Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small—approximately one-tenth that of monoclonal antibodies—their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesized and modified. In addition, aptamers’ long storage period and low immunogenicity are favorable properties for clinical utility. Due to their flexibility of chemical modification, aptamers are conjugated to other chemical entities including chemotherapeutic agents, siRNA, nanoparticles, and solid phase surfaces for therapeutic and diagnostic applications. However, as relatively small sized oligonucleotides, aptamers present several challenges for successful clinical translation. Their short plasma half-lives due to nuclease degradation and rapid renal excretion necessitate further structural modification of aptamers for clinical application. Since the US Food and Drug Administration (FDA) approval of the first aptamer drug, Macugen® (pegaptanib), which treats wet-age-related macular degeneration, several aptamer therapeutics for oncology have followed and shown promise in pre-clinical models as well as clinical trials. This review discusses the advantages and challenges of aptamers and introduces therapeutic aptamers under investigation and in clinical trials for cancer treatments.
Tumor-associated macrophages (TAMs) are major constituents of the tumor microenvironment in solid tumors and have been implicated as mediators of tumor progression, invasion and metastasis. Correspondingly, accumulation of TAMs is associated with unfavorable clinical outcomes in numerous types of solid tumors. E-selectin is a hallmark of inflammation and a key adhesion molecule that accommodates the initial contact of circulating immune cells with the inflamed vessel surface. Currently, the association between E-selectin and TAMs is not fully elucidated; therefore, the present study investigated the association between vessel inflammation, TAM infiltration, and clinical outcome in breast cancer. A total of 53 procedure-naïve invasive breast cancer cases were immunohistochemically analyzed for the presence of cluster of differentiation (CD)68+ TAMs, E-selectin+ vessels and tumor inflammation. The association between CD68 and E-selectin expression, and tumor inflammation as well as overall survival was evaluated using Kaplan-Meier survival curves and multivariable Cox's proportional hazards regression analysis. The abundance of TAMs was identified to be positively associated with tumor inflammation, estrogen receptor and E-selectin expression levels. A greater prevalence of TAMs and tumor inflammation was significantly associated with shorter overall survival times. E-selectin expression levels were significantly higher in tumor vessels among elderly patients, but were not associated with overall survival. The abundance of TAMs was associated with the presence of E-selectin-expressing inflamed tumor vessels and tumor inflammation, as well as overall survival in patients with invasive breast carcinoma.
E-selectin is an adhesion molecule expressed on the luminal surface of inflamed blood vessels that mediates hematogenous metastasis by assisting shear-resistant adhesion of circulating tumor cells to the vessel surface under dynamic blood flow. Previously, we developed an E-selectin antagonistic thioaptamer (ESTA) for the prevention of hematogenous metastasis through the blockade of CD44 breast cancer cells (BCa) adhesion to E-selectin-expressing premetastatic endothelial niche. The current study focuses on developing a PEGylated E-selectin targeting thioaptamer with improved pharmaceutical properties. A serial deletion of stem-loops reveled that loop-1 and -2 (ESTA7) are the minimally effective backbone structure necessary to obtain inhibition of the E-selectin/CD44 interaction and shear resistant adhesion of CD44 BCa to E-selectin-expressing human endothelial cells (HMVECs) at a level equal to ESTA. Chemical conjugation of methoxy-polyethylene-glycol (PEG) at the sizes of 5 and 10 kDa did not interfere with ESTA7-mediated shear-resistant adhesion. However, in vivo study demonstrated that only 10 kDa PEG-conjugated ESTA7 (ESTA7-p10) retains the activity to inhibit metastases at a level equal to parental ESTA. Additionally, a single intravenous injection of ESTA7-p10 inhibited the development of lung, brain, and bone metastases of MDA-MB-231, through the blockade of E-selectin. Moreover, PEGylation led to an extension of elimination half-life and increase of AUC, resulting in superior inhibition of metastasis development compared to parental ESTA with a longer interval between dosing in a spontaneous metastasis model. Lastly, repeated intravenous administration of ESTA7-p10 was tolerated in mice, highlighting the potential prophylactic application of ESTA7-p10 for metastasis prevention.
Background Time to surgery (TTS) has been suggested to have an association with mortality in early-stage breast cancer. Objective This study aims to determine the association between TTS and preoperative disease progression in tumor size or nodal status among women diagnosed with clinical T1N0M0 ductal breast cancer. Methods Women diagnosed with clinical T1N0M0 ductal breast cancer who had breast-conserving surgery as their first definitive treatment between 2010 and 2016 (n = 90,405) were analyzed using the National Cancer Database. Separate multivariable logistic regression models for hormone receptor (HR)-positive and HR-negative patients, adjusted for clinical and demographic variables, were used to assess the relationship between TTS and upstaging of tumor size (T-upstaging) or nodal status (N-upstaging). Results T-upstaging occurred in 6.76% of HR-positive patients and 11.00% of HR-negative patients, while N-upstaging occurred in 12.69% and 10.75% of HR-positive and HR-negative patients, respectively. Among HR-positive patients, odds of T-upstaging were higher for 61–90 days TTS (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.05–1.34) and ≥91 days TTS (OR 1.47, 95% CI 1.17–1.84) compared with ≤30 days TTS, and odds of N- upstaging were higher for ≥91 days TTS (OR 1.35, 95% CI 1.13–1.62). No association between TTS and either T- or N-upstaging was found among HR-negative patients. Other clinical and demographic variables, including grade, tumor location, and race/ethnicity, were associated with both T- and N-upstaging. Conclusion TTS ≥61 and ≥91 days was a significant predictor of T- and N-upstaging, respectively, in HR-positive patients; however, TTS was not associated with upstaging in HR-negative breast cancer. Delays in surgery may contribute to measurable disease progression in T1N0M0 ductal breast cancer.
Lung cancer is the leading cause of cancer-related deaths worldwide. Most patients present with advanced inoperable disease. Traditionally, responses to treatments are evaluated using different imaging modalities, which can sometimes be confusing. This is particularly more relevant in stage 3 disease where, after radiation therapy, persistent tumors on scans can represent active disease or scar tissue. We have been evaluating role of circulating tumor cells (CTCs) in that setting. Here we present the case of a 68-year-old male with stage 3 disease whose primary tumor responded to chemoradiotherapy on imaging, but whose CTC count was higher than the pre-treatment value. The patient later developed liver metastases. In this case, the CTC count more accurately predicted the patient's prognosis and highlights the need for exploration of the CTC count as a tool supplemental to imaging modalities.
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