Personal and Prognostic: Tissue and Liquid Biomarkers of Radiotherapeutic Response in Non-Small Cell Lung Cancer.

Recent treatment advances have improved outcomes for patients with non-small cell lung cancer (NSCLC), often utilizing tumor molecular characterization to identify targetable mutations. This is further enhanced by advancements in "liquid biopsies", using peripheral blood for noninvasive, serial sampling of tumor biology. While tumor genomic alterations have established therapeutic implications in metastatic NSCLC, research is also ongoing to develop applications for tissue and liquid biomarkers in earlier stage disease, such as patients treated with radiation for early stage or locoregional NSCLC.

Early Detection of Recurrence in Patients With Locally Advanced Non-Small-Cell Lung Cancer via Circulating Tumor Cell Analysis.

BACKGROUND: Assays to identify circulating tumor cells (CTCs) might allow for noninvasive and sequential monitoring of lung cancer. We investigated whether serial CTC analysis could complement conventional imaging for detecting recurrences after treatment in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS: Patients with LA-NSCLC (stage II-III) who definitively received concurrent chemoradiation were prospectively enrolled, with CTCs from peripheral blood samples identified using an adenoviral probe that detects elevated telomerase activity present in nearly all lung cancer cells. A "detectable" CTC level was defined as 1.3 green flourescent protein-positive cells per milliliter of collected blood. Samples were obtained before, during (at weeks 2, 4, and 6), and after treatment (post-radiation therapy [RT]; at months 1, 3, 6, 12, 18, and 24). RESULTS: Forty-eight patients were enrolled. At a median follow-up of 10.9 months, 22 (46%) patients had disease recurrence at a median time of 7.6 months post-RT (range, 1.3-32.0 months). Of the 20 of 22 patients for whom post-RT samples were obtained, 15 (75%) had an increase in CTC counts post-RT. In 10 of these 15 patients, CTCs were undetectable on initial post-RT draw but were then detected again before radiographic detection of recurrence, with a median lead time of 6.2 months and mean lead time of 6.1 months (range, 0.1-12.0 months) between CTC count increase and radiographic evidence of recurrence. One patient with an early recurrence (4.7 months) had persistently elevated detectable CTC levels during and after treatment. CONCLUSION: These results indicate that longitudinal CTC monitoring in patients with LA-NSCLC treated with chemoradiation is feasible, and that detectable CTC levels in many patients meaningfully precede radiologic evidence of disease recurrence.

Theranostic gold nanoparticles modified for durable systemic circulation effectively and safely enhance the radiation therapy of human sarcoma cells and tumors.

Radiation therapy (RT) is an integral component of the treatment of many sarcomas and relies on accurate targeting of tumor tissue. Despite conventional treatment planning and RT, local failure rates of 10% to 28% at 5 years have been reported for locally advanced, unresectable sarcomas, due in part to limitations in the cumulative RT dose that may be safely delivered. We describe studies of the potential usefulness of gold nanoparticles modified for durable systemic circulation (through polyethylene glycosylation; hereinafter "P-GNPs") as adjuvants for RT of sarcomas. In studies of two human sarcoma-derived cell lines, P-GNP in conjunction with RT caused increased unrepaired DNA damage, reflected by approximately 1.61-fold increase in γ-H2AX (histone phosphorylated on Ser(139)) foci density compared with RT alone. The combined RT and P-GNP also led to significantly reduced clonogenic survival of tumor cells, compared to RT alone, with dose-enhancement ratios of 1.08 to 1.16. In mice engrafted with human sarcoma tumor cells, the P-GNP selectively accumulated in the tumor and enabled durable imaging, potentially aiding radiosensitization as well as treatment planning. Mice pretreated with P-GNP before targeted RT of their tumors exhibited significantly improved tumor regression and overall survival, with long-term survival in one third of mice in this treatment group compared to none with RT only. Interestingly, prior RT of sarcoma tumors increased subsequent extravasation and in-tumor deposition of P-GNP. These results together suggest P-GNP may be integrated into the RT of sarcomas, potentially improving target imaging and radiosensitization of tumor while minimizing dose to normal tissues.

An integrated method for reproducible and accurate image-guided stereotactic cranial irradiation of brain tumors using the small animal radiation research platform.

Preclinical studies of cranial radiation therapy (RT) using animal brain tumor models have been hampered by technical limitations in the delivery of clinically relevant RT. We established a bioimageable mouse model of glioblastoma multiforme (GBM) and an image-guided radiation delivery system that facilitated precise tumor localization and treatment and which closely resembled clinical RT. Our novel radiation system makes use of magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) to define tumor volumes, computed tomographic (CT) imaging for accurate treatment planning, a novel mouse immobilization system, and precise treatments delivered with the Small Animal Radiation Research Platform. We demonstrated that, in vivo, BLI correlated well with MRI for defining tumor volumes. Our novel restraint system enhanced setup reproducibility and precision, was atraumatic, and minimized artifacts on CT imaging used for treatment planning. We confirmed precise radiation delivery through immunofluorescent analysis of the phosphorylation of histone H2AX in irradiated brains and brain tumors. Assays with an intravenous near-infrared fluorescent probe confirmed that radiation of orthografts increased disruption of the tumor blood-brain barrier (BBB). This integrated model system, which facilitated delivery of precise, reproducible, stereotactic cranial RT in mice and confirmed RT's resultant histologic and BBB changes, may aid future brain tumor research.