Download ALK+ lung cancer and the Blood-Brain Barrier

ALK+ lung cancer and the
Blood-Brain Barrier (BBB)
A concise guide
Contents
Section Page number
Section 1: Lung cancer and ALK+ NSCLC
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Section 2: The Blood-Brain Barrier (BBB): What and why?
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Section 3: Behind the Blood-Brain Barrier (BBB): The function of the barrier
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Section 1:
Lung cancer and ALK+ NSCLC
Lung cancer
Lung cancer is the most common type of cancer worldwide. There are more than 1.8 million new cases of
lung cancer each year,1 which equates to 13% of total cancer cases.2 It is also more deadly than any other
cancer, having resulted in 1.59 million deaths in 2012.3
There are two main types of lung cancer – small-cell lung cancer (SCLC) and non-small-cell lung cancer
(NSCLC). SCLC is relatively uncommon, occurring in about 15% of lung cancer patients, while NSCLC
occurs in the majority of the remaining lung cancer cases.4 Within NSCLC, there are several further
subtypes driven by different receptors and genetic mutations, including anaplastic lymphoma kinasepositive (ALK+) NSCLC.
Alveoli
Lung cancer tumours
FACT 1: More people die of lung cancer worldwide than of breast,
prostate and colorectal cancers combined5
Worldwide, approximately 90,000 new cases of ALK+ NSCLC are diagnosed each year,
which amounts to more than 5% of the total new lung cancer cases.6 The anaplastic
lymphoma kinase (ALK) gene plays an important role in the cells of the nervous system
and its expression is normally under strict genetic control.7 ALK+ NSCLC is caused by
‘activating mutations’ in the ALK gene, which cause it to fuse with another gene (most
often EML4) to create an ALK-fusion protein.8 Unlike other forms of lung cancer,
ALK+ NSCLC is most commonly diagnosed in younger people with a light or nonsmoking history.9
FACT 2: Researchers have identified 15 unique mutations and biomarkers that are responsible
for tumour growth in NSCLC10
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Section 2:
The Blood-Brain Barrier (BBB): What and why?
FACT 3: The most common cause of brain metastasis in men is lung cancer,
and women are expected to follow this trend shortly11
Lung cancer cells
can spread to the
brain (brain
metastases)
Brain
Blood-Brain Barrier (BBB) and lung cancer
Patients with this distinct form of lung cancer are at high risk of developing brain metastases. As many as 60% of
anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALK+ NSCLC) patients who are treated with the
current standard of care see their tumours spread to the brain within a year.12 This means that treatments for the disease
need to be able to reach tumours in both the lungs and the brain.
Tumours
Lungs
The ability to effectively treat brain metastases is extremely important, as tumours that spread to the brain are particularly
devastating to patients. They can result in the loss of vital functions such as vision or movement, impact mental
performance or cause changes in personality and behaviour.13 Furthermore, compared to other sites, brain metastases
are associated with a significant reduction in quality of life and life expectancy.14
Nerves
Spinal cord
FACT 4: Around 1 in 3 people with brain metastases will have
no symptoms. Symptoms are dependent upon which part of the
brain is affected, how many tumours are present and the person’s
general health15
Cell nucleus
Structure of the Blood-Brain Barrier (BBB)
Blood-Brain Barrier cells
The BBB is a tightly-joined network of cells lining the blood vessels in the brain and spinal cord, which
protects the brain and Central Nervous System by preventing the entry of certain harmful molecules.16
IN
Blood
Tight junctions
between cells
(gaps between
cells are <1nm)
RA
Brain metastases can be difficult to treat because most anaplastic lymphoma kinase (ALK) inhibitors are
able to cross the BBB, but are pumped out by active efflux so the concentration is low in the brain.17
Basement membrane
B
4
Section 3:
Behind the Blood-Brain Barrier (BBB): The function of the barrier
FACT 5: The total length of all the blood vessels in the BBB is 600 km. That’s the equivalent of 2000 stacked
Eiffel Towers!18
B LO O D
2 Some molecules
1 Some molecules
can cross by
diffusion
can fit through
the tight
junctions
between cells
3 Some larger
molecules are
transferred across
by carrier proteins
How the Blood-Brain Barrier (BBB) works
The BBB controls which molecules can enter the brain from the blood, for example, according to their
size. The BBB stops some molecules entering the brain entirely.
There are a few different ways a molecule can cross the BBB, for example:
B LOO
• By diffusion
D-B RA
IN
• Through the tight gaps between the BBB cells (for smaller molecules)
B RA
• By carrier proteins (for larger molecules)19
IN
Carrier proteins
Tight junction
The active efflux system
B LO O D
Active efflux protein
Even if a drug is able to cross the BBB, it may be pumped out of the brain and wider Central Nervous
System by a mechanism called active efflux. Active efflux occurs when special proteins recognise some
of the molecules that have crossed the BBB and transport them back into the blood.20
Only the molecules that can both cross the BBB and avoid the active efflux system are able to treat brain
metastases.
FACT 6: More than 90% of cancer morbidity (poor quality of life,
pain, impaired organ function) and cancer deaths are directly
related to metastasis21
B LOO
D-B RAI N BAR R I E R
B R AI N
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References
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2
3
4
5
6
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Roche data on file.
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