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Item Bioinformatics and Pharmacogenomics in Drug Discovery and Development- a Socio-economic Perspective(2006-07-26T14:37:43Z) Anyanwu, Chukwuma Eustace; Jones, JosetteA plethora of genomic and proteomic information was uncovered by the U.S Human Genome Project (HGP) – mostly by means of bioinformatics tools and techniques. Despite the impact that bioinformatics and pharmacogenomics were projected to have in the drug discovery and development process, the challenges facing the pharmaceutical industry, such as the high cost and the slow pace of drug development, appear to persist. Socio-economic barriers exist that mitigate the full integration of bioinformatics and pharmacogenomics into the drug discovery and development process, hence limiting the desired and expected effects.Item Drug Development for Cystic Fibrosis(Wiley, 2021-02) Sanders, Don; Chmiel, James; Pediatrics, School of MedicineThe first regulatory approval for a drug developed specifically for cystic fibrosis (CF) occurred in 1993, and since then, several other drugs have been approved. Median predicted survival in people with CF in the United States has increased from approximately 30 years to 44.4 years over that same period. Highly effective modulators of the cystic fibrosis transmembrane conductance regulator became available to approximately 90% of people with CF ages 12 years and older in the United States in 2019 and in Europe in 2020. These transformative therapies will surely reduce morbidity and further extend longevity. The drug development pipeline is filled with therapies that address most aspects of CF disease. As survival and CF therapies advance, and the complexity of CF care increases, the process of drug development has become more sophisticated. In addition, detecting meaningful changes in outcome measures has become more difficult as the health status of people with CF improves. Innovative approaches are required to continue to advance drug development in CF. This review provides a general overview of drug development from the preclinical phase through Phase IV. Special considerations with respect to CF are integrated into the discussion of each phase of drug development. As CF care evolves, drug development must continue to evolve as well, until a one-time cure is available to all people with CF.Item Harnessing Compensatory Pathways and Acquired Resistance in Treating Triple-Negative Breast Cancer(2024-08) Solzak, Jeffrey Peter; Schneider, Bryan P.; Radovich, Milan; Nephew, Kenneth P.; Palkowitz, Alan; Herbert, Brittney-SheaTriple-negative breast cancer (TNBC) is defined by the absence of estrogen-receptor (ER), progesterone-receptor (PR), and human epidermal growth factor receptor 2 (HER2) over-expression. While TNBC comprises a minority of breast cancer cases, about 15%, it results in a disproportionally higher rate of mortality compared to hormone positive breast cancers. Compared to individuals with ER and HER2 positive disease, individuals with TNBC will have a higher incidence of visceral metastasis, a higher likelihood of relapse within the first three years after chemotherapy and surgery, and a shorter overall survival after the onset of metastatic disease. Despite the recent approvals of targeted agents, including: immune checkpoint inhibition using pembrolizumab, the TROP2 antibody drug conjugate (ADC) sacituzumab govitecan, and PARP inhibitors for germline BRCA-mutated tumors, cytotoxic chemotherapy remains the mainstay treatment for metastatic TNBC. To identify novel targets that could potentially be harnessed for therapeutic combinations, we utilized a strategic method by analyzing compensatory genomic and transcriptomic responses to targeted therapy. We demonstrate this herein, by identifying a novel combination targeting the PI3K & Wnt pathways that elicited clinical efficacy in a Phase I clinical trial. We further build on our hypothesis by also studying real-world evidence to identify novel resistance mechanisms in TNBC patients treated with the TROP2 ADC Sacituzumab govitecan. Our data suggest that the comparison of compensatory mechanisms before and after treatment can potentially inform efficacious therapeutic decision-making. In summation, with these data presented, we provide opportunities for furthering the therapeutic landscape to give patients with this dreadful disease more options in the clinical setting.Item Hydrocephalus: historical analysis and considerations for treatment(Springer, 2022) Hochstetler, Alejandra; Raskin, Jeffrey; Blazer-Yost, Bonnie L.; Biology, School of ScienceHydrocephalus is a serious condition that affects patients of all ages, resulting from a multitude of causes. While the etiologies of hydrocephalus are numerous, many of the acute and chronic symptoms of the condition are shared. These symptoms include disorientation and pain (headaches), cognitive and developmental changes, vision and sleep disturbances, and gait abnormalities. This collective group of symptoms combined with the effectiveness of CSF diversion as a surgical intervention for many types of the condition suggest that the various etiologies may share common cellular and molecular dysfunctions. The incidence rate of pediatric hydrocephalus is approximately 0.1–0.6% of live births, making it as common as Down syndrome in infants. Diagnosis and treatment of various forms of adult hydrocephalus remain understudied and underreported. Surgical interventions to treat hydrocephalus, though lifesaving, have a high incidence of failure. Previously tested pharmacotherapies for the treatment of hydrocephalus have resulted in net zero or negative outcomes for patients potentially due to the lack of understanding of the cellular and molecular mechanisms that contribute to the development of hydrocephalus. Very few well-validated drug targets have been proposed for therapy; most of these have been within the last 5 years. Within the last 50 years, there have been only incremental improvements in surgical treatments for hydrocephalus, and there has been little progress made towards prevention or cure. This demonstrates the need to develop nonsurgical interventions for the treatment of hydrocephalus regardless of etiology. The development of new treatment paradigms relies heavily on investment in researching the common molecular mechanisms that contribute to all of the forms of hydrocephalus, and requires the concerted support of patient advocacy organizations, government- and private-funded research, biotechnology and pharmaceutical companies, the medical device industry, and the vast network of healthcare professionals.Item Indiana CTSI Preclinical Innovation Think Tank Program(Association for Clinical and Translational Sciences, 2022-04-21) Portonovo, Padma; Garcia, Kara; Moe, SharonThe skills and knowledge required for successful commercialization of new technologies (intellectual property protection, SBIR/STTR funding, and startup creation) are very different than those for traditional academic research (scientific publication and R01-style grant funding). The Indiana CTSI Think Tank Program is designed to provide early guidance to academic and clinical investigators interested in advancing their discoveries to the market. The program is open to investigators from Indiana University (IU), Purdue University, or the University of Notre Dame; and includes a pool of advisors across these universities and industry around the state to provide investigators with a wide range of expertise and perspectives.Item Molecular targets of alcohol action: translational research for pharmacotherapy development and screening.(Elsevier, 2011) Gorini, Giorgio; Bell, Richard L.; Mayfield, R. Dayne; Department of Psychology, School of ScienceAlcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented.Item Molecular Understanding and Modern Application of Traditional Medicines: Triumphs and Trials(2008-08-12) Corson, Timothy W.; Crews, Craig MTraditional medicines provide fertile ground for modern drug development, but first they must pass along a pathway of discovery, isolation, and mechanistic studies before eventual deployment in the clinic. Here, we highlight the challenges along this route, focusing on the compounds artemisinin, triptolide, celastrol, capsaicin, and curcumin.Item Proteomic profiling of salivary gland after nonviral gene transfer mediated by conventional plasmids and minicircles(2014-04) Geguchadze, Ramaz; Wang, Zhimin; Zourelias, Lee; Perez-Riveros, Paola; Edwards, Paul C.; Machen, Laurie; Passineau, Michael JIn this study, we compared gene transfer efficiency and host response to ultrasound-assisted, nonviral gene transfer with a conventional plasmid and a minicircle vector in the submandibular salivary glands of mice. Initially, we looked at gene transfer efficiency with equimolar amounts of the plasmid and minicircle vectors, corroborating an earlier report showing that minicircle is more efficient in the context of a physical method of gene transfer. We then sought to characterize the physiological response of the salivary gland to exogenous gene transfer using global proteomic profiling. Somewhat surprisingly, we found that sonoporation alone, without a gene transfer vector present, had virtually no effect on the salivary gland proteome. However, when a plasmid vector was used, we observed profound perturbations of the salivary gland proteome that compared in magnitude to that seen in a previous report after high doses of adeno-associated virus. Finally, we found that gene transfer with a minicircle induces only minor proteomic alterations that were similar to sonoporation alone. Using mass spectrometry, we assigned protein IDs to 218 gel spots that differed between plasmid and minicircle. Bioinformatic analysis of these proteins demonstrated convergence on 68 known protein interaction pathways, most notably those associated with innate immunity, cellular stress, and morphogenesis.