Browsing by Subject "Head and neck cancer"

Now showing 1 - 3 of 3
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    Development and characterization of CD133 positive cancer stem cell targeted toxins for use in carcinoma therapy
    (2013-05) Waldron, Nate N.
    Cancer Stem cells (CSC) have been shown to play an important role in a number of carcinomas. Although representing a subpopulation of many cancers, CSC are extremely important because they are more drug resistant than the more differentiated cancer cells which make up the bulk of most solid tumors. High numbers of CSC is an indicator of poor clinical outcome and have been shown to be a cause in drug refractory relapse, which is the single most urgent problem in carcinoma therapy. CD133 is a cell surface receptor that has been identified as a CSC marker in breast, brain, colon, pancreatic, and recently in Head and Neck (HN) carcinoma. Our laboratory bioengineered a targeted toxin called dCD133KDEL consisting of the scFv portion of a novel anti-CD133 monoclonal antibody on the same molecule as truncated pseudomonas exotoxin. Binding of dCD133KDEL was demonstrated on a variety of carcinoma lines and we verified the ability of the anti-CD133 scFv to sort tumor initiating cells. Since enhanced tumor initiation is a hallmark of CSC, we demonstrated that dCD133KDEL was able to prevent tumor initiation. Importantly, even though CD133 was expressed only on a subpopulation of cells, dCD133KDELprevented cell proliferation in vitro and had powerful anti-cancer effects in vivo in xenograft mouse models of head and neck cancer. The therapeutic potential of dCD133KDEL was further investigated in xenograft models of human breast and ovarian cancer where it was effective when administered systemically as well. To further study therapeutic potential, we assessed the reactivity of this drug on normal human progenitor cells since CD133 is a known progenitor cell marker. dCD133KDEL did not kill normal human CD133+ stem cells at the same concentrations as it did for carcinoma cells, indicating a therapeutic window exists. Drug safety studies were performed in mice and the maximum tolerated dose of dCD133KDEL was established. Liver damage was shown to be the dose limiting toxicity. Since CD133 positive cells can develop from CD133 negative cell populations, a phenomenon known as stem cell plasticity, we developed a bispecific targeted toxin (dEpCAMCD133KDEL) capable of targeting both CD133 and the epithelial cell adhesion molecule, EpCAM, an overexpressed marker on most carcinomas. dEpCAMCD133KDEL potently inhibited cell proliferation of a number of carcinoma lines in vitro and was also effective at eliminating tumor spheroids, which have been shown to be enriched for CSCs. This bispecific agent was also effective at causing tumor regression in a model of HN cancer in vivo. Because of the preliminary effectiveness of dCD133KDEL and dEpCAMCD133KDEL in preclinical evaluation, these drugs warrant further development for possible use in carcinoma therapy. These two CSC targeted toxins could be extremely useful in situations where our current drugs are failing because of the progression of a critical drug resistant CSC population. Since, targeted toxins work synergistically with current chemotherapy, these two targeted toxins could be used as an adjunct to current therapy to target the CSC population specifically, while traditional chemotherapy and radiation can still be used to target the rapidly dividing bulk of the tumor. We believe that future success in cancer treatment must include approaches to target CSC as well as the majority of less differentiated cancer cells that comprise a tumor.
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    Identification and functional activation of peroxisome proliferator-activated receptor in human upper aerodigestive cancer
    (2012-12) Wright, Simon K.
    Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive malignancy whose carcinogenesis occurs in multiple stages years to decades after carcinogen exposure. In spite of continued advances in the understanding of molecular biology of SCCHN and the introduction of a multitude of multi-modality treatment protocols, the 20-50% survival of stage III and IV disease has not changed appreciably in over twenty years. Efforts to treat or prevent recurrence have predominantly involved the use of cytotoxic chemotherapy, however the use of retinoids as a chemoprevention agent has been clinically assessed. Success has been limited by toxicity of retinoids and reversal of differentiation changes upon cessation of treatment. Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors belonging to the steroid/thyroid/retinoic acid nuclear receptor superfamily. PPARs primarily target genes involved in lipid homeostasis; one isoform, PPARã, directs the differentiation of precursor cells into adipocytes. PPARã heterodimerizes with RXRá to form a functional transcription factor. The recognition of ETYA as a PPAR activator along with the previously-discovered anti-cancer and differentiation effects of this agent invoked the possibility that a differentiation strategy could be used in the treatment in SCCHN. This study examined PPARã in SCCHN. PPARã protein was expressed in SCCHN cell lines. Treatment of two cell lines with three chemically distinct ligands of PPARã caused dose-dependent inhibition of proliferation. Cells treated with these agents caused cytoplasmic lipid vacuole accumulation consistent with adipogenic phenotype shift. Electromobility supershift analysis demonstrated DR-1 consensus sequence binding activity in SCCHN nuclear extracts. The more-specific cyp4a1 oligonucleotide also demonstrated binding, the amount of which was upregulated with treatment. Supershift analysis demonstrated presence of PPARã in nuclear extracts. Functional activation was assessed using dual transfection reporter gene assays, which demonstrated dose dependent increased PPRE activation with treatment using each agent. We conclude that PPARã ligands may represent a class of drugs which have value in the treatment of SCCHN.
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    Nutritional Status, Body Composition, and Psychosocial Outcomes Among Individuals with Advanced Head and Neck Cancers: A Prospective Investigation in An Outpatient Setting
    (2015-08) Mulasi, Urvashi
    Malnutrition among individuals with head and neck cancer (HNC) is of particular concern, with up to 40% - 57% with a compromised nutritional status even before beginning their treatment. Within the US, the prevalence of malnutrition has not been well-documented due to a lack of consensus on its definition and diagnosing markers. Therefore, the primary aim of this prospective natural history pilot study was to estimate the prevalence of malnutrition among individuals with HNC (n = 19) during and up to 3 months after treatment using the new Consensus malnutrition definition. The scored Patient-Generated Subjective Global Assessment (PG-SGA) was used as the reference standard to evaluate the sensitivity and specificity of the Consensus framework in defining malnutrition. Another aim of this research was to investigate the utility of raw bioimpedance parameters such as 50 kHz phase angle (PA) and 200 kHz/5 kHz impedance ratio (IR) to identify individuals with malnutrition, and to evaluate how bioimpedance markers relate to functional status outcomes. Finally, this research also assessed how malnutrition relates to quality of life (QoL) and self-efficacy perceptions among individuals with HNC. Results indicate that individuals with HNC are malnourished even before treatment initiation. Using the Consensus framework, 67% of our participants were malnourished before treatment; and the prevalence of malnutrition consistently increased during treatment and the post-treatment period. When compared to our reference standard PG-SGA, the Consensus criteria identified malnutrition with overall good sensitivity (95%) and specificity (43%). Bioimpedance markers PA and IR were useful in identifying individuals who were at increased risk for malnutrition and/or impaired functional status. From a psychosocial perspective, compared with well-nourished participants, malnourished individuals scored significantly lower in the global QoL and cognitive function scales and significantly higher in the disease- and treatment-related symptom scales and items. In the future, if clinicians are trained to assess malnutrition diagnostic markers before individuals with cancer undergo aggressive treatments, nutritional interventions could be initiated at an earlier time and loss in weight and/or lean tissue can be prevented. Early detection of malnutrition could also help with patient-specific intervention strategies aimed to improve overall health-related QoL outcomes.