Ogsiveo (nirogacestat)
Research Synopsis
- - Ogsiveo (nirogacestat) is a gamma-secretase inhibitor with potential uses in treating both Alzheimer’s disease and various cancers, particularly those linked to Notch signaling pathways.
- - Research indicates that gamma-secretase is crucial in producing amyloid-beta peptides, which are implicated in Alzheimer's disease; inhibiting this enzyme may offer new therapeutic avenues.
- - Nirogacestat (PF-03084014) has shown effectiveness in reducing Notch intracellular domain levels, thereby inducing cell cycle arrest and apoptosis in T-cell acute lymphoblastic leukemia (T-ALL) models.
- - In preclinical studies, PF-03084014 effectively decreased amyloid-beta levels in animal models, showcasing its potential in Alzheimer's treatment without the adverse effect of increasing amyloid levels.
- - The compound has demonstrated ability to enhance the effectiveness of other treatments, such as glucocorticoids in T-ALL and docetaxel in prostate cancer, suggesting its role in combination therapy.
- - Biomarker identification for PF-03084014's effectiveness in various cancers, including breast and colorectal cancer, is ongoing, with studies indicating that certain gene expressions can guide treatment responses.
- - Clinical trials have shown that dioses of PF-03084014 up to 220 mg could be safely tolerated in patients, with some exhibiting significant tumor response.
- - Research highlights the need for effective dose-finding studies, as results show promise but often encountered mild to moderate side effects alongside therapeutic benefits.
- - Overall, ongoing studies continue to explore nirogacestat's therapeutic potential and applicability to various malignancies, as well as strategies to mitigate its side effects.
- - Future research directions include exploring the full extent of the drug's efficacy, safety, and biomarker identification in patient populations, thus emphasizing its relevance in targeted cancer therapies.
Ogsiveo (nirogacestat)
[Alzheimer's disease treatment by inhibition/modulation of the gamma-secretase activity].
London, UK
2 hours ago
1 Received
- * Gamma-secretase, the enzyme responsible for producing Abeta, is critical to target for potential Alzheimer's therapies but also affects the Notch signaling pathway, complicating drug development.
- * Ongoing research aims to identify drugs that inhibit Abeta production while preserving Notch signaling, with some candidates already in late-phase clinical trials, and the review highlights the necessary future directions for effective Alzheimer's treatments.
$100 - $150
Hourly Rate
Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.
London, UK
2 hours ago
1 Received
- Aberrant Notch signaling is linked to cancer development, particularly in T-cell acute lymphoblastic leukemia (T-ALL), making gamma-secretase a key target for cancer therapy.
- PF-03084014, a selective gamma-secretase inhibitor, effectively reduces the Notch intracellular domain (NICD) levels and inhibits tumor cell growth, leading to cell cycle arrest and apoptosis in T-ALL cell lines.
- Studies also indicated that PF-03084014 has broad antitumor effects in various models while minimizing gastrointestinal toxicity, making it a promising candidate for treating Notch-dependent cancers, and it is currently in phase I clinical trials.
$100 - $150
Hourly Rate
Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.
London, UK
2 hours ago
1 Received
- - PF-3084014 is a new gamma-secretase inhibitor that effectively reduces amyloid-beta (Abeta) production in both whole-cell and cell-free assays, showing an impressive potency with IC(50) values ranging from 1.2 nM to 6.2 nM.
- - In animal studies, PF-3084014 led to significant dose-dependent reductions in brain, cerebrospinal fluid (CSF), and plasma levels of Abeta in Tg2576 mice and guinea pigs, indicating promising effects on Abeta dynamics.
- - Unlike other gamma-secretase inhibitors, PF-3084014 did not increase Abeta levels in various media and preferentially decreased Abeta1-40 relative to Abeta1-
$100 - $150
Hourly Rate
Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014.
London, UK
2 hours ago
1 Received
- - A new group of tetralin-based amino imidazoles was developed by modifying existing phenyl acetic acid compounds, leading to promising candidates.
- - The best candidates showed strong effects on decreasing brain Aβ levels in guinea pigs, indicating potential therapeutic benefits without harming B-cells.
- - The most effective compound identified, 14f (PF-3084014), was chosen for further clinical trials after optimizing dosage to target brain Aβ concentrations.
$100 - $150
Hourly Rate
Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia.
London, UK
2 hours ago
1 Received
- T-cell acute lymphoblastic leukemias (T-ALL) are aggressive blood cancers linked to NOTCH1 mutations, and researchers are exploring γ-secretase inhibitors (GSI) like PF-03084014 as potential treatments.
- The study found that combining PF-03084014 with glucocorticoids resulted in a strong antileukemic effect in both lab models and patient samples, enhancing the effectiveness of the treatment.
- Additionally, this combination not only reduced tumor size but also mitigated gastrointestinal side effects caused by PF-03084014, highlighting its potential for treating glucocorticoid-resistant T-ALL.
$100 - $150
Hourly Rate
Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.
London, UK
2 hours ago
1 Received
- The study aimed to evaluate the effectiveness of PF-03084014 in breast cancer treatment using xenograft models and identify biomarkers for patient selection.
- In laboratory tests, PF-03084014 demonstrated its ability to inhibit cancer cell migration and tumor growth, while also reducing metastasis and improving apoptosis in live models.
- Despite showing significant antitumor effects in many models, the study found that Notch pathway gene expressions did not reliably predict the drug's effectiveness, though certain target genes could serve as better indicators for treatment response in breast cancer patients.*
$100 - $150
Hourly Rate
Synergistic effect of the γ-secretase inhibitor PF-03084014 and docetaxel in breast cancer models.
London, UK
2 hours ago
1 Received
- Notch signaling plays a crucial role in the survival and resistance of breast cancer cells, particularly in triple-negative breast cancer (TNBC).
- The study investigated the combination of PF-03084014 and docetaxel, revealing that PF-03084014 enhances the effectiveness of docetaxel in shrinking tumors and combating resistance in various cancer models.
- PF-03084014 works by altering key cellular pathways, preventing cancer cells from becoming more aggressive and promoting tumor initiation, thus showing promise for improving taxane-based treatments in patients.
$100 - $150
Hourly Rate
Predicting pharmacokinetic profiles using in silico derived parameters.
London, UK
2 hours ago
1 Received
- Human pharmacokinetic (PK) predictions are essential for evaluating potential drugs, focusing on important metrics like clearance and plasma concentration profiles.
- While traditional methods often require in vivo data, successful predictions can also be made using in vitro or in silico data through advanced modeling and software like GastroPlus.
- Case studies show that this approach allows accurate PK profile predictions with minimal data, aiding in decisions related to dosing, drug development strategies, and clinical trial designs.
$100 - $150
Hourly Rate
Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer.
London, UK
2 hours ago
1 Received
- Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer with limited treatment options, and aberrant Notch signaling plays a significant role in its progression, leading researchers to test γ-secretase inhibitors like PF-03084014.
- In laboratory studies, PF-03084014 successfully inhibited Notch signaling and worked alongside gemcitabine to induce tumor regression in pancreatic cancer models, while gemcitabine alone was less effective.
- The combination therapy not only reduced cancer stem cell populations but also showed sustained anti-tumor effects and improved outcomes in aggressive models, suggesting that this approach merits further clinical exploration.
$100 - $150
Hourly Rate
Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.
London, UK
2 hours ago
1 Received
- Dysregulation of the Notch pathway is linked to the development of colorectal cancer (CRC), and this study used a patient-derived explant model to test the drug PF-03084014, a γ-secretase inhibitor.
- Sixteen CRC explants were treated with PF-03084014, and researchers used RBPjκ gene knockdown to confirm the drug's specificity for the Notch pathway while evaluating both Notch and Wnt pathways through various methods.
- The results showed that PF-03084014 effectively reduced Notch pathway activity and increased apoptosis in certain CRC tumors, indicating that γ-secretase inhibition could be a promising treatment for specific patients with high Notch and Wnt pathway levels.
$100 - $150
Hourly Rate
Comparison of dynamic contrast-enhanced MR, ultrasound and optical imaging modalities to evaluate the antiangiogenic effect of PF-03084014 and sunitinib.
London, UK
2 hours ago
1 Received
- Noninvasive imaging techniques like high-frequency ultrasound, dynamic contrast-enhanced MRI, and fluorescence molecular tomography were used to monitor how a cancer treatment, γ-secretase inhibitor PF-03084014, affected tumor blood vessels.
- The study found that PF-03084014 led to significant changes in tumor vascular properties, which were linked to the regulation of the Notch signaling pathway and a decrease in vascular function.
- Both PF-03084014 and sunitinib showed similar effects in reducing tumor vascularity, with ultrasound and DCE-MR imaging effectively tracking these changes over time, though FMT imaging did not detect any significant differences.
$100 - $150
Hourly Rate
Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells.
London, UK
2 hours ago
1 Received
- Resistance to anti-estrogen therapies in ERα-positive breast cancers, like those seen in tamoxifen-resistant and estrogen-deprived breast cancer models, involves increased reliance on Notch signalling and changes in cell characteristics known as epithelial to mesenchymal transition (EMT).
- Research showed that endocrine-resistant (ETR) cells not only had elevated Nicastrin and Notch target levels but also switched their Notch signalling preference to Notch4 after developing resistance.
- Targeting the Nicastrin/Notch4 pathway with specific monoclonal antibodies and inhibitors effectively reduced cell migration, invasion, and stem cell-like properties in these resistant cells, highlighting its potential as a therapeutic strategy.
$100 - $150
Hourly Rate
Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program.
London, UK
2 hours ago
1 Received
- PF-03084014 is a γ-secretase inhibitor tested on various pediatric cancer models, both in lab-grown cells and in live tumor implants.
- * In lab tests (in vitro), it showed weak effectiveness, with no cancer cell lines displaying over 50% inhibition.
- * In live tests (in vivo), it impacted survival periods in some tumor models but did not produce clear treatment responses overall.
$100 - $150
Hourly Rate
Intermittent oral coadministration of a gamma secretase inhibitor with dexamethasone mitigates intestinal goblet cell hyperplasia in rats.
London, UK
2 hours ago
1 Received
- The study investigated the impact of dexamethasone alongside the gamma secretase inhibitor (GSI), PF-03084014, on goblet cell hyperplasia (GCH) in the intestines of Sprague-Dawley rats.
- Two dosing regimens were analyzed: a pretreatment with dexamethasone followed by GSI, and concurrent intermittent treatment with both substances.
- Results showed that dexamethasone reduced the severity of GCH temporarily, but there were safety concerns, including morbidity and mortality linked to high doses of GSI and dexamethasone coadministration.
$100 - $150
Hourly Rate
Permeability analysis of neuroactive drugs through a dynamic microfluidic in vitro blood-brain barrier model.
London, UK
2 hours ago
1 Received
- - The study analyzes how well seven neuroactive drugs can pass through a dynamic microfluidic model of the blood-brain barrier (BBB) compared to traditional static models, using brain endothelial and glial cells.
- - Results show that dynamic models had significantly higher trans-endothelial electrical resistance (TEER) levels and lower permeability for the drugs, suggesting they more accurately mimic the in vivo environment than static models.
- - A strong correlation was found between the drugs' permeability values and their in vivo brain/plasma ratios, confirming that the dynamic microfluidic BBB model can effectively predict how drugs will clear from the brain.
$100 - $150
Hourly Rate
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
London, UK
2 hours ago
1 Received
- Targeting Notch signaling is a promising therapy for chronic lymphocytic leukemia (CLL), particularly in patients with harmful NOTCH1 mutations.
- The γ-secretase inhibitor PF-03084014 inhibits Notch activation and works well with fludarabine to kill CLL cells, even in protective environments.
- This treatment combines to enhance the expression of pro-apoptotic genes and reduce factors related to cell invasion, showing effectiveness specifically in NOTCH1-mutated CLL cases.
$100 - $150
Hourly Rate
A Phase I, dose-finding study in patients with advanced solid malignancies of the oral γ-secretase inhibitor PF-03084014.
London, UK
2 hours ago
1 Received
- The study aimed to find the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) for the γ-secretase inhibitor PF-03084014 in patients with advanced solid tumors, while also assessing safety and initial effectiveness.
- The phase I trial involved 64 patients taking PF-03084014 orally, twice daily, with doses ranging from 20 to 330 mg, ultimately identifying the MTD as 220 mg and RP2D as 150 mg due to better safety.
- Results showed mild to moderate side effects, with some patients achieving significant tumor responses, indicating PF-03084014's potential for further development in cancer treatment.
$100 - $150
Hourly Rate
PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a γ-secretase inhibitor.
London, UK
2 hours ago
1 Received
- The study aims to find new activating mutations in Notch receptors related to breast cancer and test a gamma secretase inhibitor (GSI) called PF-03084014 for treatment effectiveness.! -
- Researchers used advanced computational methods to analyze genetic data from breast cancer samples and tested the effects of PF-03084014 on mutant models, revealing that mutations often activated the Notch pathway, especially in triple-negative breast cancer.! -
- Findings highlight PEST domain mutations in Notch receptors as a key driver of breast cancer, suggesting they could be targeted with Notch inhibitors for potential therapy advancements.!
$100 - $150
Hourly Rate
A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
London, UK
2 hours ago
1 Received
$100 - $150
Hourly Rate
Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer.
London, UK
2 hours ago
1 Received
- The study examines the effectiveness of Notch signaling inhibition using a γ-secretase inhibitor (PF-03084014) alongside docetaxel for treating castration-resistant prostate cancer (CRPC).
- PF-03084014 was tested in both lab-based cancer cell lines and live mouse models to measure its impact on tumor growth, cell death, and other cancer-related processes.
- Results showed that the combination of PF-03084014 and docetaxel significantly reduced tumor growth more effectively than either treatment alone, suggesting that this combination could be a promising strategy in treating CRPC.
$100 - $150
Hourly Rate