January 31, 2019

Grant supports novel imaging initiative to enhance cancer care

A Vanderbilt initiative to develop predictive imaging technologies that clinicians can use to better match patients with personalized care has received National Cancer Institute (NCI) funding.

A Vanderbilt initiative to develop predictive imaging technologies that clinicians can use to better match patients with personalized care has received National Cancer Institute (NCI) funding.

Charles Manning, PhD, Ingram Professor of Cancer Research, and Jordan Berlin, MD, Ingram Professor of Cancer Research, are the principal investigators of a $3.2 million NCI grant to develop VU-PREDICT.

The work entails expanding the possibilities of PET imaging through the use of innovative radiopharmaceuticals.

Currently, genomic assays based on RNA and DNA are the primary tools used in matching patients with precision cancer medicine. VU-PREDICT aims to develop novel imaging technologies so that the phenotypes of tumors — their visual presentations — can enhance genomics as well as serve as an additional predictor. The researchers plan to devise novel quantitative imaging methods so that cancer clinicians can more quickly evaluate patient responses to drug therapies.

One new class of anti-cancer therapies that Vanderbilt investigators are working on targets cellular metabolism. Manning, Berlin and colleagues at Vanderbilt-Ingram Cancer Center (VICC) are exploring combined inhibition of glutamine metabolism and EGFR to enhance the efficacy of EGFR-targeted monoclonal antibodies (mAbs) in patients with colorectal cancer. A Phase II clinical trial combining CB-839, a glutaminase inhibitor, and panitumumab, an EGFR-targeted mAb, is scheduled to begin at VICC in early 2019.

Manning and colleagues have also developed a novel series of glutamine metabolism inhibitors that are at the preclinical stage. One promising member of the new class, termed V-9302, was reported Jan. 15, 2018, in Nature Medicine.

One common attribute of all inhibitors of cancer metabolism is that predictive biomarkers are lacking. A focus of VU-PREDICT is to develop resources that enable quantitative PET imaging to fill this gap.

In addition to clinical and preclinical validation of several PET tracers of cancer metabolism as a means to identify tumors potentially sensitive to metabolism inhibitors, Manning envisions also attaching imaging isotopes to V-9302 or similar molecules so the researchers can discern whether the molecules are reaching tumors with high rates of glutamine metabolism. Such studies could significantly accelerate drug development.

“Quantitative molecular imaging holds great promise to be the game-changing technology that allows clinicians to exploit targetable vulnerabilities in cancer metabolism,” Manning said. “We envision that deliverables of VU-PREDICT include illuminating several investigational PET tracers of cancer metabolism that will rapidly help clinicians match patients with the best possible therapy. It is also likely that VU-PREDICT will ultimately give researchers and clinicians alike the tools needed to develop better inhibitors of cancer metabolism with therapeutic potential.”

VU-PREDICT, which focuses primarily on colorectal cancer, received co-clinical funding from the NCI, meaning the initiative has dual areas of inquiry, with some research conducted in laboratories and other research involving patients. In the lab, researchers will use mouse models in conjunction with cancer metabolism inhibitors to understand the role of PET imaging within the context of cancer-related immunity. Ann Richmond, PhD, Ingram Professor of Cancer Research, and colleagues will lead that effort.

Another distinguishing component of VU-PREDICT is that the researchers will evaluate the effect of circadian rhythm, or a tumor’s biological clock, on PET imaging. Many metabolic features within cancer cells are driven by circadian rhythms, but understanding how this affects PET imaging is unknown, especially relative to glutamine metabolism. Expanding the possibilities of PET imaging may someday inform doctors of the optimum times to administer drug therapies, Manning said, noting that cells and genes have their own circadian rhythms.

As part of the grant, Vanderbilt joins a consortium of other researchers from Duke University, Washington University and the University of Pennsylvania on the initiative. PREDICT is an acronym for “PET Imaging Resource to Enhance Delivery of Individualized Cancer Therapy.”