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
Topics
Vitamin D
Bisphosphonates
Targeted Cancer Therapies
Other Novel Approaches
Vitamin D
Vitamin D
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…
Natural Medicines for Breast Cancer
SAFETY
EFFECT
Likely
Safe
Possibly
Safe
Insufficient
Evidence
Effective
Possibly
Effective
Beta Carotene
fish oil
green tea
Melatonin
Olive
soy
Vitamin A
Insufficient
Evidence
Coenzyme Q-10
Flaxseed
Shiitake mushroom
Likely
Ineffective
Vitamin E
Beta glucans
Chrysin
European mistletoe
Indole-3-carbinol
Maitake mushroom
red clover
Calcium D-glucarate
Genistein combined
poly-saccharide
Essiac
Flor-Essence
Possibly
Unsafe
Bisphosphonates
Bisphosphonates
Ca++ absorbed by
intestinal tract
Tissue
Ca++
Serum
Ca++
Kidney filters out Ca++
Ca++ in bone
• 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
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
Targeted Cancer
Therapies
Targeted Cancer Therapies
•
•
•
•
•
•
•
Tamoxifen
Arimidex
Aromasin
Faslodex
Fareston
Femara
Megace (endometrial)
Complex HER Receptor Signaling Pathway
LPA
thrombin
ET, etc
TGFα
(1)
EGF
(1)
Epiregulin
(1,4)
β-cellulin HB-EGF AmphiRegulin
(1)
(1,4)
(1)
1 3 1 2 1 1 2 2
NRG1
(3,4)
αβ
NRG2
(4)
αβ
NRG3
(4)
NRG4
Cytokines Ligands
(4)
4 2 1 4 3 2 4 4 3 4 3 3
X
X
X
Receptor
Dimers
X X
Jak
Src
Cbl
Ras-GCP
PLCy
Shc
Grb2
Sos
Nck
P(1)3K Shp2 GAP
Ras-GTP
Akt
PKC
Bad
S6 K
RAF
NEK
MAPK
Crk
Vav
Adapters
& Enzymes
Grb7
Rao
PAK
Abl
JNKK
Cascades
JNK
Jun
Sp1
Source: Y. Yardin,
“Untangling the ErbB Signaling Network”
Nature Reviews Molecular Cell Biology 2(2): 127-137, 2001
Myc
Fos
Elk
Egr1
Stat
Transcription
Factors
Tamoxifen
Blocks estrogen from entering into the cell,
blocking estrogen-dependent growth
Estrogen
biosynthesis
Nucleus
Estrogen
biosynthesis
from muscle & fat
Aromatase
Inhibitors
Aramatase
Tumor cell
DeVita, et al. Cancer Principles and Practice of Oncology. 6th ed 2001
Aromatase Inhibitors
The next generation of hormone therapy
• Works by blocking Aromatase enzyme from
converting other hormones to estrogen
Androstenedione
Testosterone
attack!
attack!
Aromatase
Inhibitor
Aromatase
Estrone
Aromatase
Estradiol
Targeting the VEGF Pathway
Anti-VEGF
Antibody
VEGF
Small-Molecule
Inhibitors
Split
Kinase
Domain
P
P
P
P
P
P
P
P
P
VEGFR-1
Source: L. Harris
“Novel Biologic and Small-Molecule Inhibitors of VEGF in Cancer Research”
Translation Therapies in Breast Cancer Symposium 2006
P
P
P
P
P
P
P
VEGFR-2
ErbB Signaling Pathway
ErbB1
ErbB2
Grb2 Sos
Ras
Shc Grb2 Sos
Lapatinib
PI3K
HKI-272
Raf
BIBW-2992
Akt
MEK1/2
mTOR
PTEN
p27
FKHR
GSK3
BAD
MAPK
Survival
Cyclin D1, E
Source: J. O’Shaughnessy,
“Inhibition of the ErbB Signaling Pathway by Targeted Therapy”
Translation Therapies in Breast Cancer Symposium 2006
Cell-cycle progression
Proliferation
ErbB and VEGFR Receptor Crosstalk
ErbB Receptor
p53
P13K
Ras
Akt
Raf
MEK3/4/6
MEK
MAPK
S6 kinase
ERK
HIF-1α
Source: Hope Rugo
“Targeting VEGF Receptors in Breast Cancer
Using Novel Small-Molecule Inhibitors
Translation Therapies in Breast Cancer Symposium 2006
Tumoral hypoxia
VEGF
Loss of tumor suppressors (VHL)
Sorafenib: Mechanism of Action and Phase II Study
VEGF
VEGF
TGFα
VEGF
VEGF
Tumor cell
membrane
Tumor
blood vessel
endothelial cell
membrane
Pericyte
P
P
VEGFR
P
P
EGFR
Sorafenib
P
P
P
PDGFR
Ras
Akt
Raf
ERK
Transcription
Factors
Source: Hope Rugo
“Targeting VEGF Receptors in Breast Cancer
Using Novel Small-Molecule Inhibitors
Translation Therapies in Breast Cancer Symposium 2006
P
VEGFR
PDGFR
P13K
mTOR
P
P
Sorafenib
MEK
Cell proliferation
Cell adhesion
Apoptosis
Cell Survival
Cell differentiation
Angiogenesis
Types of Targeted Therapies
•
•
•
•
•
Monoclonal Antibodies
Small molecules
Angiogenesis inhibitors
Vaccines
Apoptosis inducers
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
Tyrosine Kinase Inhibitors
Drug (brand name)
tretinoin (Vesanoid)
dasatinib (Sprycell)
nilotinib (Tasigna)
imatinib (Gleevec)
erlotinib (Tarceva)
gefitinib (Iressa)
lapatinib (Tykerb)
temsirolimus (Torisel)
Everolimus (Afinator)
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
Anti-angiogenesis Drugs
Drug (brand name)
celecoxib (Celebrex)
dalteparin (Fragmin)
lenalidomide (Revlamid)
sorafenib (Nexavar)
sunitinib (Sutent)
thalidomide (Thalomid)
vandetanib (Zactima)
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
Trastuzumab & Pertuzumab
• Trastuzumab
– Activates antibody-dependent
cellular cytotoxicity
– Enhances HER2 internalization
– Inhibits shedding and formation
of p95
– Inhibits angiogensis
• Pertuzumab
– Activates antibody-dependent
cellular cytotoxicity
– Prevents receptor dimerization
– Potent inhibitor of HERmediated signaling pathways
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)
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.
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
“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.
Why don’t 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
A target for chemotherapy
• Since a DNA-repair defect occurs in BRCAdeficient 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)
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
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
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.
Other Novel Approaches
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
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
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 – University’s vaccine study is now open!
Gene Therapy
• Several possible uses:
– Stimulate suppressor genes to inhibit tumor
growth
– Introduce “suicide genes” into cancer cells that
cause them to self destruct
Apoptosis Therapy
• Two important
discoveries:
– bc1-2 gene
– Almost all
tumors have
impaired
apoptosis
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