No description available.

No description available.

Neuroblastoma (NB) is a childhood cancer with a highly complex nature. High-risk NB patients undergo intensive treatment regimens that are often followed by long-term side effects. This, in addition to the emergence of resistant cancer cells, highlights a need for novel therapeutic targets and treatment strategies to improve outcome in NB. P21 is a cyclin-dependent kinase inhibitor considered to play a role in tumor resistance and aggressiveness due to its involvement in cell cycle and/or apoptosis. This project aimed to explore the expression of endogenous p21 in high-risk NB cell lines and whether p21 could be a therapeutic target for high-risk NB. Endogenous p21 levels were investigated using RT-qPCR and quantitative immunocytochemistry in eight high-risk NB cell lines. A small molecular inhibitor of p21, UC2288, was used in these cell lines to investigate tumour cell viability following p21 inhibition. In addition, combination treatment with UC2288 and the chemotherapy drug cisplatin was performed on resistant NB cell lines. Our results show variable expression of p21, where cell lines with high endogenous p21 expression showed sensitivity to single agent treatment with cisplatin or UC2288. Moreover, resistant NB cell lines showed lower endogenous p21 expression, however, combination treatment with UC2288 and cisplatin showed reduced viability, indicating sensitivity to combination treatment. This project highlights the potential of using p21 as a therapeutic target as well as a predictive biomarker in high-risk NB.

abstract: Gold nanoparticles as potential diagnostic, therapeutic and sensing systems have a long history of use in medicine, and have expanded to a variety of applications. Gold nanoparticles are attractive in biological applications due to their unique optical, chemical and biological properties. Particularly, gold nanorods (GNRs) are increasingly used due to superior optical property in the near infrared (NIR) window. Light absorbed by the nanorod can be dissipated as heat efficiently or re-emitted by the particle. However, the limitations for clinical translation of gold nanorods include low yields, poor stability, depth-restricted imaging, and resistance of cancer cells to hyperthermia, are severe. A novel high-throughput synthesis method was employed to significantly increase in yields of solid and porous gold nanorods/wires. Stable functional nanoassemblies and nanomaterials were generated by interfacing gold nanorods with a variety of polymeric and polypeptide-based coatings, resulting in unique properties of polymer-gold nanorod assemblies and composites. Here the use of these modified gold nanorods in a variety of applications including optical sensors, cancer therapeutics, and nanobiomaterials were described. / Dissertation/Thesis / Ph.D. Chemical Engineering 2012

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The potential antitumor activity of mixed CB1/CB2 cannabinoid receptor agonists, such as the aminoalkylindole WIN55,212-2 (WIN2), has been extensively studied, but little information is available as to their potential interaction with conventional cancer therapies, such as ionizing radiation (IR). In the present work, we investigated the effects of WIN2 on the antiproliferative effects of radiation in human (MCF-7 and MDA-MB-231) and murine (4T1) breast cancer cells, as well as an immortalized human breast epithelial cell line (MCF-10A). WIN2 or radiation alone inhibited breast tumor growth, while the combination of WIN2 and radiation was more effective than either agent alone in breast cancer cells. WIN2 showed lower potency in MCF-10A cells than MCF-7 cells, but was still able to augment the effects of radiation at higher doses. The stereoisomer of WIN2, WIN55,212-3 (WIN3) failed to inhibit growth or potentiate the growth-inhibitory effects of radiation, indicating stereospecificity in all cell lines tested. The combination of WIN2 and IR was examined in vivo but the results were inconclusive. Interestingly, while other aminoalkylindoles, pravadoline and JWH-015, enhanced the antiproliferative effects of radiation, this was not the case for other synthetic cannabinoids (i.e., nabilone, CP55,940 and methanandamide) or phytocannabinoids (i.e., ∆9-tetrahydrocannabinol and cannabidiol). The antiproliferative actions of WIN2 were not ameliorated by CB1, CB2, TRPV1, or PPAR receptor antagonists, suggesting the possibility of a novel site of action. Studies utilizing sphingosine-1-phosphate (S1P) agonists and estradiol suggest that WIN2 interferes with S1P signaling in cell proliferation, but agonist stimulated [³⁵S]GTPγS binding assays show that this antagonism is not occurring at the level of S1P receptors. In addition, WIN2 did not alter radiation-induced DNA damage or the rate of DNA repair based on γH2AX staining. Treatment with WIN2 and radiation promoted both autophagy and senescence, but not apoptosis or necrosis. Time course studies combined with senescence and cell death data suggest that radiation-induced senescence, while WIN2 induced classical growth arrest and the WIN2/IR combination produced parallel mechanisms of both senescent growth arrest and classical growth arrest. Taken together, these findings raise the possibility that aminoalkylindole compounds targeting a novel site of action represents a potential strategy to augment the effectiveness of radiation treatment in breast cancer.

Quatorze femmes canadiennes meurent chaque jour du cancer du sein. Le cancer du sein triple-négatif (CSTN) détient un mauvais pronostic De nombreux efforts sont fournis afin d'offrir à ces patientes des traitements ciblés, comme les inhibiteurs de poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) afin d’améliorer leur survie et de minimiser la toxicité liée à la chimiothérapie. Le sous-groupe de CSTN qui pourrait bénéficier des PARPi reste à être identifié. De plus, différentes stratégies d'administration des PARPi et de la chimiothérapie pourraient améliorer leur efficacité thérapeutique tout en diminuant la toxicité. Nous avons précédemment dérivé une signature génétique de 63 gènes prédisant la réponse aux PARPi avec une précision globale élevée. Nos objectifs sont 1) d'évaluer les implications cliniques de la signature génétique; et 2) de déterminer la séquence optimale d'administration du talazoparib et du carboplatin in vivo en cancer du sein triple-négatif BRCAWT. D'abord, nous avons évalué la fréquence mutationnelle des 63 gènes dans différents contextes cliniques. Deux bases de données publiques furent utilisées. Puis, nous avons comparé trois cohortes de xénogreffes orthotopiques: A) talazoparib en premier, combiné au carboplatin le jour 3; carboplatin en premier suivi du talazoparib B) un jour après; et C) sept jours après. La fréquence mutationnelle des 63 gènes était élevée chez les tumeurs luminales B et celles de mauvais pronostic. Les patientes luminales B mutées avaient une moindre survie que les patientes non mutées. Aussi, l'inhibition tumorale et métastatique était similaire pour les cohortes A et B, cependant la cohorte B avait moins de toxicité. Les PARPi pourraient avoir un rôle chez les tumeurs luminales B et celles de mauvais pronostic. Deuxièmement, le prétraitement avec le carboplatin semble améliorer la sensibilité au talazoparib et diminuer la toxicité. / Fourteen Canadian women die every day from breast cancer. Triple-negative breast cancer (TNBC) has a poor prognosis. Numerous efforts are made to offer these patients targeted therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) to improve survival and minimize chemotherapy-related toxicity. It is not well understood which subset of TNBC patients will benefit from PARPi; and if different sequencing strategies of PARPi and chemotherapy can improve therapeutic efficacy and decrease toxicity. We previously derived a 63-gene signature predicting response to PARPi with a high overall accuracy. Our objectives are 1) to evaluate the clinical implications of the 63-gene signature; and 2) to determine the optimal sequence of administration of talazoparib and carboplatin in vivo in BRCAWT TNBC. First, we evaluated the mutational frequency of the 63 genes in different clinical settings using two publically-available datatsets. Second, we compared three cohorts of orthotopic xenografts: A) talazoparib first, combined with carboplatin on day 3; carboplatin first, followed by talazoparib B) one day later; and C) seven days later. We found that the mutational frequency was high in breast cancer subtypes of poor prognosis. Mutated luminal B patients had a lower survival than non-mutated patients. We also found that tumoral and metastatic inhibition were similar between cohorts A and B, but cohort B had less toxicity. In conclusion, there is potential for PARPi efficacy in luminal B and poor prognosis tumors. Second, pretreatment with carboplatin may be an effective approach with less toxicity.