A5062856863- Cancer, Hypoxia, and Metabolism
- Prostate Cancer Treatment and Research
- Lung Cancer Research Studies
- Neuroendocrine Tumor Research Advances
- Radiopharmaceutical Chemistry and Applications
- Hormonal and reproductive studies
- Estrogen and related hormone effects
- Ferroptosis and cancer prognosis
- Epigenetics and DNA Methylation
- Cancer Research and Treatments
- Peptidase Inhibition and Analysis
- Renal cell carcinoma treatment
- Axon Guidance and Neuronal Signaling
- Prostate Cancer Diagnosis and Treatment
- Cancer Cells and Metastasis
- Gyrotron and Vacuum Electronics Research
- ATP Synthase and ATPases Research
- RNA modifications and cancer
- Fibroblast Growth Factor Research
- Eicosanoids and Hypertension Pharmacology
- Hepatocellular Carcinoma Treatment and Prognosis
- Cancer, Lipids, and Metabolism
- Cancer Immunotherapy and Biomarkers
- Hedgehog Signaling Pathway Studies
- Cancer Diagnosis and Treatment
Cellerant Therapeutics (United States)
2023
Merck & Co., Inc., Rahway, NJ, USA (United States)
2023
Shanxi Provincial Cancer Hospital
2021
Shanxi Medical University
2021
Pfizer (United States)
2012-2014
Fred Hutch Cancer Center
2011
Hanson Institute
2005
Baylor College of Medicine
2005
The University of Adelaide
2005
Queensland University of Technology
2005
Abstract More than 90% of clear cell renal carcinomas (ccRCC) exhibit inactivation the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as major underlying cause this malignancy. pVHL results in stabilization hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression a genetic program essential for initiation progression ccRCC. Herein, we describe potent, selective, orally active small-molecule inhibitor PT2385 specific antagonist HIF2α that allosterically...
The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical activity heavily pretreated advanced ccRCC patients. However, was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism to its glucuronide metabolite. Herein we describe the discovery second-generation PT2977 with increased potency improved pharmacokinetic profile...
Recent evidence demonstrates that the androgen receptor (AR) continues to influence prostate cancer growth despite medical therapies reduce circulating ligands castrate levels and/or block ligand binding. Whereas mutation, amplification, overexpression of AR, or cross-talk between AR and other factor pathways may explain failure ablation in some cases, there is little supporting a causal role cancer. In this study, we functionally directly address whereby contributes spontaneous progression...
Calcitriol (1,25-dihydroxycholecalciferol), the major active form of vitamin D, is antiproliferative in tumor cells and tumor-derived endothelial (TDEC). These actions calcitriol are mediated at least part by D receptor (VDR), which expressed many tissues including cells. To investigate role VDR effects on vasculature, we established TRAMP-2 tumors subcutaneously into either wild-type (WT) or knockout (KO) mice. Within 30 days post-inoculation, KO mice were larger than those WT (P < 0.001)....
HIF-2α, a member of the HIF family transcription factors, is key oncogenic driver in cancers such as clear cell renal carcinoma (ccRCC). A signature feature these overaccumulation HIF-2α protein, often by inactivation E3 ligase VHL (von Hippel–Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated identification PT2385, first antagonist to enter clinical trials. Highlights include use putative n → π*Ar interaction guide early analog design, conformational...
Glypican-3 (GPC3) is a membrane-associated glycoprotein that significantly upregulated in hepatocellular carcinomas (HCC) with minimal to no expression normal tissues. The differential of GPC3 between tumor and tissues provides an opportunity for targeted radiopharmaceutical therapy treat HCC, leading cause cancer-related deaths worldwide. <b>Methods</b>: DOTA-RYZ-GPC3 (RAYZ-8009) comprises novel macrocyclic peptide binder GPC3, linker, chelator can be complexed different radioisotopes....
The androgen receptor (AR), a member of the steroid superfamily nuclear transcription factors, mediates signaling in diverse target tissues. Here we report AR gene mutations identified human prostate cancer and autochthonous transgenic adenocarcinoma mouse model that colocate to residues 668QPIF671 at boundary hinge ligand-binding domain, resulting receptors exhibit 2- 4-fold increased activity compared with wild-type response dihydrotestosterone, estradiol, progesterone, adrenal androgens,...
We have used the autochthonoustransgenic adenocarcinoma of mouseprostate (TRAMP) model to investigate relationship between somatic mutation in androgen receptor (AR) and emergence androgen-independent prostate cancer. Here we report identification, isolation, characterization distinct classes AR variants from spontaneous tumors TRAMP model. Using cDNA cloning, single stranded conformation polymorphism sequencing strategies, 15 unique mutations were identified obtained eight mice 24 29 weeks...
Overexpression of somatostatin receptors (SSTR), particularly SSTR2, is found in gastroenteropancreatic neuroendocrine tumors (GEP-NET), and subsets other solid such as small-cell lung cancer (SCLC). SCLC accounts for approximately 13% to 15% lacks effective therapeutic options. IHC analysis indicates that up 50% are SSTR2-positive, with a substantial subset showing high homogenous expression. Peptide receptor radionuclide therapy radiolabeled analogue, Lu-177 DOTATATE, has been approved...
Abstract Mutations in the androgen receptor (AR) have been detected experimental and clinical prostate tumors. Mice with enforced prostate‐specific expression of one such variant, AR‐E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks metastatic cancer 52 weeks. The aim this study was to identify genes altered prostates AR‐E231G mice at an early stage disease that may act as drivers AR‐mediated tumorigenesis. gene profile tissue from 12‐week‐old compared equivalent...
Castration resistant prostate cancer (CRPC) is a leading cause of cancer-related deaths in men. The primary mortality and morbidity patients bone metastases remodeling resulting osteoblastic osteolytic lesions. Recently, cabozantinib, multi-kinase inhibitor (VEGFR2 c-MET inhibitor), was shown to have efficacy on lesions patients. In this study we tested inhibitors: axitinib (VEGFR inhibitor) crizotinib (c-MET combination trial mice models. VCaP-Luc cells were grown as subcutaneous implants...
525 Background: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein whose expression largely absent in normal tissues. Significant upregulation of GPC3 has been observed approximately 75% hepatocellular carcinomas (HCC), and associated with poor prognosis. The differential between tumor tissues provides an opportunity for targeted radiopharmaceutical therapy (RPT) to treat HCC, leading cause cancer-related deaths worldwide. Methods: RAYZ-8009 comprises novel macrocyclic peptide binder...
Abstract The majority of clear cell renal carcinoma (ccRCC) have deficiency in the gene encoding von Hippel Landau (VHL) protein, as a result DNA copy loss, non-sense mutations, and epigenetic silencing. Deficiency VHL its E3 ligase activity results stabilization transcription factors hypoxia-inducible factor (HIF)-1α HIF-2α. In ccRCC, HIF-2α has been proposed to function an oncogenic driver, depletion tumor cells inhibition growth. We previously described identification potent selective...
Abstract Hypoxia-inducible factor 2a (HIF-2a), a transcription factor, has been established as an oncogenic driver in clear cell renal cancer (ccRCC). The first HIF-2a antagonist being evaluated clinical development, PT2385, demonstrated activity ccRCC patients who had previously treated with multiple lines of therapy. There is continuing effort to characterize additional antagonists possessing attributes that may contribute enhanced activity. PT2977 novel improved potency preclinical tumor...
Abstract Introduction: Overexpression of somatostatin receptors (SSTRs), particularly SSTR2, is found in gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and subsets other solid such as small-cell lung cancer (SCLC). β-emitting radiopharmaceutical therapy Lu-177 DOTATATE has been approved for SSTR-expressing (SSTR+) GEP-NETs, but the relatively low objective response rate frequent post-treatment progression represent an unmet medical need. Based on preliminary clinical anti-tumor...
e16131 Background: Glypican-3 (GPC3) is a membrane-associated heparan sulfate proteoglycan primarily involved in embryonic development, and barely detectable normal adult tissues. Significant upregulation of GPC3 protein hepatocellular carcinomas (HCC) has been observed multiple immunohistochemistry (IHC) studies with up to 75% positivity rate, associated poor prognosis. not expressed healthy or non-malignant liver tissue. Targeting could fulfill an unmet medical need for HCC, leading cause...
Abstract Introduction: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein with minimal expression in normal tissues. Besides hepatocellular carcinoma, upregulation of GPC3 has been observed significant subset treatment-emergent neuroendocrine prostate cancer (NEPC), which accounts for to 30% cases refractory anti-androgen and other therapies. The differential between NEPC cells tissues provides theranostic opportunity targeted radiopharmaceutical therapy (RPT). Methods: novel RPT...
Abstract Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, are transcription that mediate cellular response to changes of oxygen supply. These proteins become stabilized under hypoxia subsequently activate the expression genes facilitate cell survival proliferation. HIF activated in many types cancers due tumor hypoxic microenvironment have been implicated cancer initiation, progression metastasis. The oncogenic role HIF-2α is pertinent clear renal carcinoma (ccRCC). In majority...
<div>Abstract<p>More than 90% of clear cell renal carcinomas (ccRCC) exhibit inactivation the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as major underlying cause this malignancy. pVHL results in stabilization hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression a genetic program essential for initiation progression ccRCC. Herein, we describe potent, selective, orally active small-molecule inhibitor PT2385 specific antagonist HIF2α that...
<p>Supplementary method includes detailed experimental procedure for the synthesis of PT2385. Supplementary Figures 1-7 - Lack cytotoxicity PT2385 in cultured 786-O and A498 cells (1); pharmacokinetics CD-1 mice (2); Inhibition HIF-2� gene expression circulating hVEGFa mouse xenograft model after treatment with (3); mRNA protein levels vitro (4); Levels HIF-1� patient-derived tumors (5); Body weight efficacy studies treated either vehicle, or sunitinib (6); Binding to rat as...
<p>Supplementary method includes detailed experimental procedure for the synthesis of PT2385. Supplementary Figures 1-7 - Lack cytotoxicity PT2385 in cultured 786-O and A498 cells (1); pharmacokinetics CD-1 mice (2); Inhibition HIF-2� gene expression circulating hVEGFa mouse xenograft model after treatment with (3); mRNA protein levels vitro (4); Levels HIF-1� patient-derived tumors (5); Body weight efficacy studies treated either vehicle, or sunitinib (6); Binding to rat as...
Abstract Pharmacokinetic properties of our first-generation HIF-2α antagonist PT2385, including modest solubility, resulted in a high recommended phase 2 dose (RP2D) 800 mg BID and motivated the pursuit novel scaffolds which could improve solubility formulation parameters with goal improved pharmacokinetics. Herein we disclose successful efforts to identify such antagonists through an optimization strategy characterized by: (1) increasing fraction sp3 hybridized carbons (Fsp3), (2) replacing...
e15113 Background: Ephrin type-A receptor 2 (EphA2) is a glycoprotein of the ephrin subfamily. EphA2 primarily involved in tissue patterning during embryonic development, and its expression levels are low or absent normal adult tissues. However, overexpression has been observed multiple malignant tumors such as bladder, cervical, ovarian, colorectal, lung esophageal cancers. In addition to being tumor biomarker, plays an active role survival, metastasis neo-angiogenesis, which can lead poor...