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Newer cancer therapies
Angiotherapy
use of agents that inhibit angiogenesis
Angiogenic therapy
Rationale
1) tumour growth is angiogenesis-dependent
2) targets the genetically-stable microvascular endothelial cell
3) anti-angiogenic compounds are cytostatic
Composition of nascent and mature blood vessel walls
(a) Nascent vessels consist of a tube of
ECs, which mature into specialized
capillaries, arteries and veins.
(b) Capillaries consist of ECs
surrounded by basement membrane
and a sparse layer of pericytes
embedded within the EC basement
membrane. Capillary endothelial
layer can be continuous (muscle),
fenestrated (kidney/ endocrine
glands) or discontinuous (liver
sinusoids). The endothelia of the
blood-brain barrier or blood-retina
barrier are further specialized to
include tight junctions, and are thus
impermeable to various molecules.
(c) Arterioles and venules have an
increased coverage of mural cells
compared with capillaries.
Steps in network formation and maturation during
embryonic (physiological) angiogenesis
Key differences in tumour
vasculature
Different flow
characteristics /
blood volume
Microvasculature
permeability
Increased
fractional
volume of
extravascular,
extracellular
space
Steps in network formation and maturation during
tumour angiogenesis
Cellular mechanisms of tumour angiogenesis
(1) host vascular network
expands by budding of
endothelial sprouts or
formation of bridges
(angiogenesis);
(2) tumour vessels remodel and
expand by the insertion of
interstitial tissue columns
into the lumen of pre-existing
vessels (intussusception); and
(3) endothelial cell precursors
(angioblasts) home from the
bone marrow or peripheral
blood into tumours and
contribute to the endothelial
lining of tumour vessels
(vasculogenesis)
(4) Lymphatic vessels around
tumours drain the interstitial
fluid and provide a gateway
for metastasizing tumour
cells.
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Angiogenesis-overview
Nature Reviews Drug Discovery 1, 415-426 (2002)
Angiogenesis-overview
Balance between inhibitory factors (endostatin) and
angiogenic factors (VEGF, bFGF)

Tumour cells release pro-angiogenic factors which activate
receptors (VEGFR)
 also stimulates secretion and activation of MMPs which
degrade the basement membrane
This allows activated endothelial cells to migrate towards
tumour, helped by integrins
ECs deposit a new basement membrane and secrete growth
factors such as platelet-derived growth factor (PDGF),
which attract supporting cells to stabilize the new vessel.

VEGF – Vascular Endothelial Growth Factor
bFGF - basic Fibroblast Growth Factor
MMPs – Matrix MetalloProteinases
‘cryptic’ angiogenesis inhibitors
Inactive until they are released from the parent protein by enzymatic
cleavage
 Endostatin
 Angiostatin
 20kDa fragment of
 38kDa fragment of
collagen XVIII
plasminogen
 Endothelial cell specific
 Complete regression in
mice
 No drug resistance
Endostatin
Discovered in 1995 by Judah Folkman et al
 Phase I clinical trial in 1999
Dr. James Watson predicted that Dr. Folkman would cure all
cancer within 2 years

Dr. Folkman’s response
“If you are a mouse and have cancer we can take good care of
you. I respectfully disagree because in our experiments we
mostly sacrifice the mice. So, I don't know if that qualifies as
taking good care” www.pbs.org/wgbh/ nova/cancer/program.html
Integrins – the ‘velcro’ of the cell

The cell moves by "ruffling" it's membrane. This is done by a
series of actin fibers, whose function is controlled by the
integrins. These fibers cause the cell membrane to move in
certain directions, and the integrins attach to the matrix as this
happens, pulling the cell along a micrometer at a time
Representation of the clinical drug
development process
suggested differences in end points between studies that are
targeted at cytotoxic agents compared with studies to test
angiogenic modulators
DLT, dose-limiting toxicity;
MTD, maximum-tolerated dose.
What is in the pipeline?
Anti-angiogenic molecules fall into 5 categories
 inhibitors of pro-angiogenic growth factors, e.g. VEGF, bFGF,
PDGF
 protease inhibitors that prevent the breakdown of the
surrounding matrix, which is needed for blood-vessel growth;
 Analogs of endogenous inhibitors of angiogenesis e.g.
endostatin;
 inhibitors of cellular adhesion molecules; and
 molecules with undefined mechanisms
Anti-VEGFR2
therapy
(c,d) Anti-VEGFR2 prunes
immature vessels, leading
to a progressively
'normalized' vasculature
(e) Further treatment leads
to a vasculature that is
inadequate to sustain
tumour growth by day 5.
(f) Perivascular cells
expressing GFP (under the
control of the VEGF
promoter) envelope some
vessels in the tumour
interior.
(g) A perivascular cell,
presumably a fibroblast,
leading the endothelial
sprout (arrow).
Imaging studies to monitor tumour angiogenesis
(blood flow)
Before treatment
after treatment
Blood-flow maps a | before treatment and b | six months after
treatment of a patient with metastatic renal-cell carcinoma with thalidomide.
Haematological malignancies!
These images are confocal microscopic sections of bone-marrow biopsies that have
been stained with antibody to von Willebrand factor, which highlights blood
vessels. In the left panel, normal bone marrow (from a child with a nonneoplastic disease) shows normal microvasculature of uniform-sized vessels. In
the right panel, bone marrow from a child with newly diagnosed acute
lymphoblastic leukaemia reveals intense neovascularization, with microvessels
of variable diameters.
matrix metalloproteinase inhibitors MMPIs

Phase III clinical trials with MMPIs (Marimastat – British
Biotech) in several solid tumours

Disappointing results. Reasons may be
 Early initiation of advanced testing (Phase III) without the
appropriate safety and efficacy indications from Phase I/II
trials.
 side-effects (mainly musculoskeletal pain) associated with
patient non-compliance in trials.
 inappropriate model (advanced-stage refractory diseases)
in spite of preclinical testing in animal models that had
indicated an advantage at an early stage of disease.

Poor survival rate in phase III clinical trials against renal cell
carcinoma
References
1) Angiogenesis modulation in cancer research:Novel clinical
approaches by M Cristofanilli, C Charnsangavej‡ and
GN.Hortobagyi
Nature reviews drug discovery VOL 1 JUNE pp 415 (2002)
2) Angiogenesis in cancer and other diseases by P Carmeliet &
RK. Jain
Nature vol 407 14 september 2000 pp 249
3) Chapter 17 : Knowles and Selby