Clinical ph, Hypoxia, and Vascular Architecture MR Imaging in Human Brain Tumors

Transcription

1 Clinical ph, Hypoxia, and Vascular Architecture MR Imaging in Human Brain Tumors Benjamin M. Ellingson, Ph.D. Director, UCLA Brain Tumor Imaging Laboratory Co-Director, UCLA Center for Computer Vision and Imaging Biomarkers Associate Professor of Radiology and Psychiatry Depts. of Radiological Sciences, Psychiatry, Bioengineering, and Biomedical Physics David Geffen School of Medicine at UCLA Brisbane 2018

2 Disclosures MedQIA, LLC Paid Consultant, Ad Board Hoffman La-Roche/Genentech Paid Consultant, Research Grant, Ad Board Agios Pharmaceuticals Paid Consultant, Ad Board Insys Paid Consultant, Ad Board OmniOx Paid Consultant, Ad Board Nativis Paid Consultant, Ad Board Bristol Myers Squibb Paid Consultant Siemens Paid Consultant, Research Grant Exelixis Paid Consultant Janssen Pharmaceuticals Research Grant National Brain Tumor Society Research Grant American Cancer Society Research Grant Medicenna Paid Consultant NIH/NCI CISC Paid Consultant Imaging Endpoints Paid Consultant Novogen Paid Consultant, Ad Board

3 Brain Cancer Incidence & Mortality Rates Adults 40+ Incidence Mortality From: CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in Neuro Oncol. 2017;19(suppl_5):v1-v88. doi: /neuonc/nox158

4 Malignant CNS Tumor Incidence Breast: Prostate: Malignant Gliomas: ~7-8 From: CBTRUS Neuro Oncol. 2017;19(suppl_5):v1-v88. doi: /neuonc/nox158

5 Glioblastoma Incidence All Primary CNS Tumors Malignant Primary CNS Tumors From: CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in Neuro Oncol. 2017;19(suppl_5):v1-v88. doi: /neuonc/nox158

6 Glioblastoma Incidence All Gliomas From: CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in Neuro Oncol. 2017;19(suppl_5):v1-v88. doi: /neuonc/nox158

7 Poor Prognosis in Glioblastoma AVAglio: Phase III Comparison of Chemoradiation with or without Bevacizumab Percent Survival Bevacizumab (N = 404) Placebo (N = 394) Log-rank, P = HR = Stupp, N Engl J Med, Overall Survival [Days] Ellingson, ASCO, 2016 Median Overall Survival Radiotherapy = 12 months Radiotherapy + TMZ = 14 months Radiotherapy + Bev Upfront = 18 months Radiotherapy + Placebo Recurrence] = 18 months

8 Glioblastoma Biology Glioblastoma (WHO IV)

9 Tumor Angiogenesis Key to Malignancy Essential for progression from low- to high-grade & clear correlation between degree of neovascularization and malignancy (Russell, Surg Neurol, 2009; Lean, Cancer, 1996; Wesseling, Hum Pathol, 1998) After infiltration/migration, growth factors (e.g. VEGF) cause co-option of local vasculature (Loges, Cancer Cell, 2009) Once tumor bed has reached a critical size (1-2mm diameter) angiogenesis is initiated (Jain, Nat Rev Neurosci, 2007; Plate, 1995; Rampling, 1994) Angiogenesis Foundation

10 The Tumor Milieu - Perfusion, Oxygen Metabolism, and ph As tumors become larger, regions away from vasculature become hypoxic and more acidic Treden, 1997 Jain et al., Nat Rev Neurosci 2007

11 Warburg Effect (Aerobic Glycolysis)

12 The Tumor Milieu - Perfusion, Oxygen Metabolism, and ph Decreased extracellular ph also occurs due to: Increased carboxylic acid and CO 2 Active pumping of [ + H] out of cancer cells to maintain intracellular alkalinity Inefficient vasculature limits elimination of excess protons Limited buffer ability of tumor interstitial fluid

13 The Tumor Milieu - Perfusion, Oxygen Metabolism, and ph Consequences of Increased Tumor Acidity: Increased mutagenesis Increased Invasion Rates Increased Angiogenesis (independent of hypoxia via HIF-2a) Increased VEGF expression Promotion of Cancer Stem Cells Conversion from Epithelial Mesenchymal Radiation Resistance Chemotherapy Resistance Immunosuppression

14 Use of Imaging for Measuring Therapeutic Response Serial biopsies are not possible or safe (few pathology-confirmed responses) MRI (and PET) imaging are routinely used for clinical monitoring and response assessment MRI has exquisite soft tissue contrast, no ionizing radiation, and a variety of flavors for evaluating anatomy and physiology

15 Imaging the Tumor Milieu - Perfusion, R 2 and Amine CEST Acidity (Amine CEST EPI) Aggressive Tumor Angiogenesis (Perfusion) Hypoxia (R 2 & roef)

16 ph-weighted MRI Using Amine CEST EPI

17 Chemical Exchange Saturation Transfer (CEST) Imaging CEST imaging uses a soft RF pulse to saturate longitudinal magnetization of protons undergoing chemical exchange with the water pool Results in attenuation of the MR signal when metabolite is present and chemical exchange is slow relative to the off-resonant frequency 1 H on NH 2 H 2 O Pool 1 H on NH 2 Sherry & Woods, Annual Rev Biomed Eng, 2008

18 ph-weighted MRI Using Amine CEST EPI Mechanism: Targeted off-resonance saturation of fast exchanging amine protons (3.0ppm) on amino acids (glutamine) results in ph-dependent attenuation of the water proton MR signal

19 Glutamine as a Primary Fuel in Tumor Cells Glutamine is a major fuel source for malignant tumors (Souba, Annals of Surgery, 1993; Kovacevic, Cancer Res, 1972; Medina, Mol Cell Biochem, 1992) Circulating concentrations mm and as high as 20mM Tumor cells act like a glutamine trap (Kovacevic, Cancer Res, 1972) Demand is so high transport systems are amplified (Medina, Mol Cell Biochem, 1992) Kaelin Jr & Thompson, Nature 456: (2010)

20 Measured Amine CEST - Amino Acid Phantoms Concentration = 100 mm Harris et al. Neuro Oncol 2015; 17(11):

21 Clinical ph-weighted MRI Using Amine CEST EPI CEST EPI Significantly faster than traditional CEST GRE/TSE techniques Whole brain coverage in ~7 min Amine CEST EPI Short RF saturation times relative to APT (300ms vs. 3-5sec) MTR asym at 3ppm (Amine) sensitive to ph, amino acid concentration, and T2

22 C57BL/6 Murine Model with GL261 Tumor Cells MTR asym at 3.0 ppm (%) Stereotactic ph Measurements and Corresponding CEST Contrast ph Harris et al. Neuro Oncol 2015; 17(11):

23 Correlation with 18 F-FDOPA PET & MR Spectroscopy

24 Image-Guided Biopsy Proliferation (Ki-67) Hypoxia (HIF-1alpha) Number of Strongly Positive Pixels within Tumor Area 30,000 20,000 10,000 Ki-67 Stain Density vs. Amine CEST MTR asym R 2 = P = MTR asym at 3.0ppm (%) Number of Strongly Positive Pixels within Tumor Area HIF-1 Positive Stain Density vs. Amine CEST MTR asym R 2 = P = MTR asym at 3.0ppm (%)

25 ph-weighted MRI Using Amine CEST EPI Standard of Care at UCLA for all Brain Tumor Patients (7 min acquisition) Glioblastoma WHO I Meningioma Vestibular Schwannoma Low Grade Glioma WHO II Meningioma 3ppm -5% 0 +5%

26 Response to Chemoradiation Acidic ph) } (Low +5% -5% CEST ppm N=20

27 Response to Bevacizumab Vascular Normalization More Efficient Perfusion Decreased Hypoxia + Acidity Farnsworth et al., Oncogene 2014; 33:

28 Response to Bevacizumab Pre-Bevacizumab Post-Bevacizumab T1+C ph T1+C ph Pre-Bevacizumab Post-Bevacizumab T1+C ph T1+C ph Change in MTR asym at 3ppm in T2 Hyperintense Lesion Change in Amine CEST Contrast After Bevacizumab vs. PFS R 2 = P = Progression Free Survival (PFS) [Days]

29 Response to Bevacizumab Early Treatment Failure 43 Days Change in MTR asym at 3ppm in T2 Hyperintense Lesion Change in Amine CEST Contrast After Bevacizumab vs. PFS R 2 = P = Progression Free Survival (PFS) [Days]

30 Response to Immunotherapy Post-Contrast T1-Weighted Pre-Treatment Post-PDL1 mab ph-weighted Amine CEST Pre-Treatment Post-PDL1 mab 3ppm -5% 0 +5% +10% } -10% Acidic (Low ph) DC Vax Anti-PD1 3ppm No Treatment Anti-PD1 + DC Vax

31 Hypoxia-Weighted MRI Using Multi-Echo Spin-and-Gradient-Echo (SAGE) EPI

32 What about Oxygen Consumption? Blood Oxygenation Level Dependent (BOLD) Effect

33 R 2 Measurement with SAGE-EPI PD-Weighted T2*-Weighted T2 -Weighted T2-Weighted roef R 2 ' Yablonskiy and Haacke, MRM, 1994 He, Magn Reson Med, 2008 Domsch, Z Med Phys, 2014 Toth, J Neurooncol, 2013 Fujita Neuroimage, 2003 Zhang, J Biomed Biotechnol, 2011 Jensen-Kondering, Int J Stroke, 2017

34 R 2 Measurement in Brain Tumors WHO III IDH Mutant Anaplastic Astrocytoma T1+C Hypoxia

35 Simultaneous ph & O 2 using Multi-Echo Amine CEST EPI ph-weighted Oxygen-Weighted PD-Weighted T2*-Weighted T2 -Weighted T2-Weighted

36 Advantages B0 Correction & Higher SNR In-line B0 correction using first 2 gradient echoes Higher SNR by (Weighted) Averaging of Multiple Echoes

37 Simultaneous ph & O 2 using Multi-Echo Amine CEST EPI Elevated acidity in all WHO grades Uncharacteristically low hypoxia (OEF) in non-enhancing tumor Necrotic regions and enhancing tumor have both high acidity and high hypoxia A) WHO II, IDH MUT, Astrocytoma B) WHO III, IDH MUT, Anaplastic Astro C) WHO IV, IDH WT, GBM (recurrent) D) WHO IV, IDH WT, GBM (new)

38 R 2 (Hypoxia) Non-enhancing tumor has significantly less oxygen utilization (Warburg) Exception is GBM (WHO IV), which has a significantly higher R 2 Contrast enhancing tumor has significantly high levels of R 2 (hypoxia)

39 MTR asym at 3ppm (Acidity) Non-enhancing tumor has significantly higher acidity than NAWM (Warburg) GBM has significantly higher acidity compared with WHO II gliomas Acidity is highest for necrosis > enhancing tumor > non-enhancing tumor

40 Combined Acidity and Hypoxia Combining MTR asym at 3ppm and R 2 further delineates tissues

41 Aerobic Glycolytic Index

42 AGI in Low and High Grade Gliomas

43 Quantitative ph (In Progress )

44 Vascular Imaging Using DSC Perfusion + SAGE-EPI

45 Dynamic Susceptibility Contrast (DSC) Perfusion MRI Acquire dynamic T2*-weighted images during injection of contrast Convert signal to R2*, then integrate for total blood volume per voxel t rcbv R 2 * t 0 dt rcbv

46 DSC-MRI with SAGE EPI Echo 1 Echo 2 Echo 3 Echo 4

47 Vessel Size Imaging (VSI) t rcbv R * 2 t dt 0 VSI MRI m rcbv ADC R * 2 3 R 2 2

48 Vessel Size Imaging (VSI) R* 2 VSI MRI m rcbv ADC 3 R2 2

49 Vessel Size Imaging (VSI) Histology Vessel Density Vessel Caliber Magnetic Resonance Imaging (MRI) rcbv VSI Vessel Density N vessels mm 2 VSI Histology m i i 4 nr i r 3 i 2 nr i r i 3 2 rcbv is correlated with Vessel Density VSI is correlated with Vessel Caliber

50 Vascular Architecture Using Dynamic VSI Patterns

51 Vessel Architectural Imaging (VAI) Tumor Tumor 50 R 2 * R 2 35 R 2 /R 2 * [ms] R 2 * [ms] Time (s) R 2 [ms] Normal White Matter Normal White Matter 50 R 2 * 50 R 2 /R 2 * [ms] R 2 R 2 * [ms] Time (s) R 2 [ms]

52 Dynamic CEST-SAGE-EPI ph, O 2, Perfusion CEST Cycling Through Z-Spectra Contrast Injection Pre-Injection Baseline Multi-Echo DSC Acquisition ph-weighting B 0 Correction O 2 -Weighting Multi-Echo DSC Perfusion for VSI, VAI, rcbv, etc.

53 Summary CEST-SAGE-EPI provides simultaneous ph- and oxygen-sensitive image contrasts for brain tumors in clinically realizable scan times (~7 min) Used for all patients at UCLA as part of standard of care for brain tumor patients Non-enhancing tumor appears to be well oxygenated, while enhancing tumor is highly hypoxic All tumor regions across all grades are highly acidic Dynamic SAGE-EPI can be used to estimate Vessel Architecture rcbv correlates with vascular density VSI correlates with vessel caliber Sequence is available (from UCLA) for most Siemens 3T systems 3 single-institution trials and 2+ multicenter clinical trials at 10+ centers throughout the world

54 Benjamin M. Ellingson, Ph.D., M.S. Associate Professor of Radiology, Biomedical Physics, Psychiatry and Bioengineering Director, UCLA Brain Tumor Imaging Lab (BTIL) UCLA Neuro-Oncology Program Depts. of Radiological Sciences and Psychiatry David Geffen School of Medicine University of California - Los Angeles bellingson@mednet.ucla.edu