Download PBOXs: A new treatment for neuroblastoma?

PBOXs: A new treatment for neuroblastoma?
Jenny Lennon1 , Dr Anne O’Meara2 , Dr Daniela Zisterer1
of Biochemistry and Immunology, Trinity College Dublin.
2Our Lady’s Children’s Hospital, Crumlin.
1School
What is neuroblastoma?
What’s the problem?
•A rare childhood cancer
•It occurs when immature ‘neuroblasts’ grow
uncontrollably
•Normally, these cells grow and mature into nerve
cells.
•But in neuroblastoma, they become cancer cells
which grow to form tumours
• They can ‘metastasize’ to other parts of the body,
such as the lymph nodes, skin, liver, and bones.
•Very low survival rates
•Chemotherapy stops working
•The cancer cells become resistant to drugs
How?
•Neuroblastoma cells have pumps which efflux drugs out of cells…..
….so the drugs can’t kill the neuroblastoma cells.
A solution?
Drugs are pumped out of the
cell
•We have designed a group of novel
drugs called the PBOXs
•They target cancer
cells without being
toxic to normal cells
Chemotherapeutics
drugs
•They kill neuroblastoma cells
apoptosis
Neuroblastoma
cell
PBOXs stay
inside and kill
the cancer cells
by
PBOXs
What’s the advantage?
•Unlike other chemotherapeutics, the cells don’t
become resistant to the PBOXs
•They are not a substrate for these drug pumps
•So the PBOXs stay in the cell and induce
apoptosis
•The can work with other chemotherapeutics to
kill even more cells
•Can use lower doses….less toxic side effects
What do we do?
•Cells have been isolated from the bone marrow of patients with
neuroblastoma
•We grow these cells in culture and perform a series of experiments to
see if our drugs induce cell death
•We determine how the cancer cells are dying
Our results
•The PBOXs induce cell death in neuroblastoma cells
•Cell death increases with increasing time and dose
60
PBOX-6
vehicle
% cell death
40
20
Bak is high, Mcl-1 is low = cancer cell dies
PBOX-6
vehicle
•Treatment with the PBOXs results in an increase in Bak and a decrease in Mcl-1
causing the cell to die
40
20
0
0
0
5
0
10
12
24
36
48
60
72
Time
[PBOX-6]
Healthy cells
Increasing doses of PBOX
Cells after PBOX treatment
control
% cell death
60
•There are proteins in the cell which determine if the cell will die
•When: Mcl-1 is high, Bak is low = cancer cell survives
Mcl-1
dying cells
Bak
PARP
•PBOXs work in combination with other chemotherapeutics
•They induce cell death in drug sensitive and drug resistant
neuroblastoma cells
40
60
What next?
% cell death
20
20
10
in
rb
op
la
tin
6
op
la
t
rb
O
X-
6+
ca
ca
hi
c
O
XPB
PB
6+
C
O
XPB
ve
in
6
ar
bo
pl
at
in
O
XPB
ca
rb
op
la
t
cl
e
Drug sensitive
le
0
0
Ve
hi
% cell death
30
40
Drug resistant
•Continue to test the PBOXs in combination with other drugs
•Isolate neuroblastoma cell from the bone marrow of patients and test the
PBOXs on these primary cells
•Investigate the ‘in vivo’ effects of the PBOXs in a neuroblastoma murine
model