A5062422926- PI3K/AKT/mTOR signaling in cancer
- Advanced Breast Cancer Therapies
- Metabolism, Diabetes, and Cancer
- Cancer, Hypoxia, and Metabolism
- Pancreatic and Hepatic Oncology Research
- Biochemical and Molecular Research
- Pancreatic function and diabetes
- Cancer Genomics and Diagnostics
- Lung Cancer Research Studies
- Protein Degradation and Inhibitors
- Lung Cancer Treatments and Mutations
- PARP inhibition in cancer therapy
- Colorectal Cancer Treatments and Studies
- Cancer Treatment and Pharmacology
- Cardiovascular Function and Risk Factors
- Genetic Mapping and Diversity in Plants and Animals
- Genetic Associations and Epidemiology
Scorpion Therapeutics (United States)
2022-2024
Pfizer (United States)
2023
Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head neck squamous cell carcinoma tumors. Mutations occur throughout gene, but hotspot mutations in helical kinase domains predominate. The therapeutic benefit isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against wild-type mutant enzyme. Inhibition associated severe hyperglycemia rash, limits alpelisib use suggests...
Summary paragraph Heart failure (HF), a syndrome of symptomatic fluid overload due to cardiac dysfunction, is the most rapidly growing cardiovascular disorder. Despite recent advances, mortality and morbidity remain high treatment innovation challenged by limited understanding aetiology in relation disease subtypes. Here we harness de-confounding properties genetic variation map causal biology underlying HF phenotypic spectrum, inform development more effective treatments. We report...
Abstract PI3Kα is highly mutated in cancer resulting hyperactivation of lipid kinase activity and downstream AKT signaling. H1047 the most common site oncogenic mutation occurs ~14% all breast cancers. Initial therapeutic benefit targeting was established with alpelisib, an alpha-selective PI3K inhibitor that equipotent against wild-type mutant forms. However, inhibition results frequent dose-limiting toxicities including hyperglycemia, restricting full potential this drug. Selective...
Abstract Oncogenic PIK3CA mutations are found in 14% of all cancers and most frequently occur at amino acids E542/E545 H1047, involving the helical kinase domains, respectively (Zhang 2017). Alpelisib is a PI3Kα isoform-selective, orthosteric inhibitor, having equivalent activity on wild-type (wt) mutant (mt) forms was approved to treat mt, HR+/HER2- breast cancer combination with fulvestrant, nearly doubling progression-free survival (Andre 2019). Hyperglycemia insulin resistance an...
Abstract Activating mutations in PI3Kα are among the most prevalent genetic aberrations breast cancer. Constitutive signaling of is an established oncogenic driver these cancers, as predictors response to alpelisib, approved inhibitor, which inhibits both wild type and mutant PI3Kα. While inhibiting has proven be efficacious, concomitant inhibition enzyme normal tissue results metabolic dysfunction ultimately dose-limiting toxicities. Selectively targeting expected inhibit tumor growth while...
<div>Abstract<p>Phosphoinositide 3-kinase α (<i>PIK3CA</i>) is one of the most mutated genes across cancers, especially breast, gynecologic, and head neck squamous cell carcinoma tumors. Mutations occur throughout gene, but hotspot mutations in helical kinase domains predominate. The therapeutic benefit isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against wild-type mutant enzyme. Inhibition associated severe...
<div>Abstract<p>Phosphoinositide 3-kinase α (<i>PIK3CA</i>) is one of the most mutated genes across cancers, especially breast, gynecologic, and head neck squamous cell carcinoma tumors. Mutations occur throughout gene, but hotspot mutations in helical kinase domains predominate. The therapeutic benefit isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against wild-type mutant enzyme. Inhibition associated severe...
<p>Assessment of STX-478 mutant selectivity by profiling target engagement and functional activity in cellular assays. <b>A,</b> pAKT inhibition dose–response curves (HTRF assay) MCF10A isogenic cell lines. <b>B,</b> Representative assay). <b>C,</b> Correlation plot comparing alpelisib potency (pAKT HTRF a panel kinase-domain lines (orange dots) WT PI3Kα SKBR3 (black described Supplementary Table S1. <b>D,</b> IC<sub>50</sub>...
<p>The effect of STX-478 and alpelisib on glucose homeostasis. <b>A,</b> Tumor-naive female BALB/c nude mice were dosed for 5 days as indicated (<i>n</i> = 5/group) subjected to an ITT. On day 5, animals fasted 6 hours with drug by oral administration (p.o.) 1 hour prior the end fast (−1 hour). At <i>T</i> 0, 0.75 U/kg intraperitoneal (i.p.) insulin administration. Blood levels monitored over time, group mean standard error (SEM) indicated....
<p>The efficacy of STX-478 is similar or superior to high-dose alpelisib across PI3Kα-mutant tumor xenografts while sparing insulin resistance (p.o., oral administration; q.d., daily). <b>A,</b> Final volume percent change represented for GP2d, Detroit 562, NCI-H1048, and HCC1954 CDX tumors. BrCa, breast cancer. <b>B,</b> Tumor volumes over time from PDX models (<i>N</i> = 3/group) harboring PI3Kα mutations in the kinase domain (ST1056: H1047R...
<p>STX-478 combination therapies in ER<sup>+</sup> breast cancer models with fulvestrant and palbociclib. <b>A,</b> T47D xenograft tumors were established female NOD scid gamma immunodeficient (NSG) mice. When reached approximately 200 mm<sup>3</sup>, mice randomized treated as indicated (p.o., oral administration; q.d., daily; q.w., weekly; s.c., subcutaneous injection). Data represent the percent change tumor volume of individual on day 20 relative...
<p>STX-478 combination therapies in ER<sup>+</sup> breast cancer models with fulvestrant and palbociclib. <b>A,</b> T47D xenograft tumors were established female NOD scid gamma immunodeficient (NSG) mice. When reached approximately 200 mm<sup>3</sup>, mice randomized treated as indicated (p.o., oral administration; q.d., daily; q.w., weekly; s.c., subcutaneous injection). Data represent the percent change tumor volume of individual on day 20 relative...
<p>STX-478 binds a novel allosteric site on PI3Kα and achieves mutant selectivity through differential binding kinetics. <b>A,</b> The molecular structure of STX-478. <b>B,</b> Inhibition enzyme activities WT as well kinase-domain helical-domain proteins by alpelisib STX-478 showing the geometric mean standard deviation. <b>C,</b> 2.9Å X-ray (p110 purple, p85 orange) with GDC-0077 (red spheres) bound in ATP (green an site. <b>D,</b>...
<p>Efficacy and PK/PD profiling of STX-478 alpelisib in CAL-33 xenograft tumors. <b>A</b> <b>B,</b> tumors were established female BALB/c nude mice. Animals randomized into treatment groups (<i>n</i> = 6) at approximately 160 mm<sup>3</sup> treated as indicated. Tumor (<b>A</b>) body weight (BW; <b>B</b>) measured 2×/week with group mean standard error (SEM) shown. <b>C</b> <b>D,</b> Mice...
<p>Efficacy and PK/PD profiling of STX-478 alpelisib in CAL-33 xenograft tumors. <b>A</b> <b>B,</b> tumors were established female BALB/c nude mice. Animals randomized into treatment groups (<i>n</i> = 6) at approximately 160 mm<sup>3</sup> treated as indicated. Tumor (<b>A</b>) body weight (BW; <b>B</b>) measured 2×/week with group mean standard error (SEM) shown. <b>C</b> <b>D,</b> Mice...
<p>Assessment of STX-478 mutant selectivity by profiling target engagement and functional activity in cellular assays. <b>A,</b> pAKT inhibition dose–response curves (HTRF assay) MCF10A isogenic cell lines. <b>B,</b> Representative assay). <b>C,</b> Correlation plot comparing alpelisib potency (pAKT HTRF a panel kinase-domain lines (orange dots) WT PI3Kα SKBR3 (black described Supplementary Table S1. <b>D,</b> IC<sub>50</sub>...
<p>The effect of STX-478 and alpelisib on glucose homeostasis. <b>A,</b> Tumor-naive female BALB/c nude mice were dosed for 5 days as indicated (<i>n</i> = 5/group) subjected to an ITT. On day 5, animals fasted 6 hours with drug by oral administration (p.o.) 1 hour prior the end fast (−1 hour). At <i>T</i> 0, 0.75 U/kg intraperitoneal (i.p.) insulin administration. Blood levels monitored over time, group mean standard error (SEM) indicated....
<p>STX-478 binds a novel allosteric site on PI3Kα and achieves mutant selectivity through differential binding kinetics. <b>A,</b> The molecular structure of STX-478. <b>B,</b> Inhibition enzyme activities WT as well kinase-domain helical-domain proteins by alpelisib STX-478 showing the geometric mean standard deviation. <b>C,</b> 2.9Å X-ray (p110 purple, p85 orange) with GDC-0077 (red spheres) bound in ATP (green an site. <b>D,</b>...
<p>The efficacy of STX-478 is similar or superior to high-dose alpelisib across PI3Kα-mutant tumor xenografts while sparing insulin resistance (p.o., oral administration; q.d., daily). <b>A,</b> Final volume percent change represented for GP2d, Detroit 562, NCI-H1048, and HCC1954 CDX tumors. BrCa, breast cancer. <b>B,</b> Tumor volumes over time from PDX models (<i>N</i> = 3/group) harboring PI3Kα mutations in the kinase domain (ST1056: H1047R...