knowledge is power: updates in oncology barbara bowers, m.d. medical director fairview southdale...
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Knowledge is Power:
Updates in Oncology
Barbara Bowers, M.D.Medical Director
Fairview Southdale Medical Oncology Clinic
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…
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
Natural Medicines for Breast Cancer
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
SerumCa++
TissueCa++
Kidney filters out Ca++
Ca++ in bone
Ca++ absorbed by intestinal tract
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
• Tamoxifen• Arimidex• Aromasin• Faslodex• Fareston• Femara• Megace (endometrial)
Complex HER Receptor Signaling Pathway
PKC
GAP
nucleus
Source: Y. Yardin, “Untangling the ErbB Signaling Network”Nature Reviews Molecular Cell Biology 2(2): 127-137, 2001
Sp1 Myc FosJun
Elk Egr1 Stat
Bad S6 K
Akt
MAPK
NEKRAF
Abl
Ras-GTP
Ras-GCP
SosGrb2
Shc
Nck Rao
Vav Grb7
Crk
JakSrc
CblPLCy
P(1)3K Shp2
LPAthrombinET, etc
TGFα(1)
EGF(1)
Epi-regulin(1,4)
β-cellulin(1)
HB-EGF(1,4)
Amphi-Regulin
(1)
NRG1(3,4)α β
NRG2(4)α β
NRG3(4)
NRG4(4)
Cytokines
X
1 3 1 2 1 1 2 2 4 2 1 4
X
3 2 4 4
X
3 4
X X
3 3
JNKJNKK
PAK
Transcription Factors
Cascades
Adapters& Enzymes
ReceptorDimers
Ligands
Tamoxifen
Blocks estrogen from entering into the cell, blocking estrogen-dependent growth
Nucleus
Tumor cell
Estrogen biosynthesis
Estrogen biosynthesis from muscle & fat
DeVita, et al. Cancer Principles and Practice of Oncology. 6th ed 2001
Aromatase Inhibitors Aramatase
Aromatase InhibitorsThe next generation of hormone therapy• Works by blocking Aromatase enzyme from
converting other hormones to estrogen
Androstenedione Testosterone
Estradiol
Aromatase
Estrone
AromataseAromatase
Inhibitor
attack! attack!
Targeting the VEGF Pathway
Source: L. Harris“Novel Biologic and Small-Molecule Inhibitors of VEGF in Cancer Research”Translation Therapies in Breast Cancer Symposium 2006
Anti-VEGFAntibody
VEGF
Small-MoleculeInhibitors
Split Kinase Domain
VEGFR-1PPP
PPP
PP
P
P
PP
PP
P P
VEGFR-2
ErbB Signaling Pathway
Lapatinib
HKI-272
BIBW-2992
mTOR
Grb2
PTEN
Cyclin D1, E
FKHR
SosShc
ErbB1 ErbB2
Cell-cycle progression
Survival
Source: J. O’Shaughnessy, “Inhibition of the ErbB Signaling Pathway by Targeted Therapy” Translation Therapies in Breast Cancer Symposium 2006
Grb2 Sos
Proliferation
MEK1/2
MAPK
Ras
RafPI3K
Akt
p27GSK3 BAD
ErbB and VEGFR Receptor Crosstalk
P13K
Akt MEK3/4/6
Source: Hope Rugo“Targeting VEGF Receptors in Breast Cancer Using Novel Small-Molecule InhibitorsTranslation Therapies in Breast Cancer Symposium 2006
p53
Ras
Raf
MEK
ERK
MAPK
ErbB Receptor
HIF-1α
S6 kinase
VEGF
Tumoral hypoxia Loss of tumor suppressors (VHL)
Sorafenib: Mechanism of Action and Phase II Study
Tumor cellmembrane
Pericyte
Source: Hope Rugo“Targeting VEGF Receptors in Breast Cancer Using Novel Small-Molecule InhibitorsTranslation Therapies in Breast Cancer Symposium 2006
TGFα
EGFR
PP
VEGFRPP
VEGF
PDGFRPP
VEGF
PDGFR
PP
VEGF
nucleus
TranscriptionFactors
Cell proliferationCell adhesionApoptosisCell SurvivalCell differentiationAngiogenesis
Sorafenib SorafenibRas
MEKERK
P13K
Akt
mTOR
Tumor blood vessel
endothelial cell membrane
VEGFRPP
VEGF
Raf
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) treatednon-Hodgkins lymphomanon-Hodgkins lymphomanon-Hodgkins lymphomachronic lymph. leukemiacolorectal, head & neckcolorectalbreastcolorectal, NSC lung,
breastcolorectal
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) treatedacute promyelo. leukemia
chronic myelo. leukemiachronic myelo. leukemiaChronic myelo,leukemiaGI stromal tumorglioblastoma, NSC lungNSC lungbreastrenal
Anti-angiogenesis DrugsDrug (brand name)celecoxib (Celebrex)dalteparin (Fragmin)lenalidomide (Revlamid)
sorafenib (Nexavar)
sunitinib (Sutent)thalidomide (Thalomid)
vandetanib (Zactima)
Cancer(s) treatedcolorectalovarian, pancreaticmult. myeloma, myelodysplastic syndromes
hepatocellular, melanoma, NSC lung, renal
renalmult. myeloma, hepatocellular, small/NSC lung, fallopian tube, peritoneal
NSC lung
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
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 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)
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.
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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