David Gauden - Genesis conference

“PET Molecular Imaging in oncology: drug development or (and?) routine clinical
usage”
Genesis 9 December 2014
David Gauden, Head of Development
www.blueearthdiagnostics.com
Introduction
●
Biotech funded by Syncona Partners,
based Oxford Science Park
●
Licensing of IP from GE Healthcare
●
Mission : To develop and commercialize
Fluciclovine [18F], aka FACBC, a PET
amino acid imaging agent for the
detection of recurrent prostate cancer
and glioma
●
Experienced management team medical imaging / drug development.
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In this presentation
•
•
•
Review rationale for amino acid PET imaging in cancer and
some of the radiolabelled amino acids that have been
developed
Discuss challenges for transition of molecular imaging from
‘scientifically interesting’ to ‘clinically & commercially useful’
Review unmet imaging needs in prostate cancer clinical
decision making and the ongoing development of new
tracers for PSA recurrent prostate cancer
Disclaimer: For educational purposes only. Some of the
products discussed are still under development and may
never come to market.
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Scientific basis for amino acid
PET imaging in oncology
●
Cancer cells are rapidly proliferating
and may have aberrant cell energetics.
Amino acids are in demand for both
anabolism & catabolism.
●
Mammalian cells may have many aa
transporters, four of which in particular
are over-expressed in cancer cells:
ASCT2; LAT1; xCT and ATB0,+ (1).
●
Certain amino acids (leucine,
glutamine) are involved in prooncogenic signaling via mTOR, activity
in prostate cancer cells is linked to
androgen driven LAT1 & LAT3
expression (2)
●
Amino acid metabolism as a drug target is not new, with drugs such as asparaginase used
in acute lymphoblastic leukaemia and LAT1 transporting the anti-cancer drug melphalan (3).
More recently glutaminase inhibition has also been shown to be a viable drug target (4).
(1) V. Ganapathy et al., Pharmacol. & Therap. 121 (2009); (2) Wang et al, Cancer Res. 71(24) (2011); (3) Fuchs & Bode, Semin. Cancer Biol. 15 (2005); (4) Hensley et al, J. Clin.
Invest. 123 (9) (2013)
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Radiolabelled amino acids (5)
CO2H
H 2N
H 2N
CO2H
OH
18F
O
FET
18F
FACBC
H 2N
18F
CO2H
MeAIB
18F
S
11CH
MET
FACBC
CH3
HN CO2H
CO2H
3
H 2N
CO2H
CO2H
18F
OH
CO2H
H 2N
3
HN
FDOPA
H 2N
11CH
MeFAMP
H 2N
CO2H
H 2N
CO2H
18F
5-FAsu
H 2N
CO2H
18F
18F
N
N N
O
AFETP
4-FGln
NH2
CO2H
18F
CO2H
4-FPGlu
Extracellular
A
AA Na+
● F-DOPA used in neuroendocrine tumors and Parkinson’s disease; [18F] FET
and [11C] MET in glioma; fluciclovine transported by ASCT2 & LAT1 (6) but not
metabolised or incorporated into protein.
(5) McConathy, J. et al., 2012. Radiohalogenated nonnatural amino acids as PET and SPECT tumor imaging agents, Med Res Rev. 32: 868-905.
(6) Oka et al. Nuc. Med & Biol. 39 (2012)
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Challenges to wider use of new PET
tracers in oncology
•
Most PET agents used in drug
development are available at few
centres (mostly neuro)
•
Molecular Imaging Agents
Drug
development
tools
A (very) limited number are widely
available for diagnostic use, even
fewer with NDA/MAA
•
Widespread
clinical use
CT/MR/SPECT and FDG have shown
widespread utility in oncology
applications, with some exceptions
•
So…how do we go from beautiful
science to commercial use for new
tracers?
•
Find an initial ‘killer app’ for product
•
•
•
high un-met need
clear therapy ‘decision node’
willingness to pay
[18F] FDG
[11C] Raclopride
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The ‘niche’ of biochemically recurrent
prostate cancer
Diagnosis &
staging
Surgery and or Radiotherapy (incl IGRT)
PSA recurrence
(20-40%)
3
Cure
• Clinicians identify 5 areas for
better imaging:
2
1
• Biopsy guidance after repeat
negative TRUS biopsy
• Staging high risk primary cases for
LN or bone involvement
• 1o radiotherapy planning
• Detection of local vs distant PSA
recurrence (BCR)
• Monitoring of progression or
response in late stage disease
Surveillance
Progression
PSA, bone scan
+/- CT, MR, US
PET based stratification
Prostate bed
Pelvic region
4
Metastatic disease
Curative salvage
(e.g. RT ± ADT)
Systemic therapy
(e.g. ADT, Zytiga
Chemotherapy)
Monitor with PSA
Monitor with PSA,
CT, bone scan,
PET?
Monitor with PSA
(7) Choueri et al, J Urology Vol. 179, 906-910, March 2008
• In BCR choice made between
focal curative or systemic therapy
• Only 10-20% BCR patients in the
USA have positive findings with
conventional imaging (7)
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Non FDG PET tracers in BCR Pca
•
•
•
Several recent reviews, see below (8,9,10,11).
Choline & acetate. Meta-analyses: 11C Cho more sensitive
than 18F Cho in 1o LN staging (9); 18F cho more sens. in
BCR, inc. LR & bone (10); CHO higher sens vs 99mTc BS
(11). 11C Ac, small intra-pt study seems similar to Cho (12)
18F
NaF intra-pt study shows higher sensitivity vs 18F-Cho
for spinal mets, however with much lower specificity (13).
•
Fluciclovine 18F: In 28 pts with negative conventional
imaging, (mean PSA 2.9) 11C Cho visualised 7 lesions / 5
pts, fluciclovine detected 18 lesions in 10 patients (14).
•
Many PSMA (PET/SPECT: 99mTc, 18F, 68Ga, 89Zr)
industrial effort aligned with stratifying PSMA therapy. In a
37 pt study (avg PSA 11.1) total of 78 lesions in 32 pts
were detected with 68Ga-PSMA PET/CT & 56 in 26 patients
using Choline PET/CT (15). Impact of PSMA
heterogeneity (16) on diagnostic utility is not established.
Fluciclovine (18F) PET image of patient with suspected recurrence of prostate cancer.
Following Fluciclovine (18F) injection, 10x3mm node detected with SUV 4.6 vs background SUV of 1.
Radical Prostatectomy in Sept 2011. Radiotherapy, no Androgen deprivation therapy.
Rising PSA Aug 6 2013. Negative conventional imaging Oct 8th 2013
Image reproduced courtesy of Dr Cristina Nanni, Ospedale St’Orsola, Bologna, Italy
(8) Yu et al, Am J Nuc Med Mol Img 2014; 4(6) (9) Evangelista et al Eur Urol. 2013 Jun;63(6); (10) Evangelista et al Clin Nucl Med. 2013 May;38(5):305-14; (11)
von Eyben FE and Kairemo Nucl Med Commun 2014;35. (12) Buchegger et al Eur J Nucl Med Mol Imaging (2014) 41; (13) Poulsen et al BJU Int 2014 Dec:
114(6); (14) Nanni et al, Clinical Genitourinary Cancer April 2014; (15) Afshar-Oromieh et al Eur J Nucl Med Mol Imaging (2014) 41 (16) Mannweiler et al Pathol.
Oncol. Res. (2009) 15:167–172
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CONCLUSION
Newer PET molecular imaging agents have the
potential to solve key diagnostic challenges in
oncology applications where anatomic imaging and
FDG perform poorly.
Widespread availability of novel PET agents for
diagnostic use will enhance access for drug
development researchers wishing to investigate new
mechanisms of action, such as those associated with
amino acid metabolism or specific receptor based
imaging.
THANK YOU
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