Benjamin M. Ellingson, Ph.D.

Transcription

1 Simultaneous ph- and Oxygen-Weighted Metabolic Imaging of Brain Tumors using Multi-Echo Amine Chemical Exchange Saturation Transfer (CEST) Echo Planar Imaging Benjamin M. Ellingson, Ph.D. Associate Professor of Radiology, Psychiatry, Bioengineering and Biomedical Physics UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers Depts. of Radiological Sciences and Psychiatry David Geffen School of Medicine at UCLA March 15, 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 WHO Classification of Cancer WHO = World Health Organization Grade: How abnormal cells look under the microscope How quickly they are likely to grow or spread Also called differentiation I-IV from least to most malignant/differentiated I: Well differentiated (low Grade) II: Moderately differentiated (Intermediate Grade) III: Poorly differentiated (High Grade / Malignant) IV: Undifferentiated (High Grade / Malignant)

4 WHO Classification of Cancer Stage: Extent or severity of the cancer Tumor size, number of tumors, distance of lesion from primary cancer site (mets?), lymph node involvement

5 Brain Cells Neurons Direct Communication Oligodendrocytes Myelination Increases signal transduction Astrocytes Support Cells Communication? Nourishment (BBB)

6 Brain Cancer - Gliomas Brain Cancer Does Not Metastasize (No Staging, Only Grading) Neuroblastomas & Epidemoma Oligodendrogliomas Oligodendroglioma (WHO II) Anaplastic Oligodendroglioma (WHO III) Astrocytomas Astrocytoma (WHO II) Anaplastic Astrocytoma (WHO III) Mixed Gliomas Astrocytoma and Oligodendroglioma Glioblastoma (GBM) - WHO IV

7 Glioma Biology Glioblastoma (WHO IV)

8 Brain Cancer Incidence

9 Glioma Incidence Central Brain Tumor Registry United States, 2012

10 Glioma Incidence Central Brain Tumor Registry United States, 2012

11 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

12 Glioma Biology Brat & Mapstone, Ann Int Med, 2003

13 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

14 Overview of Basic MRI Sequences for GBM Evaluation T2-Weighted MRI T2-Weighted FLAIR MRI Diffusion-Weighted MRI (DWI) Pre-Contrast T1-Weighted MRI Post-Contrast T1-Weighted MRI Pre-Contrast T1w Post-Contrast T1w NOTE: ALL MRI TECHNIQUES ARE SURROGATES OF TUMOR BIOLOGY - All techniques measure some aspect of tumor biology, not tumor cells directly - All MRI techniques measure impact on extracellular water protons ** Limited Physiologic Information About the Tumor

15 Tumor Angiogenesis Aggressive cancers are characterized by angiogenesis 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

16 Contrast Enhancement as a Surrogate of Tumor These new vessels are leaky and inefficient (Yuan, Cancer Res, 1994; Hobbs, PNAS, 1998; Monsky, Cancer Res, 1999) Contrast agents that highlight BBB permeability 1941 First case using X-ray and Diodrast (sodium iodide) to highlight vasculature published in Radiology 1946 Study with 130 patients with cerebral masses published T1 Pre T1 Post

17 Contrast Enhancement as a Surrogate of Tumor Confirmed (surgically) to contain most aggressive tumor (Butler, 1978; Lilja, 1981; Berger, 1983; Kelly, 1987; Earnest, 1988; Dean, 1990; Barajas, 2010; Kubben, 2012 ) Cancer Info Database: 28 June 2012

18 Warburg Effect (Aerobic Glycolysis)

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

20 Hypoxia, Acidity, and Malignant Transformation Perfusion

21 Hypoxia, Acidity, and Malignant Transformation

22 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)

23 ph-weighted MRI Using Amine CEST 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

24 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 or -OH H 2 O Pool 1 H on -NH 2 or -OH H 2 O Pool Sherry & Woods, Annual Rev Biomed Eng, 2008

25 Chemical Exchange Saturation Transfer (CEST) Imaging Chemical exchange between amine protons on amine acids are a base-catalyzed process à decreasing exchange rate (k ex ) with decreasing ph Allows for separation of metabolites and a larger exchange effect at the resonant frequency of the amine proton(s)

26 Bloch-McConnell Equations

27 Bloch-McConnell Equations

28 Amine CEST EPI Harris et al., NMR Biomed 2016; 29(11):

29 Estimation of k b Initial Estimation of k b à Simulation fit to phantom data using Gaussian saturation pulses Verification of k b Estimation à Simulation using k b to phantom using Sinc3 saturation pulse (different B 1 conditions) Harris et al., NMR Biomed 2016; 29(11):

30 Simulated vs. Measured z-spectrum Z-Spectrum for Gaussian, Sinc3, and Rect Saturation Pulses à MTR asym for Gaussian, Sinc3, and Rect Saturation Pulses à Correlation between simulated and measured MTR à 50mM ph = 6.0 Harris et al., NMR Biomed 2016; 29(11):

31 Simulated z-spectrum for Brain Tumor Tissues Z-Spectrum for Normal White Matter, Glioma, and CSF à MTR asym for Normal White Matter, Glioma, and CSF à Assuming T1 and T2 for NAWM, Glioma and CSF Harris et al., NMR Biomed 2016; 29(11):

32 Effects of Saturation Parameters Pulse Train à No effect on MTR asym Effects of TR à Shorter TR = higher MTR asym Pulse Train Length + Minimum TR à 3 pulses with shortest TR Harris et al., NMR Biomed 2016; 29(11):

33 Effects of T1 and T2 Bulk water T1 and T2 à Amine proton T1 and T2 à Harris et al., NMR Biomed 2016; 29(11):

34 Effects of Glutamine Concentration 3ppm vs. ph for different concentrations à 3ppm vs. concentration for different phà Harris et al., NMR Biomed 2016; 29(11):

35 18 F-FDOPA PET FLAIR FDOPA PET FLAIR FDOPA PET

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

37 Correlation with 18 F-FDOPA PET

38 Correlation with 18 F-FDOPA PET

39 FDOPA Uptake 4 6 MTRasym (%) 3.0ppm(%) F-FDOPA 1.2 Uptake Slope Describing Linear Relationship Betwen 3.0ppm and 18F-FDOPA PET Uptake in FLAIR Regions 4 2 Median = P < Compared w/ Zero -2-4 Amine CEST EPI Contrast Observed in Tumor Regions of Low vs. High 18F-FDOPA Uptake FDOPA Uptake ppm (%) MTRasym (%) 4 Slope 3.0ppm (%)/ Normalized 18F-FDOPA PET Uptake (a.u.)] Correlation with 18F-FDOPA PET P < Low 18 F-FDOPA High 18 F-FDOPA

40 Correlation with 18 F-FDOPA PET

41 Amine CEST Contrast by WHO Grade & Recurrence Average MTR asym at 3.0ppm in T2 Hyperintense Regions WHO II WHO III * * WHO IV Average MTR asym at 3.0ppm WHO II & III ** WHO IV Average MTR asym at 3.0ppm in T2 Hyperintense Regions WHO II - New WHO III - New WHO IV - New WHO II - Recurrent WHO III - Recurrent WHO IV - Recurrent ** In T2 hyperintense regions

42 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):

43 Biopsy of Suspected Low Grade Glioma Harris et al. Neuro Oncol 2015; 17(11):

44 Biopsy of Recurrent Glioblastoma Ellingson et al. Neuro Oncol 2015; 17(11):

45 Results Image-Guided Biopsy ph (MTR asym ) Number of Strongly Positive Pixels within Tumor Area 30,000 20,000 10,000 Area of Posiitve Tumor [um 2 ] Proliferation (Ki-67) Ki-67 Stain Density vs. Amine CEST MTR asym R 2 = P = MTR asym at 3.0ppm (%) Ki-67 Positive Tumor Area vs. Amine CEST MTR asym R 2 = P = MTR asym at 3.0ppm (%) Cancer Stem Cells (CD133 + ) Number of Strongly Positive Pixels within Tumor Area Area of Posiitve Tumor [um 2 ] CD133(+) Stain Density vs. Amine CEST MTR asym R 2 = P = MTR asym at 3.0ppm (%) CD133(+) Tumor Area vs. Amine CEST MTR asym R 2 = P = MTRasym (%) Number of Strongly Positive Pixels within Tumor Area Area of Posiitve Tumor [um 2 ] Hypoxia (HIF-1alpha) HIF-1α Positive Stain Density vs. Amine CEST MTR asym R 2 = P = MTR asym at 3.0ppm (%) HIF-1α Positive Tumor Area vs. Amine CEST MTR asym R 2 = P = MTR asym at 3.0ppm (%)

46 Predictive of Radiotherapy Response Acidic Lesion Prior to Radiation Therapy N = 20 Ellingson et al. Neuro Oncol 2015; 17(11):

47 Response to Radiotherapy Change in Acidity During Radiochemotherapy N = 20 Ellingson et al. Neuro Oncol 2015; 17(11):

48 Anti-Angiogenic Agents to Modulate ph Farnsworth et al., Oncogene 2014; 33:

49 Anti-Angiogenic Agents to Modulate ph T1+C FLAIR ph Pre-Bev CEST 3ppm +5% -5% Post-Bev

50 Detection of Early Progression in Bevacizumab via ph

51 Detection of Early Progression in Bevacizumab via ph 4/20/15 (Pre-Bev) 6/1/15 (Post- Bev) 6/22/15 7/13/15 FLAIR T1+C T1 Subtraction CEST 3ppm +5% } Low ph -5% ph

52 Simultaneous ph & roef using Multi-Echo Amine CEST BOLD Effect PD-Weighted T2*-Weighted T2 -Weighted T2-Weighted Toth, J Neurooncol, 2013

53 Simultaneous ph & roef using Multi-Echo Amine CEST

54 Simultaneous ph & roef using Multi-Echo Amine CEST

55 Simultaneous ph & roef using Multi-Echo Amine CEST

56 Aerobic Glycolytic Index

57 Results AGI in Tumor vs. Normal Tissue MTR 3.0ppm(%) MR Estimate of Acidity P = rcmro MR Estimate of Relative Cerebral Metabolic Rate of Oxygen (rcmro 2 ) P < Tumor NAWM 0 Tumor NAWM Acidity (MTR 3.0ppm) and Relative Rate of Oxygen Metabolism (rcmro 2 ) MTR 3.0ppm(%) rcmro 2 Tumor NAWM MR Glycolytic Index (MTR 3ppm / rcmro 2 ) MR Glycolytic Index P < Tumor NAWM

58 Results AGI in Low and High Grade Gliomas

59 Results AGI in Low and High Grade Gliomas

60 Results Image-Guided Biopsy Aerobic Glycolytic Index (AGI) Proliferation (Ki-67) Cancer Stem Cells (CD133 + ) Hypoxia (HIF-1alpha) Number of Strongly Positive Pixels within Tumor Area 30,000 20,000 10,000 Area of Posiitve Tumor [um 2 ] Ki-67 Stain Density vs. Aerobic Glycolytic Index (AGI) R 2 = P < Aerobic Glycolytic Index (AGI) Ki-67 Positive Tumor Area vs. Aerobic Glycolytic Index (AGI) R 2 = P = Aerobic Glycolytic Index (AGI) Number of Strongly Positive Pixels within Tumor Area Area of Posiitve Tumor [um 2 ] CD133(+) Stain Density vs. Aerobic Glycolytic Index (AGI) R 2 = P = Aerobic Glycolytic Index (AGI) CD133(+) Tumor Area vs. Amine CEST MTR asym R 2 = P = MTRasym (%) Number of Strongly Positive Pixels within Tumor Area Area of Posiitve Tumor [um 2 ] HIF-1α Positive Stain Density vs. Aerobic Glycolytic Index (AGI) R 2 = P = Aerobic Glycolytic Index (AGI) HIF-1α Positive Tumor Area vs. Aerobic Glycolytic Index R 2 = P = Aerobic Glycolytic Index (AGI)

61 Results Specific to Tumor (not Inflammatory Cells) T1+C FLAIR ph AGI Tumor Cells Aerobic Glycolytic Index (AGI) vs. Tumor Cellularity R 2 = P = Aerobic Glycolytic Index (AGI) Aerobic Glycolytic Index (AGI) vs. CD45+ (Immune) Cellularity R 2 = P = CD45+ Cells Aerobic Glycolytic Index (AGI)

62 Results Treatment with Immunotherapy T1+C ph Imaging Aerobic Glycolytic Index (AGI) Pre-Treatment Post-Treatment PD-L1 mab

63 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