A5000640064- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- Microtubule and mitosis dynamics
- Glioma Diagnosis and Treatment
- Cancer, Hypoxia, and Metabolism
- Hip and Femur Fractures
- Cancer, Lipids, and Metabolism
- Cardiac, Anesthesia and Surgical Outcomes
- Colorectal and Anal Carcinomas
- Lung Cancer Treatments and Mutations
- Bone fractures and treatments
- DNA Repair Mechanisms
- Gynecological conditions and treatments
- Healthcare Systems and Public Health
- Theology and Philosophy of Evil
- Organ Transplantation Techniques and Outcomes
- Medical Education and Admissions
- Genetic factors in colorectal cancer
- Nursing Roles and Practices
- Gestational Trophoblastic Disease Studies
- Monoclonal and Polyclonal Antibodies Research
- Uterine Myomas and Treatments
- Peptidase Inhibition and Analysis
- Cardiac and Coronary Surgery Techniques
- Brain Metastases and Treatment
University Hospitals Bristol and Weston NHS Foundation Trust
2024
University Hospitals Bristol NHS Foundation Trust
2024
Bristol Royal Infirmary
2020-2024
Peter MacCallum Cancer Centre
2020-2023
The University of Melbourne
2020-2023
James Paget University Hospital
2021-2022
University of Alberta
1985-2017
Hospital for Sick Children
2011
Case Western Reserve University
2006
Mercy San Juan Medical Center
1997
Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance CDK4/6 inhibitors (CDK4/6i). The precise impact pharmacologic inhibition CDK2 not known due the lack selective inhibitors. Here we describe INX-315, a novel potent inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX),...
Recruitment and retention strategies are indispensable in targeting the medical workforce crisis.
Fourteen patients with malignant ovarian germ cell tumors were treated vinblastine, bleomycin, and cisplatin. A complete clinical response was achieved in all 14 patients; however, 1 patient had small macroscopic disease present at second-look laparotomy. One died of bleomycin pulmonary toxicity. The remaining 13 are alive free from 20 months to 8 years after initial diagnosis. Serum alpha-fetoprotein beta-human chorionic gonadotropin levels monitored found be reliable indicators treatment...
<div>Abstract<p>Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring <i>CCNE1</i> amplification and breast cancers that have acquired resistance CDK4/6 inhibitors (CDK4/6i). The precise impact pharmacologic inhibition CDK2 not known due the lack selective inhibitors. Here we describe INX-315, a novel potent inhibitor with high selectivity over other CDK family members. Using...
Abstract Eight colorectal and 5 ovarian cancer patients were evaluated with preoperative immunoscintigraphy intraoperative gamma probe detection of 111 indium‐labeled monoclonal antibody B72.3. Immunoscintigraphy detected the presence tumor in every patient shown to have at surgery. There was one false‐positive scan. A total 21 pathologically verified lesions identified surgery 11 tumor. localized 12 (57%) located 17 (81%) lesions. Intraoperative 6 8 smaller than 1 cm 3 that not on initial...
<p>Description of methods to synthesize INX-315</p>
Penile squamous cell carcinoma (SCC) is a rare and aggressive urological malignancy. Advanced penile SCC requires multimodal management, including surgery systemic therapy. Given its rarity, there have been few substantial advances in our understanding of the molecular genomic drivers SCC, especially for patients with relapsed or advanced disease. In this review, we discuss landscape clinical trials progress implications novel therapeutic targets. Future work should focus on preclinical...
Abstract Cyclin-dependent kinases (CDK) are a family of serine/threonine that heterodimerize with regulatory subunits called cyclins to drive cell cycle progression. Uncontrolled cellular proliferation is hallmark cancer commonly driven by dysregulated kinase activity specific CDK members, including cyclin-dependent 2 (CDK2). Aberrant CDK2 most frequently occurs through amplification CCNE1 and/or overexpression its protein product cyclin E1, which canonical binding partner CDK2....
<p>INX-315 delays the onset of acquired CDK4/6i resistance. <b>A,</b> Representative images from a clonogenic assay in which MCF7 and T47D cells were treated with control vehicle, abemaciclib (500 nmol/L), INX-315 (300 nmol/L for MCF7, 100 T47D), or combination. Six technical replicates per condition. <b>B,</b> (right) quantification (left) after treating as <b>A</b> 7 days followed by staining beta-galactosidase (β-gal) activity (scale bar = μm)....
<p>TIS after INX-315 treatment of <i>CCNE1-</i>amplified cancers. <b>A,</b> Left, representative images staining OVCAR3 and MKN1 cells for beta-galactosidase activity with (scale bar = 100 μm). Experiments performed three technical replicates. Right, quantification integrated signal per cell. Dashed line indicates cutoff used to define positivity, numbers represent percentage beta-galactosidase–positive cells. <b>B,</b> DAPI phalloidin relative...
<p>Discovery and characterization of INX-315. <b>A,</b> Amino acid sequence homology at the ATP-binding pockets several CDKs. <b>B,</b> Derivation INX-315 through serial modifications trilaciclib, a CDK4/6i. Table indicates biochemical IC<sub>50</sub>s (± SEM) to cyclin/CDK pairings shown using Nanosyn assay. Trilaciclib IC<sub>50</sub> for CDK1/cyclin B1 was ND (for trilaciclib: <i>n</i> = 6 CDK2/cyclin E1 A2, 9 CDK4/cyclin...
<p>INX-315 delays the onset of acquired CDK4/6i resistance. <b>A,</b> Representative images from a clonogenic assay in which MCF7 and T47D cells were treated with control vehicle, abemaciclib (500 nmol/L), INX-315 (300 nmol/L for MCF7, 100 T47D), or combination. Six technical replicates per condition. <b>B,</b> (right) quantification (left) after treating as <b>A</b> 7 days followed by staining beta-galactosidase (β-gal) activity (scale bar = μm)....
<p>Supplementary Figure 1: Characterization of INX-315. Supplementary 2: Effect INX-315 and PF-07104091 on viability cancer non-malignant cell lines. 3: cycle in CCNE1-amplified 4: Further characterization the effects vitro vivo models cancer. 5: Effects treatment gene expression CCNE1amplified ovarian carcinoma. 6: CDK4/6 inhibitor-resistant 7: Response breast cells to PF-07104091. 8: cells. 9: Impact +/- continued inhibition inhibitorresistant 10: a new mouse model acquired inhibitor...
<p>INX-315 treatment of CDK4/6i–resistant breast cancer reinstates a senescence phenotype. <b>A,</b> Representative images (top) and quantification (bottom) staining MCF7 T47D cells for beta-galactosidase activity after with agents shown (500 nmol/L abemaciclib, INX-315: 300 100 T47D) 7 days (scale bar = μm). Resistant were cultured continuously in drugs to which they resistant abemaciclib ± fulvestrant). Experiments performed three technical replicates. Quantification is...
<p>INX-315 treatment of CDK4/6i–resistant breast cancer reinstates a senescence phenotype. <b>A,</b> Representative images (top) and quantification (bottom) staining MCF7 T47D cells for beta-galactosidase activity after with agents shown (500 nmol/L abemaciclib, INX-315: 300 100 T47D) 7 days (scale bar = μm). Resistant were cultured continuously in drugs to which they resistant abemaciclib ± fulvestrant). Experiments performed three technical replicates. Quantification is...
<div>Abstract<p>Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring <i>CCNE1</i> amplification and breast cancers that have acquired resistance CDK4/6 inhibitors (CDK4/6i). The precise impact pharmacologic inhibition CDK2 not known due the lack selective inhibitors. Here we describe INX-315, a novel potent inhibitor with high selectivity over other CDK family members. Using...
<p>Supplementary Figure 1: Characterization of INX-315. Supplementary 2: Effect INX-315 and PF-07104091 on viability cancer non-malignant cell lines. 3: cycle in CCNE1-amplified 4: Further characterization the effects vitro vivo models cancer. 5: Effects treatment gene expression CCNE1amplified ovarian carcinoma. 6: CDK4/6 inhibitor-resistant 7: Response breast cells to PF-07104091. 8: cells. 9: Impact +/- continued inhibition inhibitorresistant 10: a new mouse model acquired inhibitor...
<p>TIS after INX-315 treatment of <i>CCNE1-</i>amplified cancers. <b>A,</b> Left, representative images staining OVCAR3 and MKN1 cells for beta-galactosidase activity with (scale bar = 100 μm). Experiments performed three technical replicates. Right, quantification integrated signal per cell. Dashed line indicates cutoff used to define positivity, numbers represent percentage beta-galactosidase–positive cells. <b>B,</b> DAPI phalloidin relative...
<p>Discovery and characterization of INX-315. <b>A,</b> Amino acid sequence homology at the ATP-binding pockets several CDKs. <b>B,</b> Derivation INX-315 through serial modifications trilaciclib, a CDK4/6i. Table indicates biochemical IC<sub>50</sub>s (± SEM) to cyclin/CDK pairings shown using Nanosyn assay. Trilaciclib IC<sub>50</sub> for CDK1/cyclin B1 was ND (for trilaciclib: <i>n</i> = 6 CDK2/cyclin E1 A2, 9 CDK4/cyclin...
<p>Activity of INX-315 in CDK4/6i–resistant breast cancer. <b>A,</b> Dose–response curves for MCF7 and T47D cell lines treated with 7 days. Parent, parent cells DMSO; Abema-resistant, abemaciclib-resistant growing 500 nmol/L abemaciclib; Abema/Fulv-resistant, resistant to abemaciclib/fulvestrant abemaciclib plus 100 fulvestrant; Fulv-resistant, fulvestrant Parent + abema, parental concurrently. Table shows IC<sub>50</sub>s each case, derived from measurement...