Browsing by Subject "Sirolimus"

Now showing 1 - 5 of 5
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    Critical Role of the mTOR Pathway in Development and Function of Myeloid-Derived Suppressor Cells in lal−/− Mice
    (Elsevier B.V., 2014-02) Ding, Xinchun; Du, Hong; Yoder, Mervin C.; Yan, Cong; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Lysosomal acid lipase (LAL) is essential for the hydrolysis of cholesteryl esters and triglycerides to generate cholesterol and free fatty acids in cellular lysosomes. Ablation of the lal gene (lal−/−) systemically increased expansion of cluster of differentiation molecule 11b (CD11b), lymphocyte antigen 6G (Ly6G) myeloid-derived suppressor cells (MDSCs) that caused myeloproliferative neoplasms in mice. Study of lal−/− bone marrow Ly6G+ MDSCs via transcriptional profiling showed increases in mammalian target of rapamycin (mTOR) signaling pathway transcripts. Injection of mTOR pharmacologic inhibitors into lal−/− mice significantly reduced bone marrow myelopoiesis and systemic CD11b+Ly6G+ cell expansion. Rapamycin treatment of lal−/− mice stimulated a shift from immature CD11b+Ly6G+ cells to CD11b+ single-positive cells in marrow and tissues and partially reversed the increased cell proliferation, decreased apoptosis, increased ATP synthesis, and increased cell cycling of bone marrow CD11b+Ly6G+ cells obtained from lal−/− mice. Pharmacologic and siRNA suppression of mTOR, regulatory-associated protein of mTOR, rapamycin-insensitive companion of mTOR, and Akt1 function corrected CD11b+Ly6G+ cell in lal−/− mice development from Lin− progenitor cells and reversed the immune suppression on T-cell proliferation and function in association with decreased reactive oxygen species production, and recovery from impairment of mitochondrial membrane potential compared with control mutant cells. These results indicate a crucial role of LAL-regulated mTOR signaling in the production and function of CD11b+Ly6G+ cells. The mTOR pathway may serve as a novel target to modulate the emergence of MDSCs in those pathophysiologic states in which these cells play an immunosuppressive role.
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    Intravitreal sirolimus for persistent, exudative age-related macular degeneration: a Pilot Study
    (BMC, 2021-02-16) Minturn, Robert J.; Bracha, Peter; Klein, Margaret J.; Chhablani, Jay; Harless, Ashley M.; Maturi, Raj K.; Ophthalmology, School of Medicine
    Background and objective: To evaluate the safety and efficacy of intravitreal sirolimus for persistent, exudative age-related macular degeneration (AMD). Methods: This institutional review board approved, registered (NCT02357342), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative Age-related macular degeneration compared intravitreal sirolimus monotherapy (every 2 months) versus monthly anti-vascular endothelial growth factor (VEGF) over six months. Results: 20 subjects were randomized to each arm of the trial. Upon completion of the trial 20 patients were analyzed in the control (anti-vascular endothelial growth factor) group and 17 patients were analyzed in the treatment (sirolimus) group. On average, subjects had 33 previous anti-VEGF injections prior to entry. The primary end-point, mean central subfield thickness (CST), increased by 20 µm in the anti-vascular endothelial growth factor group and decreased by 40 µm in the sirolimus group (p = 0.03). Visual acuity outcomes were similar between groups. Serious ocular adverse events in the sirolimus group included one subject each with anterior uveitis, central retinal artery occlusion and subretinal hemorrhage. Conclusion: Monotherapy with intravitreal sirolimus for subjects with persistent, exudative age-related macular degeneration appears to have a limited positive anatomic benefit. The presence of adverse events in the experimental group merits further evaluation, potentially as an adjuvant therapy. Trial registration This trial was registered with the clinicaltrials.gov, NCT02357342, and was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.
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    Intravitreal sirolimus with adjunct aflibercept versus aflibercept monotherapy for persistent, exudative age-related macular degeneration: a pilot study
    (BMC, 2023-01-05) Rowe, Lucas W.; Minturn, Robert J.; Burgett, Lauren A.; Bracha, Peter; Maturi, Raj K.; Ophthalmology, School of Medicine
    Background: To determine the safety and efficacy of intravitreal sirolimus and adjunct aflibercept in subjects with persistent, exudative age-related macular degeneration despite previous intravitreal anti-vascular endothelial growth factor (VEGF) treatment. Methods: This institutional review board approved, registered (NCT02732899), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative age-related macular degeneration compared alternating monthly intravitreal sirolimus and aflibercept (combination) versus aflibercept monotherapy (control) every 2 months over the course of 36 weeks. The primary measure of efficacy in the study was the mean change in central subfield thickness. Results: 20 subjects were enrolled in the study, with 10 subjects assigned to each treatment group. Subjects had an average of 38 previous anti-VEGF injections. Mean central subfield thickness decreased in the combination group by 54.0 μm compared to 0.1 μm in the control group (p = 0.28). Mean visual acuity improved in the combination group by 2.5 ETDRS letters versus 0.8 ETDRS letters in the control group (p = 0.42). There were no serious ocular adverse events in either group; however, there were three serious systemic events in the combination group, including hospitalizations due to pancreatitis, pneumonia, and worsening hypertension. Conclusion: There was no statistically significant difference in the mean central subfield thickness change between the combination and control groups. However, intravitreal sirolimus with adjunct aflibercept did appear to have potential anatomical benefits as a treatment for persistent, exudative age-related macular degeneration and requires further investigation with a larger cohort to better understand the potential risks and benefits.
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    Role of bone-anabolic agents in the treatment of breast cancer bone metastases
    (BioMed Central, 2014-12-31) Suvannasankha, Attaya; Chirgwin, John M.; Department of Medicine, IU School of Medicine
    Skeletal metastases are an incurable complication afflicting the majority of patients who die from advanced breast cancer. They are most often osteolytic, characterized by net bone destruction and suppressed new bone formation. Life expectancy from first diagnosis of breast cancer bone metastases is several years, during which time skeletal-related events - including pain, fracture, hypercalcemia, and spinal cord compression - significantly degrade quality of life. The bone marrow niche can also confer hormonal and chemo-resistance. Most treatments for skeletal metastases target bone-destroying osteoclasts and are palliative. Recent results from the Breast cancer trials of Oral Everolimus-2 trial suggest that agents such as the mammalian target of rapamycin inhibitor everolimus may have efficacy against breast cancer bone metastases in part via stimulating osteoblasts as well as by inhibiting tumor growth. Selective estrogen receptor modulators similarly inhibit growth of estrogen receptor-positive breast cancers while having positive effects on the skeleton. This review discusses the future role of bone-anabolic agents for the specific treatment of osteolytic breast cancer metastases. Agents with both anti-tumor and bone-anabolic actions have been tested in the setting of multiple myeloma, a hematological malignancy that causes severe osteolytic bone loss and suppression of osteoblastic new bone formation. Stimulation of osteoblast activity inhibits multiple myeloma growth - a strategy that might decrease breast cancer burden in osteolytic bone metastases. Proteasome inhibitors (bortezomib and carfilzomib) inhibit the growth of myeloma directly and are anabolic for bone. Drugs with limited anti-tumor activity but which are anabolic for bone include intermittent parathyroid hormone and antibodies that neutralize the WNT inhibitors DKK1 and sclerostin, as well as the activin A blocker sotatercept and the osteoporosis drug strontium ranelate. Transforming growth factor-beta inhibitors have little tumor antiproliferative activity but block breast cancer production of osteolytic factors and are also anabolic for bone. Some of these treatments are already in clinical trials. This review provides an overview of agents with bone-anabolic properties, which may have utility in the treatment of breast cancer metastatic to the skeleton.
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    The Combined Inhibition of SREBP and mTORC1 Signaling Synergistically Inhibits B‐Cell Lymphoma
    (Wiley, 2024) Zhu, Zhenhan; Jiang, Wenxia; Zhou, Jiehao; Maldeney, Alexander Robert; Liang, Jingru; Yang, Jing; Luo, Wei; Microbiology and Immunology, School of Medicine
    Background: The sterol regulatory element-binding protein (SREBP) pathway is essential for maintaining sterol homeostasis during B cell activation and germinal center B cell proliferation. However, its potential as a therapeutic target to treat B-cell lymphoma remains unclear. Methods: We examined SREBP protein expression in human B-cell lymphoma samples using immunohistochemistry. Additionally, we conducted in vitro studies using SREBP signaling inhibitors in combination with rapamycin to assess their effects on cell proliferation and lipid metabolism in B-cell lymphoma cells. Results: Our analysis revealed high levels of SREBP2 protein expression in human B-cell lymphoma samples. Inhibiting SREBP signaling or its downstream target HMG-CoA reductase (HMGCR) with Fatostatin or Simvastatin effectively suppressed B-cell lymphoma cell proliferation. However, B-cell lymphoma cells responded to statin treatment by activating the mTORC1-pS6 pathway, suggesting a compensatory mechanism to overcome statin-induced cell cycle arrest. Combining low-dose statin treatment with the mTOR inhibitor rapamycin produced a synergistic effect, significantly inhibiting B-cell lymphoma proliferation, cell cycle progression, and lipid raft formation. Conclusions: These results highlight the potential of a combined therapeutic approach targeting both SREBP and mTORC1 as a novel strategy for treating B-cell lymphoma.