Download AN OLD ANTI-ALCOHOLISM DRUG GIVES LUNG CANCER

AN OLD ANTI-ALCOHOLISM DRUG GIVES LUNG CANCER PATIENTS NEW HOPE
Kate Butcher, Vinodh Kannappan, Zhipeng Wang and Weiguang Wang
Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY
Pressing need for new anticancer drugs
Nano-Disulfiram eradicates lung cancer in mice
Problems for using Disulfiram in cancer treatment
• Lung cancer is the most common cancer in the world – 1.8 million new cases.
• The potential clinical application of DS in cancer treatment is hampered by its
• Lung cancer is the leading cause of cancer death worldwide – 1.6 million deaths.
• UK - 44,500 new cases of lung cancer diagnosed and 35,500 people died in 2012.
very short half-life in the bloodstream (less than 2 min).
Tumour cells
injected in mice
• New formulations of DS with longer half-life in the bloodstream are required
• The average price of anticancer drugs increased 15-fold over the last 10 years.
to establish the true efficacy of DS in cancer.
• Most anticancer drugs have severe side effects. Moreover, they often do not cure cancer.
• Nano-drug-delivery is a cutting edge technology that enables us to protect
Cost of
Cancer to
NHS UK
NHS
spend on
anticancer
drugs
NHSCancer
drugs fund
(CDF)
Sorafenib£39,000
Imatinib £21,000
Nilotinib £21,000
Dasatinib£31,000
Nanotechnology improves the efficacy of Disulfiram
Bosutinib£76,000
Synribo £100,000
Ponatinib £90,000
Lapatinib £24000
We recently developed and characterized novel formulations of DS such as
Liposomal DS (Lipo-DS), Poly (lactic-co-glycolic acid)-DS, DS-Gold nanoparticles
and polymeric micelle-DS (DS-NPs).
Cancer Stem Cells - Prime Targets in Cancer
• Cancers contain a small population of cancer stem cells (CSCs) that are highly resistant to
anticancer drugs. CSCs result in tumour metastasis, recurrence and poor prognosis.
Encapsulation into nanoparticles
Free Disulfiram
Kills bulk tumour cells but
CSCs Survives
Primary
Tumour
Tumour recurrence
Chemotherapy
Hypoxic core induced
Cancer Stem cells
Primary
Tumour with a
CSC core
PLGA-Nanoparticles
50-200 nm
Nano-lipid
50-200 nm
Polymeric Micelles Gold Nanoparticles
50-200 nm
20 nm
100
90
80
70
60
50
40
30
20
10
0
Days after Treatment
Free DS
Lipo-DS
DS-NPs
DS-Nano particles can suppress tumour growth in animal models and
prevents cancer spreading to other organs.
Control
A
B
DS-NPs + Copper
Normal Lung
Nodules in Lung
Metastasis to
other organs
More migration ability
Escape from Primary
Tumour Site
Empty NPs
DS-NPs
 Extended time in circulation (4 hours).
• Repurposing FDA approved drugs for new uses is an established shortcut between the lab
 Prevents non-specific tissue damage.
and clinics - An attractive strategy for anticancer drug development.
1mm
EHT = 15.00kV Signal A = SE1
WD = 5.5mm File Name = ENPs 4.5f
Date 8 Jul 2014
1mm
EHT = 15.00kV Signal A = SE1
WD = 5.5mm File Name = ENPs 4.5f
Date 8 Jul 2014
 Good bio-distribution, reduced dose.
100
Liver
80
Spleen
60
Liver
40
Spleen
**
20
0
Pathology of
Nodules
ro
l
• Development of a new drug takes an average of 15 years and costs £1.15 billion.
 Controlled drug release.
C
120
NSCLC Metast
Kidney
Lung
Kidney
A
 Versatile routes of administration.
Drug repositioning and Disulfiram
140
u
million
S/
C
billion
-D
billion
P
340
uN
1.2
Co
nt
5
Cost of Drug per
patient per year
Lung Metastasis (%)
£
0
10sec
30sec
2min
4min
10min
20min
30min
1h
2h
4h
8h
24h
£
% DS detected in serum
£
Tumour Volume (mm3)
and deliver vulnerable drugs in the bloodstream.
Treatment with DS-NPs and copper
completely blocked metastasis of
liver cancer to the lung
Lung
No Toxic effect was observed in
the vital organs of mice treated
with DS-NPs and copper gluconate
Drug development process - 10-17 years - Less than 10 % Success rate
Target Discovery
2-3 years
Lead
Optimization
1-3 years
Discovery and
Screening
0.5-1.5 years
Pre-Clinical
Studies
1-2 years
Development
and Trials
5-6 years
A very low dose of nano- DS along with oral Copper supplement showed a
Registration
1-2 years
remarkable tumour inhibiting effect in xenograft models of lung cancer and
Cancer cells grown in lab
Compound
identification
1-2 years
Compound
Acquisition
0-2 years
Pre-Clinical
Studies
0-1 years
Development
and Trials
1-6 years
Registration
1-2 years
Cancer stem cell culture
inhibited metastasis of liver cancer to lung, without any adverse side effects or
toxicity to normal tissues.
Drug repositioning – 3-8 years
• Disulfiram (DS) is an anti-alcoholism drug that has been used for over 60 years.
Assess DS-NPs ability to
kill cancer stem cells
Assess DS-NPs ability to
prevent cancer malignancy
Conclusions
• DS forms a complex with Copper (Cu) that kills cancer cells through generation of reactive
• DS is an FDA approved drug which is available for less than a £1 for a 500mg tablet.
oxygen species.
Non-Specific Killing and Anticancer drug resistance
Normal cell
Cancer Stem
Cancer cell
cells
Normal cell
Cancer cell
High ALDH
Protein
Cancer Stem
cells
targeting CSCs.
Disulfiram specifically
inhibit ALDH
• Nano-encapsulated DS may be translated quickly into clinical use.
Disulfiram blocks drug
efflux pump
Drug efflux
protein
Low Copper
Treatment with
• Nano-encapsulated DS in combination with Cu eradicates multiple cancers by
Disulfiram selectively kills cancer cells using copper
High Copper High Copper
Anticancer drugs
• Development of DS based anticancer therapeutics will provide millions of patients
Disulfiram + Copper
with affordable anticancer drug.
ALDH protein
Detoxify drugs
DS-Cu Complex
Drug pumped
out by efflux
Non specific
Cell death
killing
Cell survives
Generates Toxic Reactive
Oxygen Species that kills cells
Cell survives
Cell death
Cell death
Compared with normal tissues, cancer tissues often possess higher levels of
intracellular Cu which enables DS to selectively target cancer cells.
DS-Nano particles eradicates cancer stem cells and stop their migration
and invasion capacity in cell culture conditions.
ACKNOWLEDGEMENTS: We would thank British Lung Foundation (RG14-8) for supporting this project.
We also thank Dr. Mark Morris, University of Wolverhampton, for reviewing and providing valuable
suggestions for this poster.