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Developing and Validating Prognostic Models of Clinical Outcomes
Published in Susan Halabi, Stefan Michiels, Textbook of Clinical Trials in Oncology, 2019
Susan Halabi, Lira Pi, Chen-Yen Lin
We utilize CALGB 90401, a phase III clinical trial in advanced prostate cancer to illustrate how LASSO and ALASSO were utilized to identify the prognostic factors of the primary endpoint overall survival [8]. Our goal was to select the best prognostic model of overall survival from all sets of candidate models. Because we were in a data-rich situation, we used a rigorous statistical approach to meet this objective as described by Hastie et al. [54] Figure 17.1 presents our overall strategy for the model development and validation. We needed to estimate the performance of all the models and choose the best one. Second, we needed to assess the performance of the final chosen model by estimating the prediction error. It is difficult to give a general rule on how best to split the data [54]. We therefore randomly divided the 1,050 men in CALGB 90401 in a 2:1 allocation ratio to the training (n = 705) and validation (n = 345) sets. Using the training dataset, we fit models from all sets of potential models of overall survival. Using the validation dataset, the prediction error was estimated for all sets of models for overall survival. The final step was to use the testing dataset (Enthuse trial) as an independent dataset for external validation [55]. The Enthuse trial randomized 1,052 men to docetaxel and prednisone with and without zibotentan [55]. Using the testing dataset, we were able to estimate the prediction error on new patients independent of the development phase.
A patent review of pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Abbas Hassan, Abid Hussain Khan, Faiza Saleem, Haseen Ahmad, Khalid Mohammed Khan
After cardiovascular diseases, cancer is one of the most unsettling and life-threatening diseases in the world [18]. Common methods of treating cancer include radiotherapy, chemotherapy, and immunologic treatment [19]. Chemotherapy is an efficient method for the treatment of various types of cancers. The main issue related to chemotherapy is the associated side effects affecting healthy cells. There remains a need for more effective and selective anti-cancer drugs that have little to no cytotoxicity on healthy human cells. Anticancer activity is shown by inhibiting different growth factors and enzymes [20]. Zibotentan is an oxadiazole-based drug that is under clinical research and development by AstraZeneca, paving the way for the development of potent and non-toxic anti-cancer agents. The interest in oxadiazole core structure was reported by Yonova et al. for compounds 1 and 2 as anticancer agents shown in Figure 2 [21]. The anti-cancer activity was screened against breast cancer cell lines (MCF-7) and normal breast cell lines (MCF-10A). Thioether 1 containing trimethoxy phenyl substituent performed poorly, while the phenyl analog compound 2 was found to be a more potent cell proliferation inhibitor (EC50 = 7.9 µM).
Design, synthesis and in vitro antiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Zohor Mohammad Mahdi Alzhrani, Mohammad Mahboob Alam, Thikryat Neamatallah, Syed Nazreen
Thiazolidinediones (glitazones) are insulin sensitisers used for type II diabetes treatment. They are high-affinity ligands of PPAR-γ, which alleviates insulin resistance and effectively improves plasma glucose levels.10–11 Beside hypoglycaemic agents, thiazolidinedione derivatives are reported as anti-inflammatory,12 antimicrobial13 and anticancer agents.14–16 It has been mentioned that compounds which activate PPAR-γ might lead to differentiation induction of cancer cells.17 For example, a TZD analogue, efatutazone (CS-7017) is a potent PPAR-γ full agonist as well as a cancer differentiation-inducing agent.18 PPAR-γ agonists are reported to inhibit components of the insulin growth factor 1 (IGF1) pathway and modulate the activity of AMP-activated protein kinase (AMPK) pathway to reduce cancer risk.19,20 Thiazolidinediones derivatives have exerted anticancer effects by various mechanism of action viz. by inhibiting PI3K-α,21 blockade of the Raf/MEK/ERK and PI3K/Akt signalling pathways.22 On the other hand, 1,3,4-oxadiazoles are promising candidates in medicinal chemistry due to its wide applications. Zibotentan (ZD4054) containing 1,3,4-oxadiazole pharmacophore is an orally available selective antagonist of the ET-A receptor with potential antineoplastic effect for the treatment of various type of cancers.23,24 Recently, novel 1,3,4-oxadiazole bearing thioether derivatives has been reported as potential TS inhibitors.25