Recent Developments in Oncology

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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
• 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

• CRAB

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How Do You Treat

• Crabgrass --
• Cancer --

• Cut It or Tear it Out
• Surgery

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How Do You Treat

• Crabgrass --
• Cancer --

• Cut It or Tear it Out
• Surgery

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How Do You Treat

• Crabgrass --
• Cancer --

• Burn It
• Radiation Therapy

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How Do You Treat

• Crabgrass --
• Cancer --

• Burn It
• Radiation Therapy

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How Do You Treat

• Crabgrass --
• Cancer --

• Poison It
• Chemotherapy

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How Do You Treat

• Crabgrass --
• Cancer --

• Poison It
• 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)
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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
• 4) Limitless replication potential keep
  dividing indefinitely
• 5) Sustained angiogenesis (new blood vessels)

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Angiogenesis(New Blood Vessel Growth)
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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
• 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)5770.

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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.

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Cancer Targets

• From National Cancer Institute, US National
  Institutes of Health.

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Cancer Targets

• From National Cancer Institute, US National
  Institutes of Health.

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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
Metastases
Survival
Gene Transcription Cell Cycle Progression
Antiapoptosis
Cell Proliferation
Angiogenesis
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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
Anti-ligand mAbs -mab
tyrosine kinase inhibitors -ibs
Anti- mAbs -mab
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Philadelphia Chromosome
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Philadelphia Chromosome

• (BCR-ABL Translocation)

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BCR-ABL Translocation
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Oncogenes
c-met
RAS
PI3K
BRAF
PTEN
CRAF
MEK
AKT
p16
Cyclin D
ERK
mTor
CDK4
CDK2
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Targeted inhibitors in development
XL880
c-met
RAS
PI3K
BRAF
R115777 SCH66336
PTEN
SF1126 XL147
Sorafenib RAF-265 PLX4032
AKT
GSK690693VQD-002
PD0325901 AZD6244
MEK
p16
temsirolimus everolimus AP23573
PD332991 CYC202
mTor
Cyclin D
ERK
CDK4
CDK2
BMS-387032
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Signal Pathways in the Cancer Cell
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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
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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
RAS
PI3K
BRAF
MEK
AKT
Endothelial cell Pericyte
mTor
ERK
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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, HN
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

• Epratuzumab
• Matuzumab
• Nimotuzumab
• Zalutumumab
• Pertuzumab
• Mapatumumab
• Lexatumumab
• Volociximab
• Pemtumomab
• Labetuzumab

• ch806
• CP-751,871
• IMC-A12
• VEGF-Trap
• IMC-18F1
• IMC-1121B
• IMC-3G3
• Vitaxin
• CNTO 95

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Types of MoAbs
Structure Human Example Comments
Mouse 0 Tositumomab, Ibritumomab Radio-conjugates
Chimeric 65 Cetuximab, Rituximab
Humanized 95 Trastuzumab
Human 100 Panitumumab Transgenic mice
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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

• 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

• 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