targeting prostate cancer metabolismhybrid cellular automata: discrete cellular populations,...
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Targeting Prostate Cancer Metabolism Robert Gillies,
et al. H. Lee Moffitt Cancer Center and Research Institute; Tampa FL USA;
Frontiers in Urologic Oncology!
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Disclosures
• Nothing to disclose relevant to this presentation.!
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Objec.ves• High Grade Prostate Cancers exhibit a Warburg
Effect (aerobic glycolysis); possibly related to PTEN loss!
• Aerobic glycolysis leads to acidification of the tumor microenvironment, which can be neutralized with oral buffers!
• Oral buffers neutralize acidity and reduce spontaneous and experimental metastases; and can retard emergence of cancer in TRAMP models.!
• This is related to buffers reducing the evolutionary fitness of aggressive cells in favor of more benign cell types within the tumor.!
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Pasteur Effect is acute; Warburg Effect is hardwired
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pHe=6.74 pHi=7.28
β− NTP
α− NTP γ− NTP
3-APP GPC
PME
P i
Chemical Shift, d (ppm) -30 -20 -10 0 10 20 30
Elevated glycolysis leads to tumor acidosis!
H2N-CH2-CH2-CH2-P=O
O
OH
pKa = 6.91
H2N-CH2-CH2-CH2-P=O
O
OH
pKa = 6.91
Resolution = 8 x 8 x 8 mm3 Gillies, et al. NMRiB, 1994
In vivo 31P spectrum of MCF-7/s tumor in SCID mouse!
pHex=6.84!
pHin=7.32!
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pHe mapping with MRSI of IEPA
DCE of MDA-435 pHe map of MDA-435
6.8
6.4
Extra
cellu
lar p
H
Van Sluis et al., MRM, 2001
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FITC-pHlipimagingofperi-tumoralacidity(MDA-mb-231inDWC)
5X, 45 min
(Tumor)!
(Stroma)!
Estrellaetal“AcidityGeneratedbytheTumorMicroenvironmentDrivesLocalInvasion”CancerResearch,2013
pHlip = pH low insertion peptide, which undergoes an acid catalyzed transition causing membrane insertion
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Day 7 Day 14
A
6.6
pH
6.6
7.4
270º
180º
90º
0º
C
B
6.836.83
7.15
7.15
7.26
7.26
7.27
7.267.26 7.15
7.04
7.02
6.73
6.65
6.78
7.15
0º
270º
180º
90º
B
6.836.83
7.15
7.15
7.26
7.26
7.27
7.267.26 7.15
7.04
7.02
6.73
6.65
6.78
7.15
0º
270º
180º
90º
B
D
Estrella et al Canc Res (2013)
Both growth and acidity were
inhibited with 200 mM bicarbonate Tx!
Local Invasion is associated with an acidic pH!
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It’sallaboutthatbase…NaHCO3raisesTumorpH
Chemical Shift (ppm)-30-20-100102030
β-NTP
α-NTPγ-NTP
3-APP
GPC
PME
Piδ (ppm)
182022242628
B.
A.
+ bicarbcontrol
Bicarb Control p!pHe 7.4 ± 0.06 7.0 ± 0.11 <0.005!
pHi 7.0 ± 0.06 7.1 ± 0.09 n.s.!
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MDA-mb-231 br. ca.
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Differen.alSensi.vity(PC3mareverysensi.ve,B16reresistant)
Robey et al., Canc. Res., 2009
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BufferTherapyinhibitsinvasionandmetastasis(PC3mandTRAMP)
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Arig Ibrahim-Hashim
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BicarbraisespHandprevents1otumorsifgivenearly
Ibrahim-Hashim, Urology, 2012!
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BicarbTreatTRAMPmice:Lowdoseearlyorhighlateà
nomets
Ibrahim-Hashim et al., Cancer Research 2017
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C2/C3cellphenotypesinTRAMPtumors
C2:!-glycolytic!-invasive!
-high CA-IX!-high GLUT1!
!C3:!
-oxidative!-not invasive!
!Ibrahim-Hashim et al., Cancer Research 2017
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BufferTxselectsforlessaggressiveC3phenotype
Ibrahim-Hashim et al., Cancer Research 2017
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Glycoly.cPhenotypeassociatedwithPTENloss
P T E N -P 8 P T E N -C a P 80
5
1 0
1 5
G ly c o ly s is
PP
R(p
Mo
les
/min
/ug
pro
tein
)
****
P T E N -P 8 P T E N -C a P 80
1
2
3
G ly c o ly t ic R e s e rv e
PP
R(p
Mo
les
/min
/ug
pro
tein
) ****
P T E N -P 8 P T E N -C a P 80
2
4
6
8
A T P L in k e d O C R
OC
R (
pM
ole
s/m
in/u
g p
rote
in) ****
P T E N -P 8 P T E N -C a P 80
5
1 0
1 5
2 0
M ito c h o n d r ia l R e s e rv e C a p a c ity
OC
R (
pM
ole
s/m
in/u
g p
rote
in)
****
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Model
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Eco-Evolu.onarySolidTumorModel
Hybrid cellular automata: Discrete cellular populations, continuous chemical fields.
Focused on tumour-mE interactions Evolving tumour phenotypes
Mark Robertson-Tessi
normal.ssuecellsbloodvessels
nocells(ECM)
Tumorcells
Robertson-Tessi, M. et al. Cancer Research. 2015 Apr 15;75(8):1567-79.
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Eco-Evolu.onarySolidTumorModel
Robertson-Tessi, M. et al. Cancer Research. 2015 Apr 15;75(8):1567-79.
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SteeringProstateCancerEvolu.on
5! 1!
3!4!
5
4
1
3
Untreated Low dose bicarbonate given early
Low dose bicarbonate given late High dose bicarbonate given late
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CAmodelpredictsC2àC3withbicarbtreatment
5 No Treatment
Treated Early 200 1
Treated Late 400 4
3 Treated Late 200
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Summary
• Tumorsarecomprisedofcellspecieswithdifferentphenotypes.– Glycoly.càmoreaggressive(pioneer)– Oxida.veàmorebenign(engineer)
• FitnessofpioneercanbereducedbyneutralizingtumorpH.
• NeutralizingtumorpHreducesmetastases(insomesystems).
”Oneshouldmakethingsassimpleaspossible…butnotsimpler.“
AlbertEinstein
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Acknowledgements• Moffi`
– BobGatenby– ArigIbrahim-Hashim– DomAbrahams– VeronicaEstrella– PedroEnriquez-Navas– MehdiDamaghi– ShonaghRussell– MarkRobertson-Tessi(IMO)– SandyAnderson(IMO)
!• NIH
• U54CA143970;R01CA077575;U01CA143062;R01CA189295;R01CA190105;R01CA187532;P30CA076292-13