A5018121404- PI3K/AKT/mTOR signaling in cancer
- Protein Degradation and Inhibitors
- Circadian rhythm and melatonin
- Multiple Myeloma Research and Treatments
- Histone Deacetylase Inhibitors Research
- Cell death mechanisms and regulation
- Receptor Mechanisms and Signaling
- Cancer Genomics and Diagnostics
- Spaceflight effects on biology
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- Pancreatic and Hepatic Oncology Research
- Metabolism, Diabetes, and Cancer
- Chronic Lymphocytic Leukemia Research
- Genetics, Aging, and Longevity in Model Organisms
- Advanced Breast Cancer Therapies
- Estrogen and related hormone effects
- Cancer, Hypoxia, and Metabolism
- Cancer Cells and Metastasis
- Neuroendocrine regulation and behavior
Harvard University
2019-2024
Beth Israel Deaconess Medical Center
2019-2024
Purdue University West Lafayette
2014-2016
Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained stress may cause cell death. The mechanisms by which AMPK dictates death are not fully understood. We report that promoted receptor-interacting 1 (RIPK1) activation mediated TRAIL receptors, whereas inhibited RIPK1 phosphorylation at Ser
More than 50% of human tumors display hyperactivation the serine/threonine kinase AKT. Despite evidence clinical efficacy, therapeutic window current generation AKT inhibitors could be improved. Here, we report development a second-generation degrader, INY-05-040, which outperformed catalytic inhibition with respect to cellular suppression AKT-dependent phenotypes in breast cancer cell lines. A growth screen 288 lines confirmed that INY-05-040 had substantially higher potency our...
Circadian clocks regulate homeostasis and mediate responses to stressors. Lactation is one of the most energetically demanding periods an adult female's life. Peripartum changes occur in almost every organ so dam can support neonatal growth through milk production while maintained. How circadian are involved adaptation lactation currently unknown. The abundance temporal pattern core clock genes' expression were measured suprachiasmatic nucleus, liver, mammary from late pregnant early mice....
A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations PIK3CA , the gene encoding p110α. Preclinical studies have suggested that PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence such correlation demonstrated human tumors. In two independent cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional...
Circadian clocks influence virtually all physiological processes, including lactation. Here, we investigate the role of CLOCK gene in regulation mammary epithelial cell growth and differentiation. Comparison morphology late-pregnant wild-type ClockΔ19 mice, showed that gland development was negatively impacted by genetic loss a functional timing system. To understand whether these effects were due, part, to function gland, mouse line, HC11, transfected with short hairpin RNA targeted Clock...
SUMMARY The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half tumors exhibiting aberrant AKT activation. Although potent small molecule inhibitors have entered clinical trials, robust and durable therapeutic responses not been observed. As an alternative strategy to target AKT, we report development INY-03-041, a pan-AKT degrader consisting ATP-competitive inhibitor GDC-0068 conjugated lenalidomide, recruiter E3 ubiquitin ligase substrate...
Abstract The high frequency of PI3K pathway alterations in cancer has motivated numerous efforts to develop drugs targeting this network. Although many potent and selective inhibitors have been developed evaluated preclinical models, their progress clinical approval limited. Here we discuss the pressing need improved biomarker strategies guide patient selection improve assessment responses address unresolved issues surrounding efficacy tolerability these compounds patients with cancer.
Changes in modern lifestyle such as lack of sleep, stress, and light exposure late at night are associated with increased rates breast cancer. Most physiological processes, including growth, development, metabolism, controlled by circadian clocks. Circadian clocks respond to environmental cues synchronize internal thus, the disruption this system may be responsible for connection. The master clock brain coordinates peripheral located every tissue body, mammary gland, core component CLOCK...
Abstract Over 50% of human tumors display hyperactivation the serine/threonine kinase AKT. Despite evidence clinical efficacy, there remains scope to improve upon therapeutic window current generation AKT inhibitors. Here we report development a second-generation degrader, INY-05-040, which outperformed catalytic inhibition with respect cellular suppression AKT-driven phenotypes in breast cancer cell lines. A systematic growth screen across 288 lines confirmed substantially higher potency...