Dania Movia – PhD, MSc Senior Research Fellow Department of Clinical Medicine / Trinity Translational Medicine Institute Trinity College Dublin Predicting the efficacy of inhaled anti-cancer drugs in NSCLC patients

1. Non-animal models of NSCLC
Dania Movia – PhD, MSc
Senior Research Fellow
Department of Clinical Medicine / Trinity Translational Medicine Institute
Trinity College Dublin
Predicting the efficacy of inhaled anti-cancer drugs in NSCLC patients
01/10/2021 https://www.linkedin.com/in/dania-movia/
dmovia@tcd.ie
Find me on: @daMovia ● @daMovia

2. Trinity College Dublin, The University of Dublin
Respiratory diseases:
What is the clinical need?
2
Source: European Respiratory Society (ERS) Lung White Book

3. Trinity College Dublin, The University of Dublin
Respiratory diseases:
Overview of the global respiratory drug market

4. Trinity College Dublin, The University of Dublin 4
1. Drug delivery directly at the site of action
• Rapid therapeutic onset with considerably lower drug
doses
2. Painless and minimally invasive
3. Avoidance of first-pass metabolism
• Optimal pharmacokinetic conditions for drug
absorption
• Reduced systemic side effects
Treating respiratory diseases:
Advantages of orally inhaled
drug products (OIDPS)

5. Trinity College Dublin, The University of Dublin 5

6. Trinity College Dublin, The University of Dublin 6
Drug discovery and development – The Valley of Death
© Dania Movia

7. Trinity College Dublin, The University of Dublin
Treating lung cancer with orally
inhaled drug products (OIPDs)
7
What’s the problem?
Inhalation clinical trials make for the 2.6% of the total number of interventional studies registered in the time
period under consideration (2016–2020), and 23.2% of the total drug interventions examined
• Attrition rate of respiratory drug development: 70%
• The cumulative probability to reach the clinical market for drugs targeting respiratory diseases is equal to 3%,
compared to the 6–14% probability that applies to drugs used to treat other diseases
What prevents preclinical successes from translating into cures and effective OIPDs for lung cancer?
Movia et al., Animals 2020, 10, 1259; doi:10.3390/ani10081259

8. Trinity College Dublin, The University of Dublin
What prevents preclinical
successes from translating into
cures and effective OIPDs for lung
cancer?
Potential contributors:
• Poor understanding of the underlying mechanisms of
lung cancer resistance
• Difficulties in drug formulation
• Poor performances of the drug administration
devices;
• Limitations of the current preclinical models play a
role in the high attrition rate of respiratory drugs
Movia et al., Animals 2020, 10, 1259; doi:10.3390/ani10081259
Main conclusion: Published preclinical data does not
predict clinical success of therapeutics in lung cancer.
Published
preclinical
studies
Clinical
success

9. Trinity College Dublin, The University of Dublin
Current state-of-the-art
In vitro models In vivo models
Preclinical model
Conventional in vitro models 3D in vitro spheroids Heterotopic / orthotopic in
vivo model
PDX GEMMs
Description
Established cell lines; primary
cells
Multicellular aggregates of
human cell lines / primary cells
Human cell lines in immuno-
deficient host
Patient-derived tumour tissue
(xenograft) in immuno-
deficient host
Genetically engineered mouse
models (GEMMs) of
spontaneous NSCLC
Strength
• Human tumour cells
• Ease-of-use
• Scalable
• May reproduce direct
contact of cancer cells with
air (ALI cultures)
• Human tumour cells
• Relatively easy to use
• Scalable
• Three-dimensional growth
mimicking the NSCLC tissue
structure
• Human tumour cells
• Relatively easy to use
• Realistic heterogeneity of
tumour cells
• Patient-derived tumour
cells
• Some preserved human
stromal element
• Spontaneous co-evolution
of tumour epithelium and
micro-environment in
native organ
• Mimics the disease
progression stages
• Competent immune system
Limitations
• 2D dimensional growth
• Lack of TME
• Absence of appropriate
tumour architecture: loss of
NSCLC-tissue direct contact
with air
• Heterologous
• Cross-species growth of tumour cells
• Absence of intact immunity
• Absence of appropriate tumour architecture: loss of NSCLC-
tissue direct contact with air
• Murine cancer
• Labour- and resource-
intensive
• High variability within the
model
Pre-clinical models of lung cancer for testing drug efficacy
State of the art

10. Trinity College Dublin, The University of Dublin 10
ALI multilayered mono-/co-cultures of non-small-cell lung cancer
New approach methodology (NAM)
Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

11. Trinity College Dublin, The University of Dublin
Minchinton et al. Nature Reviews Cancer 6, 583–592 (2006)
Air-Liquid Interface
(ALI) cultures
3D cultures
+
We merged 2D ALI (Air-Liquid Interface) culturing techniques with
a 3D modelling approach, to create an ALI multi-layered culture.
Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

12. Trinity College Dublin, The University of Dublin
Minchinton et al. Nature Reviews Cancer 6, 583–592 (2006)
Air-Liquid Interface
(ALI) cultures
3D cultures
+
Movia et al. Nature Scientific Reports 8, 12920 (2018)
We added healthy lung fibroblasts, to create an ALI multi-layered
co-culture.
Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

13. Trinity College Dublin, The University of Dublin Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

14. Trinity College Dublin, The University of Dublin Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

15. Trinity College Dublin, The University of Dublin Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

16. Trinity College Dublin, The University of Dublin Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

17. Trinity College Dublin, The University of Dublin Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

18. Trinity College Dublin, The University of Dublin Movia et al., Nature Sci Rep, 2018, 8:12920; Movia et al., BMC Cancer, 2019, 19:854

19. Trinity College Dublin, The University of Dublin
Conclusions
19
My argument is scientific rather than ethical
• Lack of efficacy is now the most common cause of OIDP attrition
• This appears to be associated to the fact that preclinical animal models are poorly representative
for testing OIDPs
• The facts presented above indeed underscore the pressing need for increasing confidence in
preclinical evidence in respiratory disease research, complementing animal studies with new
approach methodologies and, when needed, abandoning animal studies
• Our group has made the first steps towards the creation of an in vitro NAM that enables, on one
hand, reproducing MDR mechanism seen in lung cancer patients, and, on the other, testing both
systemically administered and orally inhaled drugs
. Movia et al., Front. Bioeng. Biotechnol. 8:549. doi: 10.3389/fbioe.2020.00549
Movia et al., Nature Sci Rep, 2018, 8:12920
Movia et al., BMC Cancer, 2019, 19:854
Movia et al., Animals 2020, 10, 1259; doi:10.3390/ani10081259

20. Trinity College Dublin, The University of Dublin
Thank you!
Trinity College Dublin, The University of Dublin
• Prof. Adriele Prina-Mello
• Prof Yuri Volkov
• Dr Luisana Di Cristo
• Ms Solene Bruni-Favier
• All present and past members of the
LBCAM team
Funding agencies
https://www.linkedin.com/in/dania-movia/
dmovia@tcd.ie
Find me on: @daMovia ● @daMovia