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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?.

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Knowledge is power updates in oncology

Knowledge is Power:Updates in Oncology

Barbara Bowers, M.D.

Medical Director

Fairview Southdale Medical Oncology Clinic


Topics
Topics

Vitamin D

Bisphosphonates

Targeted Cancer Therapies

Other Novel Approaches




What does vitamin d do
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…




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

Ca++ absorbed by intestinal tract

Tissue

Ca++

Ca++ in bone

Serum

Ca++

Kidney filters out Ca++


Biphosphonates
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
Complex HER Receptor Signaling Pathway

LPA

thrombin

ET, etc

TGFα

(1)

EGF

(1)

Epi-

regulin

(1,4)

β-cellulin

(1)

HB-EGF

(1,4)

Amphi-

Regulin

(1)

NRG1

(3,4)

αβ

NRG2

(4)

αβ

NRG3

(4)

NRG4

(4)

Cytokines

Ligands

4

2

1

4

3

2

4

4

Receptor

Dimers

1

1

2

2

3

4

1

2

3

3

1

3

X

X

X

X

X

Jak

Src

Crk

Adapters

& Enzymes

Cbl

Ras-GCP

Shc

PLCy

Vav

Grb7

P(1)3K

Shp2

GAP

Grb2

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


Tamoxifen

E

E

Nucleus

E

E

R

R

x

E

E

Tumor cell

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


Aromatase inhibitors

The next generation of hormone therapy

Works by blocking Aromatase enzyme from converting other hormones to estrogen

Aromatase Inhibitors

Androstenedione

Testosterone

attack!

attack!

Aromatase

Aromatase

Inhibitor

Aromatase

Estrone

Estradiol


Targeting the vegf pathway

P

P

P

P

P

P

P

P

P

P

P

P

P

P

P

P

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


Erbb signaling pathway

Ras

Raf

MEK1/2

MAPK

Proliferation

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

Source: J. O’Shaughnessy,

“Inhibition of the ErbB Signaling Pathway by Targeted Therapy”

Translation Therapies in Breast Cancer Symposium 2006

Cell-cycle progression


Erbb and vegfr receptor crosstalk
ErbB and VEGFR Receptor Crosstalk

ErbB Receptor

P13K

Ras

Akt

MEK3/4/6

Raf

MEK

MAPK

p53

S6 kinase

ERK

HIF-1α

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)


Sorafenib mechanism of action and phase ii study

VEGF

VEGF

TGFα

VEGF

VEGF

Raf

ERK

mTOR

P

P

P

P

P

P

P

P

P

P

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


Types of targeted therapies
Types of Targeted Therapies

  • Monoclonal Antibodies

  • Small molecules

  • Angiogenesis inhibitors

  • Vaccines

  • Apoptosis inducers


Monoclonals currently used in treating cancer
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
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
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 & 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

  • 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
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
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
“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
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
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
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

  • 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
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
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
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 data1
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
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
Apoptosis Therapy

  • Two important discoveries:

    • bc1-2 gene

    • Almost all tumors have impaired apoptosis


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