Knowledge is Power: Updates in Oncology

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Knowledge is Power Updates in Oncology
Barbara Bowers, M.D. Medical Director Fairview
Southdale Medical Oncology Clinic
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Topics
Vitamin D Bisphosphonates Targeted Cancer
Therapies Other Novel Approaches
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Vitamin D
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Vitamin D
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What does Vitamin D do?

• Regulates cell growth and differentiation
• Some studies show low levels of Vitamin D
• More aggressive tumors
• Increased BMI
• Increased insulin levels
• More research needed

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Natural Medicines for Breast Cancer
SAFETY EFFECT Likely Safe Possibly Safe Insufficient Evidence Possibly Unsafe
Effective
Possibly Effective Beta Carotene fish oil green tea Melatonin Olive soy Vitamin A
Insufficient Evidence Coenzyme Q-10 Flaxseed Shiitake mushroom Beta glucans Chrysin European mistletoe Indole-3-carbinol Maitake mushroom red clover Calcium D-glucarate Genistein combined poly-saccharide Essiac Flor-Essence
Likely Ineffective Vitamin E
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Bisphosphonates
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Bisphosphonates

• Zometa draws calcium from surrounding tissues and
  places it back into the bones to stimulate
  regrowth
• Reverses osteopenia
• Used to strengthen bones in patients with bone
  metastases

Tissue Ca
Ca absorbed by intestinal tract
Ca in bone
Serum Ca
Kidney filters out Ca
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Biphosphonates

• Recent studies for breast cancer show
• Some anti-tumor effects
• Some anti-metastases effects
• These are results from initial clinical studies,
  and further study and testing is still required

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Targeted Cancer Therapies
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Targeted Cancer Therapies

• Tamoxifen
• Arimidex
• Aromasin
• Faslodex
• Fareston
• Femara
• Megace (endometrial)

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Complex HER Receptor Signaling Pathway
LPA thrombin ET, etc
TGFa (1)
EGF (1)
Epi- regulin (1,4)
ß-cellulin (1)
HB-EGF (1,4)
Amphi- Regulin (1)
NRG1 (3,4) a ß
NRG2 (4) a ß
NRG3 (4)
NRG4 (4)
Cytokines
Ligands
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2
1
4
3
2
4
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Receptor Dimers
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1
2
2
3
4
1
2
3
3
1
3
X
X
X
X
X
Jak
Src
Crk
Adapters Enzymes
Ras-GCP
Cbl
Shc
PLCy
Vav
Grb7
GAP
Grb2
P(1)3K
Shp2
Ras-GTP
Sos
Nck
Rao
Akt
RAF
PKC
PAK
Abl
NEK
Cascades
Bad
S6 K
JNKK
MAPK
JNK
Jun
nucleus
Fos
Myc
Sp1
Elk
Egr1
Stat
Transcription Factors
Source Y. Yardin, Untangling the ErbB
Signaling Network Nature Reviews Molecular Cell
Biology 2(2) 127-137, 2001
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Tamoxifen

• Blocks estrogen from entering into the cell,
  blocking estrogen-dependent growth

Estrogen biosynthesis
Estrogen biosynthesis from muscle fat
x
x
x
Aromatase Inhibitors
Aramatase
DeVita, et al. Cancer Principles and Practice of
Oncology. 6th ed 2001
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Aromatase Inhibitors

• The next generation of hormone therapy
• Works by blocking Aromatase enzyme from
  converting other hormones to estrogen

Androstenedione
Testosterone
attack!
attack!
Aromatase
Aromatase
Aromatase Inhibitor
Estradiol
Estrone
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Targeting the VEGF Pathway
Anti-VEGF Antibody
VEGF
Small-Molecule Inhibitors
Split Kinase Domain
VEGFR-1
Source L. Harris Novel Biologic and
Small-Molecule Inhibitors of VEGF in Cancer
Research Translation Therapies in Breast Cancer
Symposium 2006
VEGFR-2
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ErbB Signaling Pathway
ErbB1
ErbB2
Sos
Grb2
Lapatinib
Shc
Sos
Grb2
HKI-272
PI3K
BIBW-2992
Akt
mTOR
PTEN
GSK3
BAD
FKHR
p27
Survival
Cyclin D1, E
Cell-cycle progression
Source J. OShaughnessy, Inhibition of the
ErbB Signaling Pathway by Targeted Therapy
Translation Therapies in Breast Cancer Symposium
2006
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ErbB and VEGFR Receptor Crosstalk
ErbB Receptor
P13K
Ras
Akt
MEK3/4/6
Raf
MEK
MAPK
p53
S6 kinase
ERK
HIF-1a
VEGF
Source Hope Rugo Targeting VEGF Receptors in
Breast Cancer Using Novel Small-Molecule
Inhibitors Translation Therapies in Breast Cancer
Symposium 2006
Tumoral hypoxia
Loss of tumor suppressors (VHL)
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Sorafenib Mechanism of Action and Phase II Study
Tumor blood vessel endothelial cell membrane
Tumor cell membrane
Pericyte
VEGFR
PDGFR
VEGFR
PDGFR
EGFR
Ras
P13K
Sorafenib
Sorafenib
Akt
MEK
nucleus
Cell proliferation Cell adhesion Apoptosis Cell
Survival Cell differentiation Angiogenesis
Transcription Factors
Source Hope Rugo Targeting VEGF Receptors in
Breast Cancer Using Novel Small-Molecule
Inhibitors Translation Therapies in Breast Cancer
Symposium 2006
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Types of Targeted Therapies

• Monoclonal Antibodies
• Small molecules
• Angiogenesis inhibitors
• Vaccines
• Apoptosis inducers

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Monoclonals currently used in treating cancer

• Drug (brand name)
• rituximab (Rituxan)
• tositumomab-1131 (Bexxar)
• ibritumomab-Y90 (Zevalin)
• alemtuzumab (Campath)
• cetuximab (Erbitux)
• panitumumab (Vectibix)
• trastuzumab (Herceptin)
• bevacizumab (Avastin)
• edrecolomab (Panorex)

• Cancer(s) treated
• non-Hodgkins lymphoma
• non-Hodgkins lymphoma
• non-Hodgkins lymphoma
• chronic lymph. leukemia
• colorectal, head neck
• colorectal
• breast
• colorectal, NSC lung, breast
• colorectal

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Tyrosine Kinase Inhibitors

• Cancer(s) treated
• acute promyelo. leukemia
• chronic myelo. leukemia
• chronic myelo. leukemia
• Chronic myelo,leukemia
• GI stromal tumor
• glioblastoma, NSC lung
• NSC lung
• breast
• renal

• Drug (brand name)
• tretinoin (Vesanoid)
• dasatinib (Sprycell)
• nilotinib (Tasigna)
• imatinib (Gleevec)
• erlotinib (Tarceva)
• gefitinib (Iressa)
• lapatinib (Tykerb)
• temsirolimus (Torisel)
• Everolimus (Afinator)

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Anti-angiogenesis Drugs

• Cancer(s) treated
• colorectal
• ovarian, pancreatic
• mult. myeloma, myelodysplastic syndromes
• hepatocellular, melanoma, NSC lung, renal
• renal
• mult. myeloma, hepatocellular, small/NSC lung,
  fallopian tube, peritoneal
• NSC lung

• Drug (brand name)
• celecoxib (Celebrex)
• dalteparin (Fragmin)
• lenalidomide (Revlamid)
• sorafenib (Nexavar)
• sunitinib (Sutent)
• thalidomide (Thalomid)
• vandetanib (Zactima)

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Trastuzumab Pertuzumab

• Pertuzumab
• Activates antibody-dependent cellular
  cytotoxicity
• Prevents receptor dimerization
• Potent inhibitor of HER-mediated signaling
  pathways

• Trastuzumab
• Activates antibody-dependent cellular
  cytotoxicity
• Enhances HER2 internalization
• Inhibits shedding and formation of p95
• Inhibits angiogensis

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Triple Negative Breast Cancer

• Triple Negative Breast Cancer
• Estrogen Receptor (ER) Negative
• Progesterone Receptor (PR) Negative
• HER2 Receptor Negative
• Considered to have a poorer prognosis than many
  other types of breast cancer
• Many existing targeted therapies do not have a
  place in TN Breast Cancer therapy (e.g.
  Herceptin, Tamoxifen)

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Origins of Triple (-) Basal-like Breast Cancers

• Triple Negative tumors have a also commonly been
  found to be BRCA-deficient.
• BRCA-deficient tumors are often at least ER (-)
• BRCA-deficiency can be hereditary or can be
  caused by a cell mutation.
• These tumor cells often over express
  myoepithelial-cell-like cytokeratins.
• Myoepithelial cells are found in the outer basal
  layer of cells in a normal breast duct.
• Therefore, these tumors are defined as
  basal-like.

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BRCA Deficiency or Mutation

• BRCA1 is a gene that play a part in a large
  number of cellular processes
• DNA repair
• Transcriptional Regulation
• Chromatin Remodeling
• Cell that lack BRCA1 cannot repair DNA
  double-strand breaks by the conservation
  mechanism or homologous recombination

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BRCAness BRCA1 mutation

• BRCA1 deficiency inevitably leads to repair of
  DNA lesions by non-conservative mechanisms that
  can be potentially mutagenic.
• If cancerous cells form from these mutagenic DNA
  repairs, they often develop along a basal-like
  pathway.

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Why dont the cells just die?

• Unrepaired damage in normal cells usually
  triggers programmed cell death
• It has been found that BRCA1 tumors generally
  have a higher frequency of Tumor Suppressor p53
  mutations.
• This increase in p53 mutations shut down
  programmed cell death leading to cancerous cell
  growth

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A target for chemotherapy

• Since a DNA-repair defect occurs in
  BRCA-deficient cancers, this can be exploitedas a
  target for chemotherapy
• Tumors with BRCA1 mutations may have increased
  sensitivity to DNA-crosslinking agents that cause
  DNA double-strand breaks (e.g. carboplatin)

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Are PARP-inhibitors an option?

• Poly(ADP-ribose) Polymerase (PARP)
• An enzyme involved in base excision repair and is
  key in the repair pathway of DNA single-strand
  breaks
• Since DNA repair is already limited in BRCA
  deficient tumors, it is hypothesized that the
  addition of a PARP-inhibitor may futher decrease
  DNA repair leading to increased apoptosis of
  tumor cells

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PARP-Inhibitors

• PARP inhibitors are designed to target a weakness
  rather than a strength
• Utilizing the fact that BRCA-deficient tumor
  cells cannot effectively repair double-stranded
  DNA breaks, PARP inhibitors may be able to push
  the cells over the edge by also inhibiting their
  ability to fix single-strand breaks

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Model of Tumor-Cell killing by PARP inhibitors

• BRCA-deficient tumors have diminished ability to
  repair double-stranded DNA breaks, yet the tumor
  cells continue to survive
• Adding the inability to repair single-strand
  breaks via a PARP-Inhibitor provides enough
  instability in the mouse model and the cells
  dies.
• If the model holds true, this may provide a good
  target for BRCA-deficient breast or ovarian
  tumors in humans.

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Other Novel Approaches
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Vaccines

• Need specific targets that are unique to the
  cancer cell (but not to normal cells)
• All current vaccine studies are targeting Her2Neu
• In the future, other targets that are identified
  can be used
• Animal data Marked decrease in ability for
  transplanted tumors to grow in animals treated
  with the vaccine

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Human Data

• Walter Reed MD Anderson

171 patients
90 LN
81 LN
90 qualified for E75
45 LN
45 LN
9 patients not able to evaluated
LN Lymph Node
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Human Data

• Results at 24 months
• Vaccinated patients had 5.6 reoccurrence
• Non-vaccinated patients had 14.8 reoccurrence
• Several centers have started vaccine studies this
  year, including U of M

UPDATE Universitys vaccine study is now open!
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Gene Therapy

• Several possible uses
• Stimulate suppressor genes to inhibit tumor
  growth
• Introduce suicide genes into cancer cells that
  cause them to self destruct

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Apoptosis Therapy

• Two important discoveries
• bc1-2 gene
• Almost all tumors have impaired apoptosis

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Digital
Film
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Questions?