With the establishment of Canary Center at Stanford, we’ve realized our goal in building the first integrated facility that can attract and develop the best minds in the world to tackle the problem of early cancer detection.

Don Listwin

Founder and Co-Chair, Canary Foundation

Imaging

Imaging plays a critical role in early cancer detection. It allows us to see the unseen and visualize tumor parameters such as imaging depth, spatial resolution, contrast and more. Our imaging projects are led by a world-renowned expert in molecular imaging—Dr. Sanjiv Sam Gambhir. He is Chair of the Radiology department and Virginia and D.K. Ludwig Professor of Cancer Research at the Stanford School of Medicine. Along with teams of scientists—each with their own labs—Sam is guiding the future of early cancer detection imaging.

First-in-Human Clinical Trial on Ultrasound Molecular Imaging in Patients with Prostate Cancer

We have initiated a first-in-man clinical trial in patients with prostate cancer at Stanford University exploring feasibility and efficacy of volumetric VEGFR2-targeted ultrasound imaging with BR55 for prostate cancer detection prior to radical prostatectomy. (ClinicalTrials.gov identifier: NCT02142608), using histology as reference standard (1).

Furthermore, at the Catholic University of Rome, we have been collaborating to assess feasibility of ultrasound imaging with BR55 in patients with suspected ovarian and breast cancer (European Union ClinicalTrials identifier: 2012-000699-40). These first in-human proof-of-concept feasibility studies will stimulate further developments and refinement of this promising imaging technique and explore and validate novel clinical niche applications where the strength of ultrasound combined with molecular imaging capabilities can be leveraged.

(1) Abou-Elkacem L, Bachawal SV, Willmann JK. Ultrasound molecular imaging: Moving toward clinical translation. Eur J Radiol 2015.

Development of a Photoacoustic Imaging Instrument and First-in-Man Clinical Trial for Prostate Cancer Detection

Over the past five years, the Gambhir Lab has developed a photoacoustic instrument to improve the diagnostic accuracy of ultrasound in breast, ovarian, prostate, and thyroid cancer screening.

The existing handheld PAI instrument was then adapted to include an ultrasound mode and has dimensions in accordance with the standard dimensions of clinical ultrasound instruments. Currently, this new device is being tested in a first clinical trial at Stanford in patients suspected for prostate cancer. Clinical trials for ovarian, thyroid, and breast cancer are to follow soon.

Kothapalli, S.R., Ma, T.J., Vaithilingam, S., Oralkan, O., Khuri-Yakub, B.T., and Gambhir, S.S. 2012. Deep tissue photoacoustic imaging using a miniaturized 2-D capacitive micromachined ultrasonic transducer array. IEEE Trans Biomed Eng 59:1199-1204.

Development of Photoacoustic Imaging Agents

Photoacoustic imaging is a non-ionizing modality that combines optical and ultrasound imaging to produce images with high optical contrast and high ultrasound resolution.

Photoacoustic imaging can be used in conjunction with imaging agents to obtain structural, functional and molecular information that will enable early cancer detection. The first ever activatable photoacoustic agent was developed at the Canary Center, which gets activated and produces signal only in the presence of its target, matrixmetalloproteinases MMP-2 and MMP-91. The agent showed promise in detecting the target in follicular thyroid carcinoma that is very hard to be distinguished from the benign adenomas by any other means but surgery. As such, the agent could prove useful in providing a non-invasive way to detect follicular carcinomas and minimizing the number of unnecessary surgeries2. Recently, we received Institutional Review Board (IRB) approval to evaluate photoacoustic imaging of thyroid nodules in humans. Another area of focus is application of photoacoustic imaging in prostate cancer diagnosis and lesion-directed biopsy guidance. A new imaging agent was developed that can bind to the gastrin-releasing peptide receptor (GRPR) with good specificity and sensitivity and provide visualization of the molecular profile of the tumors with relatively high resolution3. One of the most pressing issues in prostate cancer is overdiagnosis and overtreatment, caused by our current inability to differentiate between an aggressive and an indolent disease. The differentiation between the low- and high-risk tumors could be enabled by the use of agents, such as the one we developed, that target the molecular differences between the lesions.

Papers:

Levi J, Kothapalli SR, Ma TJ, Hartman K, Khuri-Yakub BT, Gambhir SS. Design, Synthesis, and Imaging of an Activatable Photoacoustic Probe. J Am Chem Soc. 2010;132: 11264-11269.

Levi J, Kothapalli SR, Bohndiek S, et al. Molecular photoacoustic imaging of follicular thyroid carcinoma. Clin Cancer Res. 2013;19: 1494-1502.

Levi J, Sathirachinda A, Gambhir SS. A high-affinity, high-stability photoacoustic agent for imaging gastrin-releasing peptide receptor in prostate cancer. Clin Cancer Res. 2014;20: 3721-3729.

Photoacoustic Imaging (PAI)

At Stanford, we are adapting traditional ultrasound imaging with an emerging non-ionizing photoacoustic imaging (PAI) technique that essentially lets us “hear” light.

Photoacoustic strategies allow deeper tissue penetration than optics alone while preserving the spatial and temporal resolution advantages of ultrasound. Therefore, tissues within a human body can be more clearly visualized at a depth that is clinically relevant. Because hemoglobin is one of the primary molecules present naturally that produce a photoacoustic signal, PAI is especially suitable for detecting blood vessels associated with tumors, as well as monitoring changes in blood vessel growth that can accompany tumor formation and growth.

Photoacoustic Imaging for Ovarian Cancer

At Stanford, we have engineered a new PAI device that is being tested for visualization of prostate cancer. We are adapting this device for use in ovarian cancer imaging.

After development and pre-clinical testing of the device, we will move into the clinical setting to test in patients. Our goal is to reliably visualize cancer even from several centimeters deep inside ovarian tissue. We propose the following specific aims:

1. Refine and validate a combined transvaginal ultrasound and photoacoustic imaging device by imaging models of ovarian tissue and surgically removed human ovaries. In this aim, we will adapt the current transrectal ultrasound and PAI system shown in figure 1, to develop the probe for transvaginal imaging of ovaries.

Figure 1. Photograph of the transrectal ultrasound and photoacoustic-imaging instrument currently used for prostate cancer imaging. The capacitive micromachined ultrasound transducer (CMUT) array is flip-chip bonded to a custom-designed integrated circuit that comprises the front-end circuitry for the transducer elements. The CMUT and integrated circuit are flip-chip bonded and placed on a PCB (printed circuit board). The PCB is rested in between two parallel fiber optic light guides that focus light 0.5 inches above the CMUT surface.

Subsequently the combined ultrasound and PAI device will be tested and refined using models of ovarian tissue, as well as surgically removed whole ovaries with predicted ovarian tumors. Key parameters such as imaging depth, spatial resolution, contrast, and frame rate of both photoacoustic and ultrasound modes of the combined instrument will be evaluated and optimized for deep tissue ovarian imaging. The goal of these experiments is to identify image metrics required to achieve a clinical grade imaging system that will visualize suspected tumors in the clinic, allowing for more accurate diagnosis of suspected ovarian cancer.

2. Conduct a pilot test of the combined transvaginal ultrasound and PAI instrument in patients undergoing ovarian cancer excision surgery. Fully optimized dual-modality transvaginal ultrasound and PAI with well-defined image metrics have the potential to further enhance the sensitivity and specificity of standard transvaginal ultrasound imaging of ovaries prior to surgery. In this study, we will test the efficacy of the combined device for clinical ovarian imaging. We anticipate that the combined procedure should not be more uncomfortable than a traditional transvaginal ultrasound procedure, since both are done with a hand-held transvaginal device of similar dimensions. The combined transvaginal ultrasound-PAI can be done at the time of traditional ultrasound, and in preclinical studies adds less than five to 10 minutes to each procedure.

The primary objective of this specific aim is to assess the combined instrument performance in a clinical setting, to understand the limitations of this instrumentation, to help improve the next-generation instrument design, and to understand how to integrate the combined transvaginal ultrasound and photoacoustic imaging into the standard clinical ultrasound workflow.