Christine M. Heske
A5018153866- Sarcoma Diagnosis and Treatment
- Chronic Myeloid Leukemia Treatments
- PI3K/AKT/mTOR signaling in cancer
- PARP inhibition in cancer therapy
- Cancer, Hypoxia, and Metabolism
- Lung Cancer Treatments and Mutations
- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Lymphoma Diagnosis and Treatment
- Neuroblastoma Research and Treatments
- Renal cell carcinoma treatment
- RNA modifications and cancer
- Hormonal Regulation and Hypertension
- Cancer therapeutics and mechanisms
- Ubiquitin and proteasome pathways
- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- CAR-T cell therapy research
- Sirtuins and Resveratrol in Medicine
- Renal and related cancers
- Cancer, Lipids, and Metabolism
- Quinazolinone synthesis and applications
- Biochemical and Molecular Research
- Autophagy in Disease and Therapy
- ATP Synthase and ATPases Research
National Cancer Institute
2015-2024
Center for Cancer Research
2013-2024
National Institutes of Health
2014-2024
Molecular Oncology (United States)
2015-2017
Altered cellular metabolism, including an increased dependence on aerobic glycolysis, is a hallmark of cancer. Despite the fact that this observation was first made nearly century ago, effective therapeutic targeting glycolysis in cancer has remained elusive. One potentially promising approach involves glycolytic enzyme lactate dehydrogenase (LDH), which overexpressed and plays critical role several cancers. Here, we used novel class LDH inhibitors to demonstrate, for time, Ewing sarcoma...
Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored in vitro response of sarcoma cell lines against a large collection investigational and approved drugs identify candidate combinations.Experimental Design: Drugs displaying activity as single agents were evaluated combinatorial (matrix) format highly active, synergistic drug combinations,...
<p>NAD<sup>+</sup> and NADH analysis of UOK365 cells. Analysis the relative levels NAD<sup>+</sup> their ratio after 24 hour treatment cell line model with a range concentrations (0.5-100 nM) either GNE-618 (A-B) or OT-82 (C-D). All were compared to cells treated amount DMSO present in highest concentration utilized drugs.</p>
<p>Real-time invasion analysis of UOK262 and UOK365 cells treated with OT-82. Real-time demonstrating cell line over 5 days (120 hrs) was performed (A) to show that DMSO (used as the vehicle for OT-82) did not affect in comparison untreated (B) demonstrate effects OT-82 treatment at either 1 nM or 10 alone (DMSO) non-invasive control (no serum lower chamber). In each case, a representative graph from one three separate experiments is shown. (C) The inhibition repeats dose shown line....
<p>In vitro analysis of NAMPT inhibition on glycolysis in FH-deficient tumor cells. (A) Effects the inhibitor OT-82 (100 nM) extracellular acidification rate (ECAR) UOK262 and UOK365 HLRCC cell lines RPTEC normal line. (B) Representation different effects versus DMSO at time point 5 (designated by a star) after injection glucose UOK262, UOK365, RPTEC. 2-DG, 2-deoxyglucose.</p>
<p>Structural figures of NAMPT inhibitors.</p>
<p>In vivo effects of NAMPT inhibitors in HLRCC xenograft models. Mean body weights are constant throughout the drug study for animals harboring UOK262 xenografts (A) and UOK365 (B; shown Figure 3A-B, <i>n</i> = 10 mice per arm, 95mg/kg OT-82 8 week duration). (C-D) H&E stained sections retinas obtained from NSG treated with vehicle or 5 days. (E-F) Caspase 3 95 mg/kg Histological were evaluated signs retinal toxicity by a trained veterinary pathologist. No overt...
<div>Abstract<p>Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited syndrome caused by germline pathogenic variants in the fumarate hydratase (<i>FH</i>) gene. Affected individuals are at risk for developing cutaneous uterine leiomyomas aggressive FH-deficient carcinoma (RCC) with a papillary histology. Due to disrupted tricarboxylic acid cycle, kidney cancers rely on aerobic glycolysis energy production, potentially creating compensatory metabolic...
<p>Expression levels of NAD<sup>+</sup> biosynthetic and salvage pathway genes in HLRCC tumors, normal kidney samples pan-kidney data from TCGA. (A) Overview pathways. (B-E) Box plots for selected NAD+ derived RNA-seq analysis tumors specimens. (F) TCGA data. NAMPT (nicotinamide phosphoribosyltransferase), NAPRT (nicotinate phosphoribosyltransferase ), QPRT (quinolinate NMNAT mononucleotide adenylyl transferase), KIRP (kidney renal papillary cancer), CIMP (CpG island...
<p>Validation studies to evaluate inhibition of additional HLRCC cell lines by NAMPT inhibitors. A) Effects the inhibitor GNE-618 on viability in FH <sup>-/</sup>- cells UOK348, UOK271, UOK350, UOK268, UOK365, restored UOK268WT and non-transformed kidney epithelial RPTEC. Cell was assessed Titer-Glo assay at 96 h. B) OT-82 -/- RPTEC.</p>
<p>Proliferation analysis of UOK268 and RPTEC in response to OT-82 nicotinic acid rescue NAD<sup>+</sup>/NADH depletion. (A-B) or cells were grown 96 well plates from an initial plating 2,000 cellular confluency was monitored real-time by Incucyte S3 Live-Cell Imaging System. After 24 hours measurements treated with either DMSO, 1 nM OT-82, 5 10 plus mM nicotinamide mononucleotide (NMN) evaluated for additional days. (C-D) The effect NMN on depletion is shown. (E) Effects...
<p>Cell proliferation rates of HLRCC cell lines treated with low and high concentrations NAMPT inhibitors. A) Effect OT-82 at 0.8nM or 100nM (left) GNE-618 8nM 200nM (right) on UOK262 after 96 hours. B) UOK268 C) UOK365 hours.</p>
<p>HLRCC spheroid characterization and OT-82 effect on 3D culture. A) UOK262 (B) UOK365 spheroids plated at different cell densities (8000, 4000, 2000 cells/well in triplicate) after 24h, showing degrees of aggregation. Cell viability (C) (D) treated with GNE-618 (1 nM-500 nM) or (0.2 nM-100 assessed Cell-Titer Glo assay decreases a dose dependent manner.</p>
<p>Time course study design for imaging and OT-82 treatment hyperpolarized pyruvate 13C-MRSI. Post MRSI was performed 5 hours post dose #2.</p>
<p>Pharmacokinetic profile of OT-82 in nude and NSG mice. (A) Bioanalysis plasma concentrations were made using a validated LC-MS/MS assay (<i>n</i>=3 mice, 50 mg/kg, 7 intervals; <i>n</i>=3 75mg/kg, intervals). (B) Pharmacokinetic parameters calculated after single dose OT-82. The data from all mice each group pooled together to assume one “average” mouse per group.</p>
<p>NAMPT immunohistochemical analysis in HLRCC tumors and normal kidney. (A) In patient #1, both a primary kidney tumor (upper panel) an associated metastatic mass (lower demonstrated strong NAMPT staining. Surrounding non-tumor tissues show little (B) #4, shows staining comparison to tissue present on the same slide panel). (C) #5, Material from this was used derive UOK262 cell line, which similar positive when grown as xenograft (D) #6, Matching H&E is included for all samples...
The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles pro-survival and anti-apoptotic signaling.However, development of resistance IGF-1R blockade represents hindrance limits treatment efficacy the clinic.In this study, we identified acquired with R1507, an antibody against IGF-1R, BMS-754807, small molecular inhibitor IGF-1R/insulin (IR).We showed that IGF-IR antibody, or IR/IGF-IR kinase inhibitor, was...
Abstract Purpose: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been to mediate IGF (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R resulted sustained murine RMS models. We conducted a phase I trial of the anti–IGF-1R ganitumab combined dasatinib, multi-kinase inhibitor targeting YES, (NCT03041701). Patients Methods:...
ABSTRACT Background Prognostic factors are crucial in tailoring treatments for patients with rhabdomyosarcoma (RMS). The European paediatric Soft tissue sarcoma Study Group (EpSSG) and the Children's Oncology (COG) employ similar prognostic factors, but utilize them differently resulting diverse stratification systems. This diversity may result dissimilar treatment approaches comparable hinder comparison of clinical trial results. Procedure We reclassified 1993 enrolled EpSSG RMS 2005 MTS...
Long-term survival in patients with metastatic, relapsed, or recurrent Ewing sarcoma and rhabdomyosarcoma is dismal. Irinotecan, a topoisomerase 1 inhibitor, has activity these sarcomas, but due to poor bioavailability of its active metabolite (SN-38) had limited clinical efficacy. In this study we have evaluated the efficacy toxicity STA-8666, novel drug conjugate which uses an HSP90 inhibitor facilitate intracellular, tumor-targeted delivery SN-38, thus preferentially delivering...