Knowledge is Power:

Updates in Oncology

Barbara Bowers, M.D.Medical Director

Fairview Southdale Medical Oncology Clinic

TopicsVitamin 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…

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

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

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.

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

Film Digital

Questions?