BASICS OF TARGET THERAPY

MOHAMED ABDULLA PROF. OF CLINICAL ONCOLOGYCAIRO UNIVERSITY

NEMROCK – CAIROPFIZER TRAINING COURSESUNDAY: 22/11/2015

SPEAKER DISCLOSURES Member of Advisory Board, Consultant, and Speaker for:Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer

THE NORMAL CELL CYCLE

Class Example Method of Action Cycle Specific

Alkylating agents Cytoxan Effects DNA chemically All

Antimetabolites 5-FUGemzar

Substitutes for normal cell building blocks

S

Anthracyclines Adriamycin DNA damage or inhibit topoisomerase

All

Anti-tumor Antibiotics

Bleomycin DNA damage All

Topoisomerase Inhibitors

Irinotecan Complex DNA and topoisomerase together

SG-2

Vinca Alkaloids Vincristine Binds to tubulin, interferes with mitosis

M

Taxanes TaxolTaxotere

Prevents microtubules from disassociating

M

CLASSES OF CYTOTOXIC THERAPIES

COULD WE DO BETTER?

CHEMOTHERAPY VS TARGETED THERAPYChemotherapy:

• Drugs that effect cells that are doubling• Not very specific• Mostly intravenous, some oral agents• Cytotoxic

Targeted therapy:• Drugs that inhibit a more specific target in cells• Many are oral agents• Mixture of cytostatic and cytotoxic

BIOGRAPHY OF CANCER:Normal Mother Cells Normal Daughter Cells

Abnormal Daughter Cells

Programed Cell Death: APOPTOSIS

RESISTANCE TO APOPTOSIS

Continued Un-opposed Proliferation

Malignant Tumor PROGRESSIONANGIOGENESIS

• Life• Growth• Maintenance

P53

+++Growth Signals

BIOGRAPHY OF CANCER:CANCER = ARREST OF APOPTOSIS + ANGIOGENESIS

P53 GROWTH SIGNALS

Repair of Critical Damage

Growth Factor Receptor Biological Path Nuclear Material Proliferation, Angiogenesis ..

BIOGRAPHY OF CANCER:Growth Factor

Monoclonal Antibody

Normally Existing

++ By The Tumor

TK

1

2

3

Formation of New Blood

Vessels

Physiological

Wound Healing

Placental Implantation

Growth

Pathological

Pre-Eclampsia

Diabetic Retinopathy

Tumors

ANGIOGENESIS:THE WHOLE MARK OF MALIGNANCY:

Proliferation Invasion Metastases

VEGF +

+

TK

+

m-TOR

ANGIOGENESIS: THE WHOLE MARK OF MALIGNANCY:

New Blood Vessel Proliferation

Release of GFs Receptor Activation

Degradation & Proteolytic Enz.

Disruption of ECM & Wall

Invasion & Migration

ANGIOGENESIS: THE WHOLE MARK OF MALIGNANCY:

VE

GFR

PI3K AKT

Grb SOS

mTOR

Protein Synthesis

HIF-1@Metabolism

Growth

Angiogenesis

RAS

RAF

Mek

Erk

Cell Cycle Progression & Proliferation

PDG

F

EGFR

1. Avastin [package insert]. South San Francisco, CA: Genentech; 2009. 2. Escudier B et al; TARGET Study Group. N Engl J Med. 2007;356:125-134. 3. Escudier B et al. J Clin Oncol. 2009;27:3312-3318. 4. Nexavar [package insert]. Wayne, NJ: Bayer

Healthcare Pharmaceuticals; 2007.

Bevacizumab

RAD 001 Sorafinib

ANGIOGENESIS: THE WHOLE MARK OF MALIGNANCY:

Tyrosine Kinase Receptors

VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2

VEGFs

VEGF - A VEGF - B VEGF - C VEGF - D PlGF

ANGIOGENESIS: THE WHOLE MARK OF MALIGNANCY:

Hypoxia

HIF

VEGF Gene

VEGF VEGFR on Nearby Vessels VEGFR on Tumor Vessels

ANGIOGENESIS: THE WHOLE MARK OF MALIGNANCY:

ANGIOGENESIS: THE WHOLE MARK OF MALIGNANCY:

Possible Targets for Treatment

Growth Factors

Extracellular Receptor Domain

Tyrosine Kinase Receptor Domain

Critical Protein in Biological Cascade

Blocking VEGF Small Molecule TKI EGFR Inhibitors Soluble VEGF Decoy Receptor

Bevacizumab Sorafinib, Sunitinib, Pazopanib,

Axitinib,Regorafinib

Erlotinib,Gefitinib

Aflibercept

Blocking 100% of VEGF-A Anti-

angiogenic Activity

Wide Range: PDGFR,

C-kit,EGFR,

FGFR Both Anti-angiogenic & Anti-mitogenic Activity

Blocking ERB-1 Receptors Both Anti-angiogenic

and Anti-mitogenic Activity

Blocking VEGF – A and B, PlGF Anti-angiogenic

Activity

IV Bioavailability Oral Bioavailability Oral Bioavailability IV Bioavailability

17 – 21 HLT Short Lived Short Lived Higher Affinity to VEGF-A than other MAB.

ANGIOGENESIS: THE WHOLE MARK OF MALIGNANCY:

BREAKTHROUGHS:1. Trastuzumab in Breast Cancer.2. Rituximab in B-Cell NHL.3. Bevacizumab in Colon and Ovarian Cancer.4. Cetuximab and Panitumumab in Colon Cancer.5. Denosumab in GCTB and Metastatic Bone Disease.6. Imatinib in GIST.7. Everolimus in NET and RCC.8. Sunitinib in RCC.9. Erlotinib and Gefitinib in Non Squamous NSCLC.10. Crizotinib in Non Squamous NSCLC.11. ………

THE ART OF TODAY:• Chemotherapy is still the backbone of most of cancer

treatment protocols.• Targeted Therapies could represent an opened era of

being more personalized and specific in cancer management when added to conventional therapies.

• Some of the TARGETED THERAPIES represent a breakthrough in management (Combo and Sole)

• Others pave the way of pessimistic disease entities.• Still we need to understand much of the molecular events

playing in the back-stage of disease.

THANK YOU