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Mitigation of Cancer Associated Effects Using Combination Therapies
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- Author / Creator
- Luna, Ismat Zerin
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Cisplatin contributes to the approximately 80% five-year survival rate for childhood cancer patients. Despite its effectiveness, cisplatin causes several toxicities, particularly ototoxicity which manifests as permanent hearing loss. To date, limited success in otoprotection without compromised anticancer effect has been observed in clinical trials. Development of effective therapies for preventing hearing loss is therefore of primary importance. Studies from the lab of Dr. Amit Bhavsar (MMI) identified a significant and biologically plausible association between cisplatin induced ototoxicity (CIO) susceptibility and expression of Toll-like receptor 4 (TLR4), an innate immune receptor protein. It is found that cisplatin treatment induces TLR4 expression and deletion of TLR4 causes decrease in CIO. From these data we identified TLR4 protein as a target to mitigate CIO. Starting with the reference hit TAK-242, we used proven synthetic methods to probe the significance of various structural motifs through selective chemical modification of the TAK-242 scaffold in order to optimize binding to TLR4 as an otoprotection strategy. Robust in vitro cisplatin “ototoxicity” platforms were developed to assess the efficacy of synthesized TLR4 inhibitors in reducing cisplatin “ototoxicity” phenotypes. Promising small molecule candidates were tested in a zebrafish CIO model in vivo. Two of the new TAK-242 based derivatives were shown to have a potent inhibitory effect on CIO in both in vitro and in vivo experiments. We carried out in silico docking studies with the synthesized inhibitors and TLR4 protein to interpret molecular interaction and refine the preferred structural features for effective inhibition.
A separate cancer-related project was focused on developing inhibitors of breast cancer (BrCa) metastasis. The most aggressive form of BrCa is the triple-negative phenotype (TNBC) which does not express estrogen receptors, progesterone receptors and human epidermal growth factor receptors. Treatment of TNBC is very difficult as it is refractory to the present BrCa treatment regimens. This highlights the lack of effective treatment strategies for TNBC and the need for innovative treatment approaches. The in vivo data from Dr. Persad lab (Department of Pediatrics) showed that the herbicide nitrofen efficiently blocks metastatic tumor growth, especially to the liver. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which could allow modulation of polarity. In vitro anti-invasive activity of nitrofen analogues were evaluated which showed three of the nitrofen analogues significantly reduced invasive potential of TNBC cells. Further in vitro studies suggested that these inhibitory activities of nitrofen and its analogues are not due to cytotoxicity, but rather are due to impairment of invasive capacity of the cells. -
- Graduation date
- Fall 2022
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.