Transcript Targeted Therapies and Monoclonal Antibodies - hof

Recent Developments in Oncology
Robert H. Cassell, M.D., Ph.D.
Medical Director, Cassidy Cancer Center
Clinical Assistant Professor, Dept. of Medicine,
University of Florida College of Medicine
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Recent Developments in
Oncology
There have been many new and exciting
developments in cancer
• New diagnostic modalities
• New ways to predict the outcome and prognosis
of various cancers
• New treatment advances
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New surgical techniques
New ways of delivering radiation therapy
New chemotherapy drugs
New supportive therapies
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Recent Developments in
Oncology – My Favorite
Use of new knowledge in science, including
genetics and molecular biology, and the new
fields of genomics and proteomics, to develop
“rational” therapies to treat cancer
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“CANCER”
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“CRAB”
How Do You Treat…
Crabgrass
-- Cut It or Tear it Out
Cancer
-- Surgery
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How Do You Treat…
Crabgrass
-- Cut It or Tear it Out
Cancer
-- Surgery
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How Do You Treat…
Crabgrass
-- Burn It
Cancer
-- Radiation Therapy
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How Do You Treat…
Crabgrass
-- Burn It
Cancer
-- Radiation Therapy
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How Do You Treat…
Crabgrass
-- Poison It
Cancer
-- Chemotherapy
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How Do You Treat…
Crabgrass
-- Poison It
Cancer
-- Chemotherapy
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What If…
• You could understand what makes crab grass
crab grass, so that you could do something
specific to kill only the crab grass
OR
• You could change the crab grass, so it behaved
and looked like normal grass
***********
I don't think we can do this with crab grass but we
are starting to be able to do this sort of thing with
cancer
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Terminology
• The current buzzword in medicine is
"personalized medicine."
• This means treating each patient as a separate
individual based on their characteristics and the
characteristics of their disease(s).
• In oncology, we generally use the term “targeted
therapy” or, more precisely, “molecularly
targeted therapy.”
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What Makes Cancer Cells
Cancerous?
• 1) Increased response to growth signals and
production of their own growth signals
• 2) Insensitivity to anti-growth signals
• 3) Evasion of apoptosis – failure to die at the
right time
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Apoptosis
(Programmed Cell Death)
What Makes Cancer Cells
Cancerous?
• 1) Increased response to growth signals and
production of their own growth signals
• 2) Insensitivity to anti-growth signals
• 3) Evasion of apoptosis – failure to die at the
right time
• 4) Limitless replication potential – keep dividing
indefinitely
• 5) Sustained angiogenesis (new blood vessels)
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Angiogenesis
(New Blood Vessel Growth)
What Makes Cancer Cells
Cancerous?
• 1) Increased response to growth signals and
production of their own growth signals
• 2) Insensitivity to anti-growth signals
• 3) Evasion of apoptosis – failure to die at the
right time
• 4) Limitless replication potential – keep dividing
indefinitely
• 5) Sustained angiogenesis (new blood vessels)
• 6) Tissue invasion and metastasis
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What Makes Cancer Cells
Cancerous?
Other characteristics of cancer cells:
• Stem cell or progenitor cell phenotype – they
start out looking like normal (or benign) cells but
at a primitive stage of development
• Increased mutation rate
• Evasion of, or resistance to, normal immune
responses
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Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100(1):57–70.
“Targeted” Cancer Treatment
How does it work?
Attack targets which are specific for the cancer cell
and are critical for its survival or for its malignant
behavior
Why is it better than chemotherapy?
More specific for cancer cells –
chemotherapy hits rapidly growing cells
not all cancer cells grow that rapidly
some normal cells grow rapidly
Possibly more effective
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Cancer Targets
From National Cancer Institute, US National Institutes of Health.
Cancer Targets
From National Cancer Institute, US National Institutes of Health.
Cancer Targets
From National Cancer Institute, US National Institutes of Health.
Targets
• The targets currently being used are those that block the
growth and spread of cancer by interfering with specific
molecules involved in tumor growth and progression.
• The focus is on proteins that are involved in cell
signaling pathways, which form a complex
communication system that governs basic cellular
functions and activities, such as cell division, cell
movement, how a cell responds to specific external
stimuli, and even cell death.
• We use the term “signal transduction” to refer to the
actions of these proteins.
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Tumor Cell Stimulation
ATP
TK
TK
ATP
+
Survival
Gene Transcription
Metastases
Cell Cycle Progression
Antiapoptosis
Cell Proliferation
Angiogenesis
Targeted Therapy
• The first molecular target for targeted cancer
therapy was the cellular receptor for the female
sex hormone estrogen, which many breast
cancers require for growth. When estrogen
binds to the estrogen receptor (ER) inside cells,
the resulting hormone-receptor complex
activates the expression of specific genes,
including genes involved in cell growth and
proliferation.
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Therapy Targeted at the Estrogen
Receptor
• Selective estrogen receptor modulators (SERMs)
– tamoxifen (Nolvadex)
– toremifene (Fareston)
• Estrogen receptor inhibitor and destroyer
– fulvestrant (Faslodex)
• Estrogen synthesis inhibitors – aromatase inhibitors
(AIs)
– anastrozole (Arimidex)
– letrozole (Femara)
– Exemestane (Aromasin)
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Strategies to Inhibit Signaling
tyrosine kinase Anti- mAbs
inhibitors
“-mab”
“-ibs”
ATP
TK
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Anti-ligand
mAbs
“-mab”
TK
TK
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Philadelphia Chromosome
Philadelphia Chromosome
(BCR-ABL Translocation)
BCR-ABL Translocation
Oncogenes
c-met
RAS
BRAF
PI3K
PTE
N
CRAF
MEK
AKT
p16
Cyclin D
ERK
CDK2
CDK4
mTor
Targeted inhibitors
c-met
in development
XL880
RAS
BRAF
R115777
SCH66336
Sorafenib
RAF-265
PLX4032
MEK
PI3K
SF1126
XL147
GSK690693
VQD-002
PD0325901
AZD6244
PD332991
CYC202
p1
6
Cyclin D
ERK
BMS-387032
CDK2
CDK4
PTE
N
AKT
temsirolimus
everolimus
AP23573
mTor
Signal Pathways in the Cancer Cell
The “Nibs”
Small molecule tyrosine kinase inhibitors (or TKIs)
– generic names end in “-nib”
Generally oral
Side effects vary, depending on which enzymes
they inhibit (what their target is)
Eight are FDA-approved, numerous others are in
development
Several are effective against cancers resistant to
most previous therapies
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FDA-Approved TKIs
Generic Name
Brand Name
Cancer
Imatinib
Gleevec
CML, GIST, others
Dasatinib
Sprycel
CML, ALL
Nilotinib
Tasigna
CML
Gefitinib
Iressa
Lung
Erlotinib
Tarceva
Lung, Pancreas
Lapatinib
Tykerb
Breast
Sorafenib
Nexavar
Kidney, Liver
Sunitinib
Sutent
Kidney
Monoclonal Antibodies
Another type of targeted therapy – they are large
molecules produced through genetic
engineering
They usually have to be given IV
Side effects can include reactions to non-human
proteins
They can cause cell damage in several ways, most
often by attacking cell-surface receptors
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Tumor
NRPs
TGFβ
bFGF
PDGF
VEGF
Ang
HGF
RAS
BRAF
PI3K
MEK
AKT
Endothelial cell &
Pericyte
ERK
mTor
Eph
Trastuzumab
• Monoclonal antibody against epidermal growth
factor receptor 2 (EGFR2, HER-2)
• Very effective against breast cancers in which
HER-2 is “over-expressed” (more than usual
amount per cell) (about 20% of all breast
cancers)
• Often used in combination with chemotherapy
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Cetuximab
• Monoclonal antibody against epidermal growth
factor receptor 1 (EGFR1)
• Effective in colon cancer and head and neck
cancer; possibly useful in lung cancer
• Used with chemotherapy and with radiation
therapy
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Bevacizumab
• Monoclonal antibody against vascular
endothelial growth factor (VEGF), which
stimulates angiogenesis (growth of new blood
vessels into tumor)
• Deprives tumors of the blood supply they need
for growth and invasion
• Effective against cancers of colon, lung, breast,
kidney, and brain
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Monoclonal Antibodies
FDA-Approved “Naked” (Non-Conjugated) MoAbs
Generic Name
Brand Name
Target
Cancer(s)
Alemtuzumab
Campath
CD52
CLL
Bevacizumab
Avastin
VEGF
Multiple
Cetuximab
Erbitux
EGFR1
Colon, H&N
Panitumumab
Vectibix
EGFR1
Colon
Rituximab
Rituxan
CD20
Lymphomas
Trastuzumab
Herceptin
HER-2
Breast
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Monoclonal Antibodies
• Conjugated antibodies currently approved
– Radio-conjugated antibodies
• Tositumomab (Bexxar)
• Ibritumomab (Zevalin)
• Both used against refractory lymphomas
– Toxin-conjugated antibody
• Gemtuzumab ozogamicin (Mylotarg)
• Used against AML
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Monoclonal Antibodies In
Development
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Epratuzumab
Matuzumab
Nimotuzumab
Zalutumumab
Pertuzumab
Mapatumumab
Lexatumumab
Volociximab
Pemtumomab
Labetuzumab
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•
•
•
•
•
•
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•
ch806
CP-751,871
IMC-A12
VEGF-Trap
IMC-18F1
IMC-1121B
IMC-3G3
Vitaxin
CNTO 95
Types of MoAbs
Structure
% Human
Example
Comments
Mouse
0
Tositumomab,
Ibritumomab
Radioconjugates
Chimeric
65
Cetuximab,
Rituximab
Humanized
95
Trastuzumab
Human
100
Panitumumab
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Transgenic mice
Nomenclature of MoAbs
• Last syllable is always –mab
• Next to last syllable




-u- human (100%) : Panitumumab
-zu- humanized (95%) : Trastuzumab
-xi- chimeric (65%) : Rituximab
-o- mouse, -a- rat, -e- hamster, -i- primate : Tositumomab
• Previous syllable
– -tu(m)- for tumor in general [-ma(r)- breast, -pr(o)- prostate, co(l)- colon, etc.]
– -ci(r)- for circulatory : Bevacizumab
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New Directions
• Combination of different targeted therapies
(multiple TKIs, TKI with MoAb; occasionally
multiple MoAbs)
• Combination with standard chemotherapy or
with radiotherapy
• Targeted agents to “clean up” after surgery
• Use with other novel agents
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Other Novel Types of Cancer
Therapies Now in Use
• Proteasome inhibitors (Bortezomib)
• mTOR inhibitors (Temsirolimus, Everolimus)
• DNA demethylating agents (Azacytidine,
Decitabine)
• Histone deacetylase inhibitors (Vorinostat)
• Translocation targeters (retinoic acid)
• Antiangiogenic agents (Thalidomide,
Lenalidomide)
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Other Novel Types of Cancer
Therapies in Development
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Integrin inhibitors (Volociximab)
“Death” receptor stimulants
Telomerase inhibitors
Apoptosis promoters
DNA repair inhibitors (PARP inhibitors, etc.)
Heat shock protein targeters
Antagonists of specific gene mutations
Antisense agents
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Biotherapeutic Agents
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Interferons
Interleukins
Cancer Vaccines
Immunomodulatory agents
Colony stimulating factors
Monoclonal antibodies
Gene therapy
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Take Home Points
• Molecularly targeted therapy is a new way of approaching cancer
treatment
• It is based on recent scientific advances in molecular biology,
chemistry, and genetics
• It involves the rational selection of drugs which target specific
processes in cancer cells that make them different from normal cells
• A number of targeted therapies are currently available and many
others are in development
• Targeted therapies are frequently effective but are not perfect: There
are side effects to the treatments, and there may be development of
resistance
• Targeted therapies are increasingly being used in combination with
other targeted therapies or with other treatment modalities
• We definitely will be hearing much more about targeted therapies for
cancer in the future
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Thank You for your Attention
Cassidy Cancer Center
Winter Haven Hospital
200 Ave. F, NE
Winter Haven, FL 33881-4131
863-292-4670
www.winterhavenhospital.com/facilities/CCC
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