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First Class Lecture notes Cancer Biology (DNA and Disease)
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Targeted therapy lecture notes
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TARGETED THERAPY: Avoids normal cells and goes directly to thecancer cells!
Precision medicine: treatments tailored to the genetic changes in each
person’s cancer.
Targeted therapy or molecularly targeted therapy is one of the major modalities
of medical treatment for cancer, others being hormonal therapy and cytotoxic
chemotherapy. As a form of molecular medicine, targeted therapy blocks the
growth of cancer cells by interfering with specific targeted molecules needed for
carcinogenesis and tumour growth, rather than by simply interfering with all
rapidly dividing cells (e.g. with traditional chemotherapy). Targeted cancer
therapies are expected to be more
effective than older forms of treatments
and less harmful to normal cells.
THERAPEUTIC TARGETS
(‘DRIVER’ MUTATIONS):
Looking at a tumour’s mutational
profile is a good way of designing
an approach to kill off the tumour
cells. The cells may express a
molecule which can act as a
therapeutic target.
TARGETED THERAPY:
1. Monoclonal antibodies
(mAbs):
Receptor Tyrosine Kinase Inhibitors (RTKIs) – inhibit EGFR, VEGFR.
e.g. bevacizumab
mAbs are chemical entities that inhibit activity of enzyme receptors.
Therapeutic mAbs can lead to tumor cell death by different
mechanisms of action. First, mAbs can block ligand-receptor growth
and survival pathways by targeting antigens that are differentially
expressed in tumor cells (tumor-associated antigens) and consequently
can be used to block molecules involved in cancer progression or
angiogenesis. Second, in cancer therapy, the innate immune effector
mechanisms of mAbs lead to antibody-dependent cell-mediated
cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), and
antibody-dependent cellular phagocytosis (ADCP) of targeted cells.
Medical advances during the past 10 y have led to the introduction of 9
antibodies for the treatment of diverse cancers, with the antibodies
targeting different tumor-associated antigens including surface
glycoproteins associated with clusters of differentiation (CD), CTLA-A,
or pathways regulated by growth factor receptors.
Five of these antibodies specifically and selectively target and block a
receptor tyrosine kinase (RTK). RTKs are cell surface receptors for
many polypeptide growth factors, cytokines, and hormones that
usually contain an intracellular kinase domain. The first two RTKs that
have been targeted by antibody therapy, with five currently marketed
antibodies, are the growth factor receptors EGFR and HER2. This kinase
, function is the first element involved in the activation of one or several
downstream intracellular signal transduction pathways. By targeting
the extracellular part of the receptor protein kinase, the mAb is able to
block the binding of the natural ligand, avoid conformational
rearrangement essential to the activation of the kinase and thus the
activation of the downstream signaling pathways, or activate immune
effector functions. As key regulators of normal cellular processes and
the development and progression of many types of cancer, RTKs are
ideal cancer targets.
Problems
o Size: the target molecule may be a large receptor and so access
is a problem
o Non-specific hits: especially if the receptor is expressed on other
tissues, e.g. the Her2 receptor
o Heterogeneous antigen expression: there may be different
antigens (epitopes of the antigen) expressed on other non-target
receptors
2. Small molecule inhibitors (SMIs):
Enzymes and receptors are often activated or inhibited by endogenous protein,
but can be also inhibited by endogenous or exogenous small molecule
inhibitors or activators which can bind to the active site or on the allosteric site.
e.g. Imatinib
Advantages
o Very specific to a particular molecule
o Well-understood pathways
o Oral delivery of drug: unlike monoclonal antibodies. This is preferred over
injections.
o Fewer adverse side effects: compared to monoclonal antibodies, especially
with immune inflammatory responses.
Problems
o More expensive to generate
o Primary resistance is common: no tumour regression response when
initially given treatment (rather than tumours initially responding and then
becoming refractory – secondary resistance)
ANGIOTHERAPY: use of agents that inhibit angiogenesis (development
of new blood vessels)
The signalling cascade involves a whole host of targets which could be
exploited.
ENDOSTATIN:
Discovered in 1995 by Judah Folkman et al. Folkman was the first to look
at the approach of cutting off the blood supply of tumours as a means of
destroying them.
, Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived
from type XVIII collagen. It is reported to serve as an anti-angiogenic
agent, similar to angiostatin and thrombospondin. It is a broad-spectrum
angiogenesis inhibitor and may interfere with the pro-angiogenic action of
growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and
vascular endothelial growth factor (VEGF).
Phase 1 clinical trial in 1999. Success is still limited, however.
CATEGORIES OF ANTI-ANGIOGENICS:
Anti-angiogenic molecules fall into 5 categories:
1. Inhibitors of angiogenic growth factors VEGF, bFGF, PDGF: target
the ligands themselves that bind to receptors
2. MMP inhibitors: inhibit Matrix metalloproteinases, also known as
matrixins, which are calcium-dependent zinc-containing endopeptidases.
Collectively, these enzymes are capable of degrading all kinds of
extracellular matrix proteins, but also can process a number of bioactive
molecules. They are known to be involved in the cleavage of cell surface
receptors, the release of apoptotic ligands (such as the FAS ligand), and
chemokine/cytokine inactivation. MMPs are also thought to play a major
role in cell behaviors such as cell proliferation, migration
(adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host
defence.
3. Analogs of endogenous inhibitors of angiogenesis: mimic
endogenous factors that prevent
angiogenesis from working
4. Inhibitors of cellular adhesion
molecules: such as Integrins
5. Molecules with undefined
mechanisms: don’t know precise
mechanism of action, but they do
block angiogenesis.
Inhibitors of angiogenic growth factors
dominate (30% of anti-angiogenic drug
classes). However, many compounds are
not commercially available yet – in discovery stage or clinical trials.
FDA APPROVED DRUGS:
Example of angiogenic drugs commercially available:
o Avastin (Bevacizmab):
most famous, is a
monoclonal antibody
based drug, binds to
ligand VEGF A directly,
neutralising its action.
Bevacizumab, sold under
the trade name Avastin, is
an angiogenesis inhibitor,
a drug that slows the
growth of new blood
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