Seth M. Miller

Nanomedicine in chemoradiation

Chemoradiotherapy, the concurrent administration of chemotherapy and radiotherapy, is a treatment paradigm in oncology. It is part of the standard of care and curative treatment of many cancers. Given its importance, one of the primary goals of cancer research has been to identify agents and/or strategies that can improve the therapeutic index of chemoradiation. Recent advances in nanomedicine have provided a unique and unprecedented opportunity for improving chemoradiotherapy. Nanoparticles possess properties that are ideally suited for delivering chemotherapy in the chemoradiation setting. The goal of this review is to examine the role of incorporating nanomedicine into chemoradiation and the potential impact of nanomedicine to chemoradiotherapy.

Why Target the Globe?: 4-year report (2009-2013) of the Association of Residents in Radiation Oncology Global Health Initiative

Departments of Radiation Oncology, *DeCesaris Cancer Institute, Anne Arundel Medical Center, Annapolis, Maryland, yHenry Ford Health Systems, Detroit, Michigan, zMayo Clinic, Rochester, Minnesota, xWashington University in St. Louis School of Medicine, St. Louis, Missouri, kKarmanos Cancer Center, Detroit Medical Center, Detroit, Michigan, {University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, **Gamma West Cancer Services, Ogden, Utah, yyMemorial Sloan-Kettering Cancer Center, New York, New York, and zzThe University of Texas, MD Anderson Cancer Center, Houston, Texas

Patient-reported quality of life during definitive and postprostatectomy image-guided radiation therapy for prostate cancer

PURPOSE The importance of patient-reported outcomes is well-recognized. Long-term patient-reported symptoms have been described for individuals who completed radiation therapy (RT) for prostate cancer. However, the trajectory of symptom development during the course of treatment has not been well-described in patients receiving modern, image-guided RT. METHODS AND MATERIALS Quality-of-life data were prospectively collected for 111 prostate cancer patients undergoing RT using the validated Prostate Cancer Symptom Indices, which assessed 5 urinary obstructive/irritative and 6 bowel symptoms. Patients who received definitive RT (N = 73) and postprostatectomy RT (N = 38) were analyzed separately. The frequency and severity of symptoms over multiple time points are reported. RESULTS An increasing number of patients had clinically meaningful urinary and bowel symptoms over the course of RT. A greater proportion of patients undergoing definitive RT reported clinically meaningful urinary symptoms at the end of RT compared with baseline in terms of flow (33% vs 19%) and frequency (39% vs 18%). Individuals receiving postprostatectomy radiation also reported an increase in symptoms including frequency (29% vs 3%) and nocturia (50% vs 21%). Clinically meaningful bowel symptoms were less commonly reported. Patients receiving definitive RT reported an increase in diarrhea (9% vs 4%) and urgency (12% vs 6%) at the completion of RT compared with baseline. Both bowel and urinary symptoms approached their baseline levels by the time of first follow-up after treatment completion. The majority of patients who had clinically meaningful urinary or bowel symptoms during RT did not have them at 2 years or beyond, and development of new symptoms in the long term was uncommon. CONCLUSIONS There is a modest increase in urinary and bowel symptoms over the course of treatment for individuals receiving definitive and postprostatectomy image-guided RT. These data can help inform both providers and patients regarding the trajectory of symptoms and allow for reasonable expectations regarding toxicity under treatment.

Multivalent binding and biomimetic cell rolling improves the sensitivity and specificity of circulating tumor cell capture

Purpose: We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in patients with cancer undergoing radiotherapy treatment. Experimental Design: Patients with histologically confirmed primary carcinoma undergoing radiotherapy, with or without chemotherapy, were eligible for enrollment. Peripheral blood was collected prospectively at up to five time points, including before radiotherapy, at the first week, mid-point and final week of treatment, as well as 4 to 12 weeks after completion of radiotherapy. CTC capture was accomplished using a nanotechnology-based assay (CapioCyte) functionalized with aEpCAM, aHER-2, and aEGFR. Results: CapioCyte was able to detect CTCs in all 24 cancer patients enrolled. Multivalent binding via poly(amidoamine) dendrimers further improved capture sensitivity. We also showed that cell rolling effect can improve CTC capture specificity (% of captured cells that are CK+/CD45−/DAPI+) up to 38%. Among the 18 patients with sequential CTC measurements, the median CTC decreased from 113 CTCs/mL before radiotherapy to 32 CTCs/mL at completion of radiotherapy (P = 0.001). CTCs declined throughout radiotherapy in patients with complete clinical and/or radiographic response, in contrast with an elevation in CTCs at mid or post-radiotherapy in the two patients with known pathologic residual disease. Conclusions: Our study demonstrated that multivalent binding and cell rolling can improve the sensitivity and specificity of CTC capture compared with multivalent binding alone, allowing reliable monitoring of CTC changes during and after treatment. Clin Cancer Res; 24(11); 2539–47. ©2018 AACR.

Abstract B10: Effects of vascular normalization when combining miR-200b with radiation

Introduction: Lung cancer is the leading cause of cancer-related deaths worldwide, and patients usually die from metastatic disease. Radiation is a mainstay treatment in lung cancer, but its efficacy is largely dependent on tumor perfusion. We recently found that miR-200b is a novel AngiomiR capable of inhibiting metastasis and tumor angiogenesis while inducing vascular normalization. We are investigating whether vascular normalization with miR-200b can enhance therapeutic efficacy of radiation in a metastatic model of lung cancer. Methods: Using lung cancer cell lines, we assessed direct effects of miR-200b on radio-sensitivity using clonogenic assays and gamma-H2AX indices. Using an orthotopic lung cancer model (344SQ) in athymic nude mice, we determined peri-vascular biodistribution of intravenously administered chitosan nanoparticles (CH) containing Cy3-labled miRNA. Using the same model, a randomized therapeutic experiment was performed as follows (n=10 mice/group): 1) NC miR-CH, 2) miR-200b-CH, 3) NC miR-CH + radiation, or 4) miR-200b-CH + radiation. Radiation groups received four fractions of 4 Gy (16 Gy total). Following two weeks of treatment, mice were necropsied, and tumor burden was annotated and subsequently analyzed for microvessel density (MVD), pericyte coverage (CD31/Desmin) and tumor hypoxia (pimonidazole staining). Results: Following a single delivery of CH nanoparticles containing Cy3-labled miRs, we found that 37% of tumor vessels had Cy3 signal within 12.5 uM, 60% within 25 uM, and 82% within 50 uM. Compared to NC miRNA, we found that miR-200b overexpression in conjunction with radiation did not diminish colony formation or increase gamma-H2AX indices, suggesting miR-200b likely has little role in directly sensitizing cancer cells to radiation. In an orthotopic model of lung cancer, compared to NC miR-CH, while delivery of miR-200b-CH alone or treatment with NC miR-CH plus radiation showed no differences in metastasis, the combination of miR-200b-CH and radiation led to a 58% reduction in aggregate metastatic disease (p Discussion: Our work demonstrates that CH nanoparticle delivery of miR-200b can effectively target tumor vasculature. The combination of miR-200b delivery with radiation effectively inhibited lung cancer metastasis and was significantly associated with a marked decrease in MVD and increase in pericyte coverage. These additive effects appear to be independent of miR-200b directly radio-sensitizing cancer cells. However, we found that the profound anti-angiogenic effects of combination treatment (miR-200b-CH plus radiation) led to a 2.5 fold increase in tumor hypoxia. Our findings suggest that vascular normalization induced by miR-200b can be exploited to create an optimal “treatment window” for combination with radiation therapy. Citation Format: Salma Azam, Seth Miller, Trent Waugh, Vivek Somasundaram, Mitchell Smith, Adrienne D. Cox, Chad V. Pecot. Effects of vascular normalization when combining miR-200b with radiation. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B10.