About UCSF CIRP

Project Aims 

While the quantitative HP ¹³C MRI acquisition and data analyses tools developed in this U24 grant are focused on assessing chemotherapy of advanced prostate cancer, they will generally be applicable to other treatments and diseases, benefitting the community at large.

This co-clinical project is based on the goal of assessing therapeutic response of small cell neuroendocrine prostate cancer (SCNC) using quantitative hyperpolarized (HP) ¹³C-pyruvate magnetic resonance imaging (MRI). The murine imaging study will be conducted in parallel to a clinical trial supported by NCI R01 CA215694, aiming to assess response of SCNC to carboplatin in men with metastatic prostate cancer (PCa), led by Drs. John Kurhanewicz and Rahul Aggarwal. Although next-generation androgen receptor signaling inhibitors have significantly improved outcomes in men with metastatic castration-resistant prostate cancer (mCRPC), these agents frequently induce SCNC, a lethal subtype of mCRPC, with median survival of <9 months. While platinum based chemotherapy is the standard of care for treatment-induced SCNC (t-SCNC), newer therapies targeting the underlying molecular events of transdifferentiation and progression of mCRPC to t-SCNC are impeded by lack of predictive biomarkers. The selection of the most appropriate treatment is hindered by the fact that neither blood tests (such as serum neuroendocrine markers) or current imaging modalities such as multiparametric ¹H MRI or positron emission tomography (PET) (e.g., somatostatin receptor-based or ¹⁸F-fluorodeoxyglucose) can reliably identify therapeutic efficacy in these metastatic tumors which are also often not amenable to biopsy. HP ¹³C-pyruvate MRI is a new, safe, non-radioactive, quantitative stable-isotope imaging approach that has the potential to enable paradigm-shifting, real-time monitoring of metabolic response to treatment in vivo. Preliminary data suggest that a rapid (~5 minute) HP MRI quantitative measurement of the rate of conversion of pyruvate to lactate, k_PL, can reflect changes in metabolic reprogramming that occur upon early response to conventional treatment (carboplatin) of t-SCNC. This proposal is timely since standardized data acquisition and data analysis approaches as well as quantitative imaging metrics for HP ¹³C MRI need to be established for ongoing clinical trials of cancer detection and therapeutic response. The study design of this project fits the goals of the NCI Oncology Co-Clinical Imaging Research Resources Program (CIRP) and aims to use appropriate patient-derived xenograft (PDX) models that reflect the genetic, metabolic and micro-environmental heterogeneity of SCNC. Quantitative HP ¹³C MRI acquisition and data analysis methods will be optimized and applied to study the response of these PDX models of SCNC to chemotherapy, paralleling the funded study in patients. This co-clinical study is aimed at developing optimal HP ¹³C MRI protocols in mice that mimic parallel clinical protocols, and modeling the dynamic HP ¹³C MRI data to determine changes in k_PL, in order to predict therapeutic response/resistance of realistic PDX models of SCNC bone and liver metastases. The deliverables of this research will include an online resource of quantitative HP ¹³C MRI imaging protocols, data analyses and modeling tools as well as correlative biology data for wider dissemination and validation by the scientific community. 

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UCSF CIRP Team

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Facilities

The findings and tools developed within this CIRP are supported directly by the Surbeck Laboratory for Advanced Imaging and the Preclinical MR Imaging & Spectroscopy Lab. The Surbeck lab (housing the clinical GE 3T and 7T MRI along with two GE SPINlab DNP polarizers) and the preclinical MRI facility at the Mission Bay campus are 600 yards apart and are part of the hyperpolarized magnetic resonance technology resource center (HMTRC, an NIH-funded P41 EB013598 center). The GE 3T clinical scanner is equipped with a multitude of ¹H and ¹³C coils that have been tested and validated for HP ¹³C MRI trials at UCSF. The preclinical MRI facility is also equipped with a Bruker cryogen-free 3T system along with two Hypersense (Oxford Instruments) polarizers, providing an ideal set-up for a co-clinical imaging study. We are also equipped with a state-of-the-art radio-frequency (RF) coil laboratory. Additionally, in the same building we have a high resolution 2D printer and machine shop critical to the development and testing of quantitative imaging phantoms.

Surbeck Laboratory for Advanced Imaging

The California Institute for Quantitative Biomedical Research (QB3) houses the Surbeck Laboratory for Advanced Imaging which includes a 7T GE 950 whole body scanner, a new 750 3T research scanner, microscopy, computational and other facilities. The Surbeck Laboratory also has facilities for managing human subjects including offices, a changing room, preparation room, and restroom.

Clinical Equipment:

3.35T GE SPINlab Polarizer

• Polarized sample temperature: ≥ 0.8K
• Polarization transfer source: 94GHz (up to 100mW)
• Polarization sample volume: 60ul to 1.5ml
• Polarization sample quantity: up to 4 sample vials simultaneous
• Daily sample quantity: up to 12 samples/regeneration cycle
• Polarization agent: Trityl radical, typical
• Dissolution volume: 15ml to 50ml, typically water based
• Helium consumption/dissolution: N.A.
• Sample polarization time: typically 15 mins to 2.5 hours
• Sample dissolution time: > 10 secs
• Sample ¹³C S/N enhancement: up to 10,000 fold 

 

 

3T GE 750 Whole Body MR Scanner

• Discovery MR750 3.0T with 60cm bore
• 18 superconducting High Order Shims, including X, Y, Z, XY, XZ, YZ Z2, X2-Y2
• Optical RF technology with 165dB dynamic range. Scalability up to 136 coil connections
• Technology enables multi-channel broadband receive for multi-nuclear studies
• Processing power to reconstruct 32-ch of high-resolution 3D volumetric data. Vector Reconstruction Engine (VRE)
• Extreme Gradient Driver (XGD)
• Supports 50mT/m peak amplitude at a slew-rate of 200mT/m/s on all 3-axis
• RF amplifier: for body coil, water cooled, solid-state 35 kW RF amplifier. Supports a 100W continuous-wave output mode for proton-decoupling & spin-labeling research.
• Multichannel spectroscopy with 8-kW broadband amplifier and 8 ch receiver converter.

QTAR Coil

 

Preclinical MR Imaging & Spectroscopy Lab

The Preclinical MR Imaging and Spectroscopy Laboratory is located in Genentech hall, the building adjacent to the Quantitative Bioscience Institute (QBI), on the UCSF Mission Bay Campus. This state-of-the-art Core facility offers MRI and MRS capabilities which are uniquely integrated with DNP polarizers for conducting hyperpolarized ¹³C MR experiments. 

Preclinical Equipment:

HyperSense DNP Polarizer

• Field strength: 3.35T
• Microwave source: Integrated 94GHz with 0.5Hz sweep, (user selectable) up to 100mW
• Sample volume: 10-200ul
• Dissolution volume: 3.5-5ml
• Dissolution solvent: water
• Temperature: (selectable) 1.3°K
• Nuclei: ¹³C, ¹⁵N, ³¹P, ²⁹Si and other spin ½ nuclei
• Polarization duration: 15min – 6hrs
• Polarization agent: 2-5mg ‘Trityl radical’ per sample
• Helium consumption: 2L per dissolution

 

 

Polarize SpinAligner

• The SpinAligner based on a 6.7 T superconducting dry magnet that is cooled by a pulse-tube coldhead and compressor

• Has a closed-cycle, continous helium circulation system cools the sample to less than 1.4 K. Does not require liquid helium or nitrogen

• DNP by irradiation with 188 GHz microwaves

• Broadband NMR spectrometer detects all nuclei with high sensitivity

• Dissolution system enables HP samples of a wide range and sizes. Carbon and Phosphorous TR switches

 

 

Bruker BioSpec® 3T Cryogen Free Pre-clinical MRI

• A low-cost, cryogen-free superconducting magnet (18 cm bore), small footprint, 3 Tesla multinuclear MRI system optimize for murine and rat imaging
• Excellent field homogeneity (0.1ppm, over a 5 cm FOV) with high order room temperature shims (x,y,z, z2, xz, yz, x2-y2, 2xy, z3) and strong gradients (960 mT/m, 3,550 T/m/s)
• System is equipped with ¹H and ¹H/¹³C body & head coils for rats/mice
• Flexible MRI operating environment allows for both the development of advanced MRI imaging protocols and provide a more push button operation mode for less experienced users

Bruker ¹H linear/¹³C linear mouse body (40 mm)