Imaging hypoxia and angiogenesis in tumors

In this study, [¹⁸F]FGA was obtained by a one-step oxidation of [¹⁸F]FDG using sodium hypochlorite. The conversion from [¹⁸F]FDG to [¹⁸F]FGA was confirmed by HPLC to be over 95% using the optimal condition. A549-luciferase NSCLC xenografted mice was used for in vivo PET imaging. Prior to either saline or cisplatin treatment, there was no significant difference on tumor uptake of [¹⁸F]FGA in all mice, with an average uptake of (0.21 ± 0.16) %ID/g. After treatment, tumor uptake of [¹⁸F]FGA was not changed significantly for saline-treated mice, whereas the tumor uptake of [¹⁸F]FGA drastically increased for cisplatin-treated mice, with an average uptake of (1.63 ± 0.16) %ID/g. The ratio of tumor uptake between cisplatin-treated vs. saline-treated mice was 7.8 ± 0.2 within one week of treatment. PET imaging results were consistent with ex vivo biodistribution data. BLI showed significant light intensity suppression after treatment, indicating necrosis. Our data indicate that [¹⁸F]FGA uptake was related to tumor necrosis. [¹⁸F]FGA PET/CT imaging might be a useful tool to monitor treatment response to chemotherapy by imaging tumor necrosis.

The ability to measure molecular properties of disease noninvasively makes molecular imaging especially well suited to clinical trials. These trials can take place in one of several settings: (1) a trial using molecular imaging to assess a new drug in early testing, (2) a trial using molecular imaging to provide response evaluation for a drug in large (Phase III) clinical trials, and (3) a trial testing the utility of molecular imaging to predict response and outcome using established drugs. Unlike the established approach to most PET imaging currently used in the clinic, where disease detection and staging are the primary goals (see Chapter 61, “Congestive Heart Failure”), most cancer clinical trials seek to address different endpoints, namely: (1) prognosis, (2) prediction (patient therapy selection/stratification), (3) early response to therapy, and (4) long-term outcome of therapy. In this chapter, the application of PET to clinical trials—specifically cancer clinical trials—is reviewed, with an emphasis on the components important in cancer imaging applied to cancer therapy clinical trials and clinical practice. Topics include the goals and study design for PET and drug therapy, technical and regulatory challenges for PET imaging in clinical cancer therapy trials, and early results applying PET to evaluate cancer drug therapy. It should be emphasized that the use of PET in clinical trials is in its infancy, with most data in the literature coming from relatively small single-center trials. Ongoing cooperative trials in ¹⁸F-fluorodeoxyglucose (FDG) PET, and future trials using other radiopharmaceuticals beyond FDG, will guide the use of PET in future drug evaluations and clinical cancer therapy.

Hypoxia is a well-established pathophysiologic feature of solid tumors that has demonstrated links to poor prognosis. It is a direct cause of radioresistance and also contributes to chemoresistance. In addition, it is immunosuppressive. Given these pleiotropic effects, there is strong rationale for developing strategies to image hypoxia. This chapter reviews the characteristics of hypoxia that enable it to be imaged. A critical review of the three major methods for imaging hypoxia (Optics, PET/SPECT, and Magnetic Resonance Imaging) is presented; the strengths and weaknesses of each method for preclinical and clinical uses are described.

Cancer is the leading cause of mortality among men and women worldwide. Despite the availability of numerous diagnostic techniques for various cancers, the overall survival rate remains low and the majority of patients die due to late diagnosis and advanced stage of the disease. Diagnosing and treating cancer at its early stages ideally during the precancerous phase could significantly increase survival rate with the possibility of cure and prolong survival. Cancer is a genetic disease and it is illicitly activated by the acquisition of somatic DNA lesions and aberrations in genome structure and defects in maintenance and repair. These somatic DNA mutations known as driver mutations seem to be the prime cause in initiating tumorigenesis. The advances in genomic technologies have immensely facilitated the understanding of cancer progression and metastasis, and the discovery of novel biomarkers. However, changes in somatic mutational landscape of the oncogenome are translated into aberrantly regulated oncoproteome which drives the cancer initiation. Thus, combination of proteomic and genomic technologies is urgently required to discover biomarkers for early diagnosis. The recent advances in human genome based detection of cancer using advanced genomic technologies like NextGen Sequencing, digital PCR, cfDNA technology have shown promise; for example oncogenic somatic mutation variants, transcriptomic analysis, copy number variant, and methylation data from the Cancer Genome Atlas. Similarly, oncoproteomics has the potential to revolutionize clinical management of the disease, including cancer diagnosis and screening based on new proteomic database which embodies somatic variants and post translational modifications, thus devising proteomic technologies as a complement to histopathology. Further, the use of multiple proteomic and genomic biomarkers rather than a single gene or protein could greatly improve diagnostic accuracy and enhance the predictive power for treatment outcome and may enable adequate monitoring of the response to treatment and could be an important option for personalized medicine. The proteogenomic approach has the promise to identify new biomarkers for radiation therapy (RT) which could reliably predict the tumor radiation resistance and which could also accurately predict normal tissue toxicity, and at the same time radiotherapy effectiveness. In this review we have summarize the recent advances in proteogenomic approaches to develop more sensitive diagnostic and prognostic biomarkers which could be translated into improved clinical care and management of the disease.

Ongoing research on malignant and normal cell biology has substantially enhanced the understanding of the biology of cancer and carcinogenesis. This has led to the development of methods to image the evolution of cancer, target specific biological molecules, and study the anti-tumour effects of novel therapeutic agents. At the same time, there has been a paradigm shift in the field of oncological imaging from purely structural or functional imaging to combined multimodal structure–function approaches that enable the assessment of malignancy from all aspects (including molecular and functional level) in a single examination. The evolving molecular functional imaging using specific molecular targets (especially with combined positron-emission tomography [PET] computed tomography [CT] using 2- [¹⁸F]-fluoro-2-deoxy-d-glucose [FDG] and other novel PET tracers) has great potential in translational research, giving specific quantitative information with regard to tumour activity, and has been of pivotal importance in diagnoses and therapy tailoring. Furthermore, molecular functional imaging has taken a key place in the present era of translational cancer research, producing an important tool to study and evolve newer receptor-targeted therapies, gene therapies, and in cancer stem cell research, which could form the basis to translate these agents into clinical practice, popularly termed “theranostics”. Targeted molecular imaging needs to be developed in close association with biotechnology, information technology, and basic translational scientists for its best utility. This article reviews the current role of molecular functional imaging as one of the main pillars of translational research.