inhibition of thymine incorporation
→ breaks → DNA fragmentation
(„radiomimetic“ effect)
– i.v. administration
– treatment of solid tumors
– typical AE: fever,
hyperkeratosis and
hyperpigmentation of skin
(flagellate = whip-like)
– risk of anaphylactic reaction
1d) bleomycin
1. Drugs that damage the structure of DNA
a) Alkylating agents
b) Platinum derivatives
c) Intercalating agents
d) Bleomycin
2. Drugs that inhibit key enzymes of DNA metabolism
a) Antimetabolites:
i. Purine analogues
ii. Pyrimidine analogues
iii.Folic acid analogues
iv.Hydroxyurea
b) Topoisomerase inhibitors:
i. Inhibitors of topoisomerase I – camptothecins
ii. Inhibitors of topoisomerase II – podophyllotoxins
3. Drugs that alter microtubules
a) Inhibitors of tubulin polymerization – Vinca alkaloids
b) Inhibitors of tubulin depolymerization – taxanes
4. Others
a) Drugs that inhibit protein synthesis – L-asparaginase
Cytostatics according to their MoA
A
C
T
G
syntesis
THF
DHF
metabolism of
nucleic acids
antimetabolites
2a. antimetabolites
- MoA: false substrates = affinity to target structure, loss of
endogenous effect → blockade of nucleic acid synthesis,
inhibition of nucleotides metabolism enzymes, production of
non-sense DNA sequences
- prodrugs: intracellular activation mostly by phosphorylation
a) purine analogues – 6-mercaptopurine, azathioprine,
fludarabine…
b) pyrimidine analogues – fluorouracil, capecitabine,
gemcitabine…
c) folic acid analogues – methotrexate, pemetrexed…
2a. antimetabolites
6-Mercaptopurin
• MoA: inhibition of purine nucleobases biosynthesis de
novo, inhibition of mutual conversion of purine nucleotides
• thiopurin methyltransferase (TPMT): MP → MeMP
– genetic polymorphism – ↑ toxicity / ↓ efficacy
– available pharmacogenetic testing of TPMT
• p.o. administration, treatment of hematologic malignancies
• azathioprine – prodrug of MP, immunosuppressant
inactive
2a. Antimetabolites – i/ purine analogs
5-Fluorouracil
• MoA: incorporation to RNA + inhibition of thymidylate
synthetase
• combined chemotherapeutic regimens of solid cancers (i.v.)
• AE – typical toxicity: GIT toxicity (mucositis)
• biochemical modulation of effect: leucovorin (folinic acid)
enhances binding on thymidylate synthetase, i.v. administered
before FU
– „FUFA“ regimen = colorectal carcinoma
• capecitabine – prodrug
2a. Antimetabolites – ii/ pyrimidines
analogs
Methotrexate – intracellular mechanism of action:
MTX
MTXPG
TYMS DHFR
other enzymes
dUMP
TMP
Pyrimidine nucleotides
biosynthesis:
DHF THF
5-Me-THF
homocysteine
methionine
Purine nucleotides
biosynthesis:
SAM
polyglutamylation
One-carbon
metabolism
2a. Antimetabolites – iii/ folic acid
analogs
Methotrexate
- MoA: inhibition of dihydrofolate reductase, thymidylate
synthetase and other enzymes
- i.v., intrathecal administration, p.o.
- leucovorin (folinic acid) – „rescue therapy“, antidote
forces free MTX out of healthy cells ; in cancer cells, polyglutamylation is
more intensive → more MTXPG → MTXPG cannot be forced out
TDM – calculation of time interval from MTX administration,
frequently in pediatric patients, less frequent in adults
- AE – typical toxicity:
nephrotoxicity – precipitation (acute renal failure)
prevention: hydration, urine alkalinization (pH 7–7,5)
pneumotoxicity
- low-dose MTX = immunosuppressant (p.o.)
- high-dose MTX = hematological malignancies
2a. Antimetabolites – iii/ folic acid
analogs
1. Drugs that damage the structure of DNA
a) Alkylating agents
b) Platinum derivatives
c) Intercalating agents
d) Bleomycin
2. Drugs that inhibit key enzymes of DNA metabolism
a) Antimetabolites:
i. Purine analogues
ii. Pyrimidine analogues
iii.Folic acid analogues
iv.Hydroxyurea
b) Topoisomerase inhibitors:
i. Inhibitors of topoisomerase I – camptothecins
ii. Inhibitors of topoisomerase II – podophyllotoxins
3. Drugs that alter microtubules
a) Inhibitors of tubulin polymerization – Vinca alkaloids
b) Inhibitors of tubulin depolymerization – taxanes
4. Others
a) Drugs that inhibit protein synthesis – L-asparaginase
Cytostatics according to their MoA
A
C
T
G
syntesis
THF
DHF
DNA replication
topoisomerase inhibitors
2b. Topoisomerase inhibitors
Topoisomerase I inhibitors – camptothecins
- plant-derived drugs – identification in bark of the tree
Camptotheca acuminata
- derivatives: irinotecan, topotecan
– treatment of solid tumors
Topoisomerase II inhibitors – podophyllotoxins
- plant-derived drugs – identification in Podophyllum peltatum
- derivatives: etoposide, teniposide
– treatment of solid tumors (etoposide) and hematological
malignancies (teniposid)
2b. Topoisomerase inhibitors
ETOPOSIDE
1. Drugs that damage the structure of DNA
a) Alkylating agents
b) Platinum derivatives
c) Intercalating agents
d) Bleomycin
2. Drugs that inhibit key enzymes of DNA metabolism
a) Antimetabolites:
i. Purine analogues
ii. Pyrimidine analogues
iii.Folic acid analogues
iv.Hydroxyurea
b) Topoisomerase inhibitors:
i. Inhibitors of topoisomerase I – camptothecins
ii. Inhibitors of topoisomerase II – podophyllotoxins
3. Drugs that alter microtubules
a) Inhibitors of tubulin polymerization – Vinca alkaloids
b) Inhibitors of tubulin depolymerization – taxanes
4. Others
a) Drugs that inhibit protein synthesis – L-asparaginase
Cytostatics according to their MoA
A
C
T
G
syntesis
THF
DHF
tubulin
Vinca alkaloids and taxanes
3. Tubulin alterating cytostatics
TAXANES VINCA ALK.
3. Tubulin alterating cytostatics
- ant-derived drugs
- MoA: inhibition of tubuline dimers polymerization
inhibition of mitotic spindle formation, depolymerization
prevails
- i.v. administration, some for p.o. (vinorelbine)
- treatment of hematological malignancies and solid tumors
- AE – typical toxicity: peripheral neuropathy
- original alkaloids: vincristine, vinblastine
- semisynthetic derivatives: vinorelbine, vindesin, vinflunine
increased affinity to mitotic spindle tubulin, ↓ AE
3a. Vinca alkaloids
VINBLASTINE
• identification:
lesser periwinkle
(Vinca minor)
• isolation:
Cataranthus roseus
Vinca alkaloids
- plant-based drugs
- MoA: inhibition of tubulin depolymerization
- i.v. administration – treatment of solid tumors
- AE – typical toxicity: neurotoxicity
- paclitaxel, docetaxel, cabazitaxel
- modern dosage form: paclitaxel conjugated with albumine
nanoparticles
- transporter protein for albumine in cancer cells = better
distribution from circulation into the tissues
– ↓ toxicity, ↑ efficacy
3b. taxanes
PACLITAXEL
• identification and
isolation: Taxus brevifolia
(Pacific yew) a Taxus
baccata (European yew)
Taxanes
- monotherapy
- combination regimens – examples:
FUFA fluorouracil, folinic acid
FOLFOX folinic acid, fluorouracil, oxaliplatin
ABVD doxorubicin, bleomycin, vinblastine, dacarbazine
BEACOPP bleomycin, etoposide, doxorubicin,
cyclophosphamide, vincristin, procarbazine,
prednisone
Combination of cytostatics
„Targeted therapy“in oncology
Targeted therapy in oncology (biological
therapy)
„target“ should be on
A/ tumor cells
-Cell membrane receptor – extracellular part or/ intracellular
signalling pathway
B/ immune system (specific T-cells) – cancer immunotherapy
-Immune check-point inhibitors (anti-CTLA-4 or anti-PD(L)1)
A/ target on tumor cells
The most common targets
̶ EGFR (epidermal growth factor receptor)
̶ VEGF(vascular endothelial growth factor receptor)
̶ PDGF (platelet derived growth factor receptor)
̶ FGF (fibroblast growth factor receptor)
…should be pharmacologically modulates
-by antagonization of extracelullar part of receptor / or
endogenous ligand - Monoclonal antibodies (-mabs)
-by inhibition of intracellular pathway – proteinkinase
inhibibitors (-nibs)
Targeted therapy – „mAbs and –nibs“
Cell
membrane
Ligand
bindingl
Receptor´s activation
Proliferation Migration
Tumor growth and
matastases
Survival
Signal
transduction
Receptors with
TKI activities
Tyrosin-
Kinases
domain
(TKI)
Monoclonal
antibodies
Tyrozin-kinases
inhibitors
B-Raf
Targeted therapy – „mAbs and –nibs“
HER-2 positive breast cancer
1985 – identification of
the human Her-2/neu gene
as a negative prognostic
marker
Methods : IHC, FISH
Incidence:
▪ worldwide: 10-25%
▪ european: 17%
▪ czech: 14,2%
Yang-Feng et al. Cytogenet. Cell Genet. 1985; Slamon et al, Science 1987; Pegram et al, JCO 1998; Owens et al. Clin Breast
Can 2004; Al-Kuraya K et al. Mod Pathol 2000; Fabian et al, Sborník BOD 2006,
HER2
HER1-4
Trastuzumab
binds to subdomain IV
and inhibits
downstream signalling
Trastuzumab (HERCEPTIN):
Mechanisms of Action
Cell membrane
Franklin MC, et al. Cancer Cell. 2004;5(4):317-328.
• INDICATIONS:
treatment of locally advanced and metastatic HER-2
positive breast cancer or adjuvant therapy of breast Ca
• ADVERSE EVENTS:
allergic reaction, fever, chills, hypotension
cardiotoxicity
diarrhea, nausea, vomiting, rash
muscle and joint pain
pulmonary infiltrates, penumonitis
Trastuzumab (HERCEPTIN):
HER2
HER1-4
Pertuzumab binds to a
specific domain II and
inhibits ligand-activated
dimerization
Trastuzumab
binds to subdomain IV
and inhibits
downstream signalling
Pertuzumab (PERJETA):
Mechanisms of Action
The combined regimen of pertuzumab and trastuzumab offers the potential
for a more comprehensive HER blockade
Cell membrane
Franklin MC, et al. Cancer Cell. 2004;5(4):317-328.
Cell membrane
T-DM1: Antibody Drug Conjugate
trastuzumab + emtansin conjugate
Intracellular emtansine release →
inhibition of microtubule polymerization
LoRusso PM, et al. Clin Cancer Res. 2011;17(20):6437-6447.
HER2 HER2
▪ Reversible inhibitor EGFR (HER-1), HER-2
▪ Activity in trastuzumab-rezistent tumors
▪ Oral administration, well tolerated
INDICATION:
Metastatic breast carcinoma after trastuzumab failure
Konecny et al, 2006, Allen et al, 2002
Lapatinib (TYVERB)
Mechanisms of Action
MAIN ADVERSE EVENTS:
• gastrointestinal toxicity (diarrhea, dehydration,
abdominal pain, nausea, vomiting)
• dermal toxicity - rash, pruritus, dry skin
RARE ADVERSE EVENTS:
• cardiotoxicity (2,5% pts.)
• neutropenia
• lung toxicity
• hepatotoxicity
•
Lapatinib (TYVERB)
VEGF (vascular endothelial growth factor
receptor) and mAb
• The growth of malignant tumor needs the continuous
supply of oxygen and nutrients
• Simple diffusion and not enough nutrition to the cells
under the influence of hypoxia
• Tumor produced a series mediators, particularly VEGF
(vascular endothelial factor).
EGF
Hypoxia PDGF
IL-8
bFGF
COX-2
NO
Oncogenes
VEGF release
Binding and activation
of VEGFR
ProliferationSurvival Migration
ANGIOGENESIS
Permeability
Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
– P
– P
P–
P–
PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1
IL-8 = insulin-like growth factor 8
IGF-1
VEGF (vascular endothelial growth factor
receptor) and mAb
Bevacizumab (AVASTIN ®)
• Monoclonal antibody against VEGF, bevacizumab
binds to VEGF and prevents it from binding to
receptors.
• This induced inhibition of angiogenesis and its longterm
use leads to regression of tumor vasculature,
the normalization of surviving tumor vessels and
inhibition of recovery and growth of new blood
vessels
INDICATION:
• Metastatic colorectal carcinoma
• Metastatic breast Ca, renal Ca, NSCLC
ADVERSE EVENTS:
• Acceleration of hypertenzion
• proteinuria
• Trombembolic complication
Bevacizumab (AVASTIN ®)
Philadelphia Chromosome
(BCR-ABL Translocation)
• Bcr-abl inhibitor – chronic myeloid leukémia
• c-KIT inhibitor – 1st line treatment of GIST
(mutation c-KIT in 85% pts.) – 70% of the
pts. Are responders!!!
AE:
- neutropenia, trombocytopenia
• diarrhoea, vomiting
- joint pain
Imatinib mesylate (GLIVEC ®)
– anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) –
ipilimumab, tremelimumab
– anti-PD-1 (programmed death-1 receptor) nivolumab,
pembrolizumab
– anti-PD-L1 – atezolizumab
Immunotherapy in oncology –
„Checkpoint inhibitors“
Activation of T lymfocytes through TCR
and co-stimulating molecule CD28
Dendritic
cell T lymfocyte
MHC
B7
TCR
CD28
Antigen
CTLA-4
Up-regulation of CTLA-4 receptors after
T- cell activation
Dendritic
cell T lymfocyte
MHC
B7
TCR
CD28
Antigen
CTLA-4
CTLA-4 receptor inhibition
Dendritic
cell T lymfocyte
MHC
B7
TCR
CD28
Antigen
CTLA-4
Antagonisation of CTLA-4 receptors
Ipilimumab
Dendritic
cell T lymfocyte
MHC
B7
TCR
CD28
Antigen
CTLA-4
Leach DR, Science 1996;271:1734-1736.
Ipilimumab
Ipilimumab: Managing Immune-Related
Adverse Events
System Symptoms Management
GI tract Diarrhea
Abdominal pain
Dark, bloody stools
Moderate enterocolitis: hold ipilimumab, administer antidiarrheal.
Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day:
start methylprednisone, permanently discontinue ipilimumab.
Consider infliximab for corticosteroid-refractory patients
Skin Rash (± itching)
Blistering/peeling
Oral sores
Moderate/nonlocalized rash: hold ipilimumab,
start topical or systemic corticosteroids. Severe dermatitis:
permanently discontinue ipilimumab, start corticosteroids
Liver Jaundice
Nausea/vomiting
Assess ALT/AST, bilirubin, and thyroid function before each dose and
as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN;
permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN.
The immunosuppressant mycophenolate can be used for
hepatotoxicity in corticosteroid-refractory patients
CNS Weakness in extremities
Numbness/tingling
Sensory changes
Moderate neuropathy: hold ipilimumab. New or worsening neuropathy:
permanently discontinue ipilimumab. Consider corticosteroids
Endocrine Headaches
Fatigue
Behavior/mood changes
Menstruation changes
Dizziness/light-headedness
Moderate endocrinopathy: hold ipilimumab, start corticosteroids.
Endocrine abnormalities can be difficult to detect, due to nonspecific
symptoms. Consider having an endocrinologist follow the patient
Eyes Vision problems
Irritation
Monitor for redness suggesting uveitis, treat with topical steroidal eye drops
Ipilimumab adverse reaction management guide.
Gajewski TF, et al. Curr Opin Immunol. 2011;23:286-292. Spranger S, Gajewski T. J Immunother cancer.
2013;1:16.
Checkpoint inhibitors – PD-(L)-1
▪ T cell recruitment
– High levels of innate
immune signals
– Chemokine expression
▪ Nevertheless, negative
immune regulators
dominate
▪ Blocking PD1:PD-L1
binding might activate
immunity within the
tumor microenvironment
Cytotoxic
T cell
Chemokines
Migration
T reg
Tumor
PD-L1
Anergy
MDSC
PD1
Clinical Development of Inhibitors of PD-1
Immune Checkpoint
Target Antibody Molecule Development stage
PD-1
Nivolumab
(BMS-936558)
Fully human IgG4
Phase III multiple tumors
(melanoma, RCC, NSCLCa,
HNSCC)
Pembrolizumab
(MK-3475)
Humanized IgG4
Phase I-II multiple tumors
Phase III NSCLC/melanoma
Pidilizumab
(CT-011)
Humanized IgG1 Phase II multiple tumors
PD-L1
MEDI-4736 Engineered human IgG1 Phase I-II multiple tumors
MPDL-3280A Engineered human IgG1
Phase I-II multiple tumors
Phase III NSCLC
MSB0010718C Fully human IgG1 Phase I solid tumors
Eventsper
100person-years
Observation period (no. pts; P-Y)
Nivolumab Exposure-adjusted irAEs:
Toxicity Is Not Cumulative
▪ Multiple occurrences of all-cause select AEs in individual pts are included in
this exposure-adjusted analysis.
▪ Treatment-related Gr 3-4 AEs occurred in 17% of pts, including select AEs in
6%.
0-6 mo. (n = 306; P-Y = 138)
6-12 mo. (n = 189; P-Y = 59)
12-24 mo. (n = 85; P –Y = 49)
140
120
100
80
60
40
20
0
Topalian SL, et al. J Clin Oncol. 2014;32:1020-1030.
Thank you for your attention