describes the role of angiogenesis in the management of different scenarios of metastatic colorectal cancer

1. Angiogenesis; a key player in all
chapters of metastatic CRC story
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
10th Annual international conference of
clinical oncology department, Assiut university
ROCHE Symposium
Luxor 20-22/02/2019

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly
Speaker Disclosures:

3. Definition of Cancer:
“Large family of diseases that involve abnormal
cell growth with the potential to invade or
spread to other parts of the body”
World Health Organization. February 2014.

4. 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
PROGRESSION, Invasion &
Metastases
ANGIOGENESIS
• Life
• Growth
• Maintenance
P53
+++Growth Signals

5. Formation of New
Blood Vessels =
Angiogenesis
Physiological
Wound Healing
Placental Implantation
Growth
Pathological
Pre-Eclampsia
Diabetic Retinopathy
Tumors
Formation of Blood Vessels:
Lamalice et al. Circ Res.2007;100:782-794

6. Tyrosine Kinase Receptors
VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2
VEGFs
VEGF - A VEGF - B VEGF - C VEGF - D PlGF
VEGF & VEGFR:
“The Key & Lock”
Bates Cardiovascular Research (2010) 87, 262–271

7. VEGFR
AKT
Grb SOS
mTOR
Protein Synthesis
HIF-1@
Metabolism
Growth
Angiogenesis
RAS
RAF
Mek
Erk
Cell Cycle Progression ,
Proliferation & Angiogenesis
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
TKI, Proliferation Cascades &
Angiogenesis:

8. VEGF A:
• Stimulation of Endothelium Proliferation.
• Enhanced Endothelial Survival.
• Control of Vascular Permeability.
• Enhanced ECM Degradation  Vascular
Migration.
Dovrak etal. Am J Pathol. 1995;146(5):1029.

9. Angiogenesis in Malignancy:
Monoclonal
Antibody
Soluble
Receptor
TKI
Tumor GF
Endogenous GF
HIF,
COX2,
IL-6β
EGF/R
PDGF/R
Others
mTOR
Inhibitors
Miles et al. J Clin Oncol. 2011;29(1):83. Epub 2010 Nov 22.

10. Tribute to History of Angiogenesis:
1787
Angiogenesis
in Reindeer
Antler
Dr. John Hunter
1971
Angiogenesis
Dependent
Tumor Growth
Dr. Judah Folkman
1975
1st
Angiogenesis
Inhibitor
(in Cartilage)
Dr. Henry Brem
1984
1st Angiogenic
Factor
(bFGF)
Dr. Michael Klagsbrun
1989
Discovery
Of
VEGF
Dr. Napoleon Ferrara
1997
Angio- &
Endostatin 
CR in Cancer
Dr. Michael O’Reilly
1999
Dr.
Richard Klaussner
Director of the U.S. NCI
designates the development of
anti-angiogenic therapies for
cancer as a national priority.
2003
2017
1st
Line
2nd
Line
3rd
Line
• Beyond Progression
• Maintenance
• Tumor Shrinkage
• RAS Wild/Mutant
• ≅ Anti-EGFR MoAb
• Not Adjuvant ttt.
No
Predictive
Markers
BRAF Mutant

Triplet + Bevacizumab
Right & Left Sided Colon
Cancer

11. Phase III Trials: Anti-Angiogenic
Therapies in mCRC
J.M. Clarke et al. / Cancer Treatment Reviews 40 (2014) 1065–1072

12. Anti-Angiogenic Agents in
Maintenance Trials:
Aprile et al. Clinical Colorectal Cancer, 2016. Vol. 15, No. 1, 7-15

13. Antiangiogenic Therapy in BRAF
Mutated Patients:
Roma et al. CANCER BIOLOGY & THERAPY 2016, VOL. 17, NO. 8, 840–848
Cremollini et al. Lancet Oncol 2015; 16: 1306–15

14. Tomasello et al. JAMA Oncol. 2017;3(7):e170278. doi:10.1001/jamaoncol.2017.0278

15. First Head-to-Head Comparisons of First-Line
Bevacizumab Versus EGFR Inhibitors in KRAS WT
mCRC
1. Schwartzberg LS, et al. J Clin Oncol. 2014;32(21):2240-2247. 2. Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.
3. Venook A, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA3.
PEAK1
Phase II
Untreated –
Unresectable mCRC
N = 285
Bevacizumab + mFOLFOX6
Panitumumab + mFOLFOX6
FIRE-32
Phase III
Untreated mCRC
N = 592
Bevacizumab + FOLFIRI
Cetuximab + FOLFIRI
CALGB-804053
Phase III
Untreated mCRC
N = 1200
Bevacizumab +
FOLFIRI or FOLFOX
Cetuximab
+ FOLFIRI or FOLFOX
No Hypothesis
OAS
ORR
DP

16. FIRE-3 Trial: FOLFIRI + Either Cetuximab or
Bevacizumab in KRAS WT mCRC
Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.
HR 0.77
P .011
Parameter Chemo + CET Chemo + Bev P
ORR (%) 62 58 .183
PFS (ms) 10 10.3 .547
OAS Dif.
= 8.5 ms

17. CALGB 80405: OAS
Alan P. Venook, MD et al. JAMA June 20, 2017 Volume 317, Number 23

18. 80405: (KRAS WT) Overall Survival by Sidedness
Presented by:ASCO ANNUAL MEETING ‘16
Side
N
(Events)
Median
(95% CI)
HR
(95% CI)
p
Left 732 (550)
33.3
(31.4-35.7) 1.55
(1.32-1.82)
<
0.0001
Right 293 (242)
19.4
(16.7-23.6)

19. Petrelli et al. Jama Oncology. 2017 Vol 3 Number 2
66 RCT = 1437846 Colon Cancer Patients
Location as an Independent
Prognostic Factor:

21. TEJPAR et al. JAMA Oncology February 2017 Volume 3, Number 2

23. Kerr et al.Lancet Oncol 2016; 17: 1543–57

24. Anti-Angiogenic Therapy: Drug
Interactions:
CartwrightTH. Clinical Colorectal Cancer, 2013 Vol. 12, No. 2, 86-94

25. Stintzing et al. Lancet Oncol 2016; 17: 1426–34

26. Treatment Platform in mCRC:
mCRC
RAS Mutant
RAS Wild
BRAF Mutant
FOLFOX/FOLFI
RI/ FOLFOXIRI
+
Bevacizumab
FOLFOXIRI +
Bevacizumab
Right Colon Left Colon
FOLFOX/FOL
FIRI + Anti-
EGFR/VEGF
Alternate
Doublet +
Biologic
Regorafinib
or TAS102 or
Trial
Anti-EGFR +
BRAF +/- MEK
Inhibitor +/-
Cytotoxic
Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564

27. Art of Today:
• Angiogenesis is an appealing target in cancer
management.
• Anti-Angiogenic Therapies had contributed positively in
treatment platform of mCRC.
• Anti-Angiogenic Therapies are proved effective in
different treatment scenarios (Bevacizumab  1st Line
& beyond progression, 2nd & 3rd Lines  Aflibercept,
Ramucirumab & Regorafinib).
• Care must be taken for toxicity and drug to drug
interactions.
• More work is mandatory for biomarker assessment and
adjuvant treatment.