This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging’s (MRI’s) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.

2-[ 18 F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamentalpropertyof neoplasia, theWarburgeffect.This molecularimaging technique offers acomplementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PETalso has significant potential for assessing therapy response. In this regard, it canimprove patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reductioninthe FDG-PETsignal withindays or weeks of initiating therapy (e.g., in lymphoma, non^small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now usedin drug approvals.These findings suggest that FDGPETcould facilitate drug development as an early surrogate of clinicalbenefit.This article reviews the scientificbasis ofFDG-PETandits development andapplicationasavaluableoncologyimagingtool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies. FDG-PET (2-[18 F]Fluoro-2-deoxyglucose positron emission tomography) is an accepted and widely used clinical imaging tool in oncology. U.S. Medicare reimbursement of FDG-PET recently expanded to encompass all cancer patients participating in certain prospective studies or registries in addition to more general coverage in 10 defined oncologic settings. Primarily covered are disease diagnosis, staging, and restaging, but FDG-PET is also approved for monitoring response to therapy in locally advanced and metastatic breast cancers when a change in therapy is anticipated. Clinical trials in breast cancer and other settings [e.g., non -small cell lung cancer (NSCLC) and esophageal cancer] have shown that FDG-PET imaging can provide an early indication of therapeutic response that is well correlated with clinical outcome. FDG-PET thus has the potential to improve patient management, particularly by signaling the need for early therapeutic changes in nonresponders, thereby obviating the side effects and costs of ineffective treatment. As an early surrogate for clinical benefit, the modality also has the potential to facilitate oncologic drug development by shortening phase II trials and detecting clinical benefit earlier in phase III investigations. Studies to further explore and validate these approaches are needed and can be conducted in parallel with those employing end points now use...

Quantitative FES-PET can predict response to hormonal therapy and may help guide treatment selection. Treatment selection using quantitative FES-PET in our patient series would have increased the rate of response from 23% to 34% overall, and from 29% to 46% in the subset of patients lacking HER2/neu overexpression. A multi-institutional collaborative trial would permit definitive assessment of the value of FES-PET for therapeutic decision making.

This is the first time that P-gp activity at the human BBB has been measured. The modest inhibition of human BBB P-gp by cyclosporine has implications for P-gp-based drug interactions at the human BBB. Our method for imaging P-gp activity can be used to identify multidrug-resistant tumors or to determine the contribution of P-gp polymorphism, inhibition, or induction to interindividual variability in drug response.