Browsing by Subject "Targeted therapies"

Now showing 1 - 5 of 5
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    Expression of the BAD pathway is a marker of triple-negative status and poor outcome
    (Nature Research, 2019-11-25) Boac, Bernadette M.; Abbasi, Forough; Ismail-Khan, Roohi; Xiong, Yin; Siddique, Atif; Park, Hannah; Han, Mingda; Saeed-Vafa, Daryoush; Daryoush, Daryoush; Henry, Brendon; Pena, M. Juliana; McClung, E. Clair; Robertson, Sharon E.; Todd, Sarah L.; Lopez, Alex; Sun, Weihong; Apuri, Susmitha; Lancaster, Johnathan M.; Berglund, Anders E.; Magliocco, Anthony M.; Marchion, Douglas C.; Obstetrics and Gynecology, School of Medicine
    Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.
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    Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia
    (Springer Nature, 2022-03-03) Lee, Miyoung; Hamilton, Jamie A.G.; Talekar, Ganesh R.; Ross, Anthony J.; Michael, Langston; Rupji, Manali; Dwivedi, Bhakti; Raikar, Sunil S.; Boss, Jeremy; Scharer, Christopher D.; Graham, Douglas K.; DeRyckere, Deborah; Porter, Christopher C.; Henry, Curtis J.; Pediatrics, School of Medicine
    The incidence of obesity is rising with greater than 40% of the world’s population expected to be overweight or suffering from obesity by 2030. This is alarming because obesity increases mortality rates in patients with various cancer subtypes including leukemia. The survival differences between lean patients and patients with obesity are largely attributed to altered drug pharmacokinetics in patients receiving chemotherapy; whereas, the direct impact of an adipocyte-enriched microenvironment on cancer cells is rarely considered. Here we show that the adipocyte secretome upregulates the surface expression of Galectin-9 (GAL-9) on human B-acute lymphoblastic leukemia cells (B-ALL) which promotes chemoresistance. Antibody-mediated targeting of GAL-9 on B-ALL cells induces DNA damage, alters cell cycle progression, and promotes apoptosis in vitro and significantly extends the survival of obese but not lean mice with aggressive B-ALL. Our studies reveal that adipocyte-mediated upregulation of GAL-9 on B-ALL cells can be targeted with antibody-based therapies to overcome obesity-induced chemoresistance.
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    Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL
    (Springer Nature, 2019-11-26) Rodriguez, Sonia; Abundis, Christina; Boccalatte, Francesco; Mehrotra, Purvi; Chiang, Mark Y.; Yui, Mary A.; Wang, Lin; Zhang, Huajia; Zollman, Amy; Bonfim-Silva, Ricardo; Kloetgen, Andreas; Palmer, Joycelynne; Sandusky, George; Wunderlich, Mark; Kaplan, Mark H.; Mulloy, James C.; Marcucci, Guido; Aifantis, Iannis; Cardoso, Angelo A.; Carlesso, Nadia; Medicine, School of Medicine
    Timed degradation of the cyclin-dependent kinase inhibitor p27Kip1 by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27Kip1 pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).
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    Treatment Strategies for Non-Small Cell Lung Cancer with Common EGFR Mutations: A Review of the History of EGFR TKIs Approval and Emerging Data
    (MDPI, 2023-01-19) Marin-Acevedo, Julian A.; Pellini, Bruna; Kimbrough, ErinMarie O.; Hicks, J. Kevin; Chiappori, Alberto; Medicine, School of Medicine
    The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations.
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    What Have We Learned from Molecularly Informed Clinical Trials on Thymomas and Thymic Carcinomas-Current Status and Future Directions?
    (MDPI, 2024-01-18) Maniar, Rohan; Loehrer, Patrick J.; Medicine, School of Medicine
    Thymic epithelial tumors (TETs), which include thymomas and thymic carcinomas, are a rare, heterogeneous group of malignancies that originate from the thymus gland. As an important organ of immune cell development, thymic tumors, particularly thymomas, are often associated with paraneoplastic autoimmune disorders. The advances in targeted therapies for both solid and hematologic malignancies have resulted in improved patient outcomes, including better and more durable efficacy and improved toxicity. Targeted therapies have also been investigated in the treatment of TETs, though the results have largely been modest. These have included somatostatin-receptor-targeting therapies, KIT- and EGFR-directed tyrosine kinase inhibitors, epigenetic modulators, anti-angiogenesis agents, and agents targeting the cell proliferation and survival pathways and cell cycle regulators. Numerous investigated treatments have failed or underperformed due to a lack of a strong biomarker of efficacy. Ongoing trials are attempting to expand on previous experiences, including the exploration of effective drugs in early-stage disease. Novel combination therapy strategies are also undergoing evaluation, with the goal of augmenting efficacy and understanding the toxicity while expanding the biomarkers of efficacy and safety. With advances in technology to improve target identification and drug delivery, old targets may become new opportunities, and the subsequently developed drugs may find their place in the treatment of thymic tumors.