GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director,...
-
Upload
lee-blankenship -
Category
Documents
-
view
216 -
download
0
Transcript of GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director,...
![Page 1: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/1.jpg)
GST-P1 or not to be?
TS to be? Heinz-Josef Lenz, MD
Associate Professor of Medicine Co-Director, Colorectal Center
Co-Director, GI Oncology Program
USC/Norris Comprehensive Cancer Center
USC Keck School of Medicine
![Page 2: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/2.jpg)
Peripheral Neurotoxicity
• Mechanism not well understood– Dorsal root ganglia neuronopathy– Axonopathy
• Agents implicated: cisplatin, oxaliplatin, taxanes, 5-FU (rare)
• Various mechanisms proposed: Sodium, Calcium Channels, DNA repair, Homocystein pathway, Cox-2
![Page 3: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/3.jpg)
Oxaliplatin-related peripheral neuropathy
• It has 2 components: – acute neurotoxicity: axonopthay – chronic neurotoxicity: dorsal root ganglia
![Page 4: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/4.jpg)
Mechanism of action of oxaliplatin on Na+ channels (Axonopathy)
+
ATP ATP
EXTRA
Membrane
INTRACa2+
oxalate
TTXHg2+
Dach-Pt
Na+
oxaliplatin
![Page 5: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/5.jpg)
Inward Na+current inhibition by oxaliplatin in
patch clamp technique
Inward Na+currentAction
potential
![Page 6: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/6.jpg)
Sodium channels
• Sodium channels regulate excitability of nerve and muscle cells (Ca dependent)
• At least seven different Na+ channels expressed in sensory neurons
• Oxaliplatin increases nerve refractory time through its effect in Na+ channels
![Page 7: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/7.jpg)
Neurotoxicity as reason for treatment discontinuation
Gamelin et al, Clin Cancer Res 2004
0
5
10
15
20
25
30
35
85 100 130
oxaliplatin dosage (mg/m2)
% o
f d
rop
ou
ts f
or
ne
uro
tox
icit
y
CaMg
no CaMg
![Page 8: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/8.jpg)
Folate-Homocysteine
• Elevated homocysteine neuronal damage– NMDA receptor stimulation Ca influx
reactive oxygen species (ROS) neural apoptosis
– Oxidative damage to endothelial cells
• High Thymidylate synthase low Homocysteine levels
![Page 9: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/9.jpg)
DNA repair
• ↓ ERCC1, XRCC1, XPD function ↑ susceptibility of dorsal root ganglia to platinum-damage peripheral neuropathy
• Oxidative Stress leading to damage of dorsal root ganglia (MnSOD, GST)
![Page 10: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/10.jpg)
Cycle to any Mucositis GSTP1-105 Ile/Ile 58 1 Ile/Val 53 1.30 (0.67-2.53) Val/Val 12 4.03 (1.75-9.30) <0.001 COX 2 G/G 83 1 G/C, C/C 40 1.70 (0.94-3.07) 0.061 TS-5’ G C SNP G/G 60 1 G/C 56 0.60 (0.32-1.15) C/C 7 2.14 (0.81-5.65) 0.020 Cycle to grade 2+ Neurotoxicity
XPD 312 Asp/Asp, Asp/Asn 99 1 Asn/Asn 24 0.43 (0.15-1.21) 0.084 TS-5’ G C SNP G/G, G/C 116 1 C/C 7 2.37 (0.83-6.77) 0.082
USC Data on 130 patients treated with CIFOX prospectively in second line
![Page 11: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/11.jpg)
Lipid peroxidationDNA damage
![Page 12: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/12.jpg)
Off Due to Neurotoxicity P-Value*
GSTP1 T/T (N=120) C/T (N=130) C/C (N=38)
11 (9%)13 (10%)9 (24%)
0.039
ERCC2 Other G/G
30 (12%)5 (13%)
0.779
XRCC1 Other C/C
16 (10%)17 (13%)
0.572
GSTM1 Absent Present
16 (11%)19 (12%)
0.742
*Chi-square P-value
Polymorphisms and Treatment Discontinuation Due to Neurotoxicity
Polymorphisms and Treatment Discontinuation Due to Neurotoxicity
![Page 13: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/13.jpg)
GSTP1
< 600 mg/m2 < 800 mg/m2
Grade 2/3 Grade 2/3
C/C (N=38)20% 27%
C/T (N=130)
T/T (N=120) 11% 18%
Cumulative OxaCumulative Oxaliplatin-Dose platin-Dose and Early Neurotoxicityand Early Neurotoxicity
Cumulative OxaCumulative Oxaliplatin-Dose platin-Dose and Early Neurotoxicityand Early Neurotoxicity
Chi-Square P = 0.030*
*Fisher’s exact P-value = 0.036
P = 0.143
![Page 14: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/14.jpg)
Future: Neurotoxicity
• To understand the mechanisms of the acute and chronic neurotoxicity
• To investigate the role of oxidative stress such as GST-P1 in neurotoxicity and how to prevent it (antioxidants?)
![Page 15: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/15.jpg)
Is TS prognostic, predictive or both?
• Prognostic markers (survival, recurrence)– Not applicable for individual patients – Usually used high/low, presence/absence
• Predictive markers (response, survival, toxicity)– Used for an individual patient– Usually absolute number
Iqbal et al. Iqbal et al. Curr Gastroenterol RepCurr Gastroenterol Rep. 2003;5:399-405.. 2003;5:399-405.
![Page 16: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/16.jpg)
Metabolism and mechanism of action of 5-Fluorouracil (5-FUra)
5-FUra H2FUra
-F--alaFdUrd
dThd phosphorylase
DPD
FdUMP
dUMP
thymidylate synthase
dTMP DNA
![Page 17: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/17.jpg)
DNADNA
mRNAmRNA
ProteinProtein
Type of ChangeNature of Change
Tools Used to Study
Polymorphisms
Allelic deletions (LOH)
Qualitative
Static
PCR
DNA Sequencing
Gene expressionQuantitative
Dynamic
Quantitative RT- PCR
Microarrays
Protein expression Protein function
Quantitative Dynamic
Enzyme assays
IHC
Iqbal et al. Iqbal et al. Curr Gastroenterol RepCurr Gastroenterol Rep. 2003;5:399-405.. 2003;5:399-405.
Assessment of TS Expression
![Page 18: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/18.jpg)
TS and Adjuvant Chemotherapy Evaluation by IHC
Author # of patients
Patient Characteristics
Outcome
Johnston, PG
294 Rectal cancer, Dukes B, CAdj Ctx
TS an independent prognosticator of DFS and OS; adj ctx for high TS equiv to low TS (with and w/o ctx)
Edler, D 862 30% rectal cancer, 70% colon cancer Dukes B & CAdj ctx
TS of no prognostic value; low TS better OS, high TS higher rate of recurrence, Pts with low TS and adj ctx had worst OS
Allegra, C
709 465 Patients220 Dukes B2245 Dukes C
TS prognostic of OS and DFS; high TS assoc with high recurrence
![Page 19: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/19.jpg)
TS Protein Expression• 5 studies have evaluated TS in adjuvant
chemotherapy for CRC• 4/5 studies consistently show TS as an independent
prognosticator of DFS and OS• Conclusions
– Patients with high TS who received chemotherapy did as well as patients with low TS with or without chmotx.
– The advantage to receiving adjuvant ctx for patients with low TS was less than for patient with high TS
– Patients with low TS have a better outcome– The benefit of adjuvant chemotherapy demonstrated
in patients with high TS
![Page 20: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/20.jpg)
Thymidylate Synthase Expression and Prognosis in
Colorectal Cancer: A Systematic Review and Meta-Analysis:
13 studies with 887 patients MCRC7 studies 2610 patients LCRC
Popat et al J Clin Onc February 2004, 529-536
![Page 21: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/21.jpg)
![Page 22: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/22.jpg)
Popat et al J Clin Onc February 2004, 529-536
![Page 23: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/23.jpg)
TS IHC versus RT-PCR
The value of TS expression in predicting poor OS seems strongest in studies using RTPCR and not IHC.
Popat et al J Clin Onc February 2004, 529-536
![Page 24: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/24.jpg)
TS Repeat Polymorphisms in 221 patients with Dukes C
Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30-1.25, P = 0.18)
Patients with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52-0.82, P = 0.005).
![Page 25: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/25.jpg)
High TS
Low TS
![Page 26: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/26.jpg)
5-FU
NO 5-FU
![Page 27: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/27.jpg)
It all makes sense again?
• High TS associated with poor outcome• High TS does not benefit from 5-FU adjuvant
chemotherapy • Consistent with data from meta analysis and
data from TS polymorphisms and gene expression data.
• Controversial data due to difference in technologies, cut off levels, patients populations
![Page 28: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/28.jpg)
Overall Survival by TS Intensity (Stage II)S
UR
VIV
AL
(Pro
ba
bil
ity
Ra
te)
Years since surgery
P=0.47
High TS
Low TS
![Page 29: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/29.jpg)
SU
RV
IVA
L (
Pro
ba
bil
ity
Ra
te)
YEARS SINCE SURGERY
Overall Survival by Treatment within high TS Staining Tumours (Stage IIIC)
5-FU
No 5-FUP=0.12
![Page 30: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/30.jpg)
The is a partial list of some common external causes of free radicals:
• Toxins – carbon tetrachloride – paraquat – benzo(a)pyrene – aniline dyes – Toluene
• Drugs – Adriamycin,bleomycin,nitrofurantoin – chlorpromazine
• Air pollution: Primary sources – carbon monoxide, nitric oxide – passive tobacco smoke
• Ingested substances – alcohol – smoked and barbecued food – peroxidized fats in meat and cheese – deep-fried foods – trans fats in processed foods
![Page 31: GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e855503460f94b88669/html5/thumbnails/31.jpg)