Recent studies describing the mutational landscape of head and neck squamous cell carcinoma (HNSCC) on a genomic scale by our group and others, including The Cancer Genome Atlas, have provided unprecedented perspective for understanding the molecular pathogenesis of HNSCC progression and response to treatment. These studies confirmed that mutations of the TP53 tumor suppressor gene were the most frequent of all somatic genomic alterations in HNSCC, alluding to the importance of the TP53 gene in suppressing the development and progression of this disease. Clinically, TP53 mutations are significantly associated with short survival time and tumor resistance to radiotherapy and chemotherapy in HNSCC patients, which makes the TP53 mutation status a potentially useful molecular factor for risk stratification and predictor of clinical response in these patients. In addition to loss of wild-type p53 function and the dominant-negative effect on the remaining wild-type p53, some p53 mutants often gain oncogenic functions to promote tumorigenesis and progression. Different p53 mutants may possess different gain-of-function properties. Therefore, mutant p53 is not just one protein but actually a variety of proteins that contribute to an exceptionally vast network of tumor-promoting processes. Herein we review the most up-to-date information about TP53 mutations available via The Cancer Genome Atlas-based analysis of HNSCC and discuss our current understanding of the potential tumor-suppressive role of p53, focusing on gain-of-function activities of p53 mutations. We also summarize our knowledge regarding use of the TP53 mutation status as a potential evaluation or stratification biomarker for prognosis and a predictor of clinical response to radiotherapy and chemotherapy in HNSCC patients. Finally, we discuss possible strategies for targeting HNSCCs bearing TP53 mutations.

Despite the remarkable progress of adoptive T cell therapy in cancer treatment, there remains an urgent need for the noninvasive tracking of the transfused T cells in patients to determine their biodistribution, viability, and functionality. With emerging molecular imaging technologies and cell-labeling methods, noninvasive in vivo cell tracking is experiencing impressive progress toward revealing the mechanisms and functions of these cells in real time in preclinical and clinical studies. Such cell tracking methods have an important role in developing effective T cell therapeutic strategies and steering decision-making process in clinical trials. On the other hand, they could provide crucial information to accelerate the regulatory approval process on the T cell therapy. In this review, we revisit the advances in tracking the tumor-specific CTLs, highlighting the latest development in human studies and the key challenges.

Histone deacetylases (HDACs) are overexpressed in various cancers. In vivo imaging to measure the expression and functions of HDACs in tumor plays an important role for tumor diagnosis and HDAC-targeted therapy evaluation. The development of stable and highly sensitive HDAC targeting probe is highly desirable. Near-infrared (NIR) fluorescence optical imaging is a powerful technology for visualizing disease at the molecular level in vivo with high sensitivity and no ionizing radiation. We report here the design, synthesis, and bioactivity evaluation of LBH589-Cy5.5 for in vivo NIR fluorescence imaging of HDACs. The IC50 value of the resulting NIR probe to HDACs was determined to be 9.6 nM. In vitro fluorescence microscopic studies using a triple-negative breast cancer cell line, MDA-MB-231, established the binding specificity of LBH589-Cy5.5 to HDACs. An in vivo imaging study performed in MDA-MB-231 tumor xenografts demonstrated accumulation of the probe in tumor with good contrast from 2 h to 48 h postinjection. Furthermore, the fluorescent signal of LBH589-Cy5.5 in tumor was successfully blocked by coinjection of nonfluorescent LBH589 with the probe. In a following therapy evaluation study, the administration of SAHA, a clinically used HDAC inhibitor, decreased LBH589-Cy5.5 accumulation in tumor, demonstrating the potential application of LBH589-Cy5.5 for evaluating therapeutic response of HDAC inhibitors in cancer treatment.

A rapid one-step 18F labeling reaction with fluoridealuminum complex, which is based on chelation chemistry, has received a surge of interest for 18F radiolabeling of peptides. In this study, a non-peptidic bivalent integrin αvβ3 antagonist (bivalent-IA) was conjugated with 1,4,7-triazacyclononane-1,4-diiacetic acid (NODA). A novel 18F labeled radiotracer, 18F-bivalent-IA, was developed via one step 18F–AlF/NODA chelation reaction in aqueous phase with high radiochemical yield (65–75%, decay corrected) and good specific activity (750–850 mCi/μmol). The tumor integrin targeting efficiency and in vivo pharmacokinetic profile of 18F-bivalent-IA were evaluated in U-87 MG (integrin positive) and MDA-MB-231 (integrin negative) models by small-animal PET/CT scan followed by a biodistribution study. The PET/CT and ROI results showed high tumor uptake of 18F-bivalent-IA in U-87 MG tumor-bearing mice from 5 to 120 min p.i. with good contrast, and the U-87 MG tumor uptake values (6.35 ± 0.67%ID/g, at 1 h p.i.) were 6 times higher than those of MDA-MB-231 tumor (1.05 ± 0.12%ID/g, at 1 h p.i.) (P < 0.0001) which correlated with the integrin αvβ3 expression in tumor tissues confirmed by immunohistochemistry. Co-injection of the 18F-bivalent-IA with 6 nmol (6 μg) of nonradioactive bivalent-IA effectively blocked tumor uptake demonstrating the integrin αvβ3-specificity. In conclusion, the first 18F labeled non-peptidic bivalent integrin αvβ3 targeting radiotracer, 18F-bivalent-IA, was developed and proved to be a highly potent and specific PET radiopharmaceutical for noninvasive imaging of integrin αvβ3, which plays a critical role in tumor angiogenesis and metastasis.