scholarly journals Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aaminah Khan ◽  
Laura D. Gamble ◽  
Dannielle H. Upton ◽  
Caitlin Ung ◽  
Denise M. T. Yu ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Polyamine Synthesis ◽  
Dual Targeting ◽  
Significant Extension ◽  
Polyamine Transporter ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
Rate Limiting ◽  
Systemic Therapies

AbstractDiffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduces uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO leads to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.

scholarly journals DIPG-15. POLYAMINE PATHWAY INHIBITION IS A POTENT NOVEL THERAPEUTIC STRATEGY AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii289-iii290
Author(s):  
Aaminah Khan ◽  
Laura Gamble ◽  
Dannielle Upton ◽  
Denise Yu ◽  
Anahid Ehteda ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Childhood Cancers ◽  
Polyamine Synthesis ◽  
Dual Blockade ◽  
Key Driver ◽  
Polyamine Transporter ◽  
Pathway Inhibition ◽  
Novel Therapeutic

Abstract DIPG is an aggressive paediatric brainstem tumour, with a median survival of less than 1 year. Polyamines are intracellular polycations that control important aspects of cell growth and are often upregulated in cancer. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is a key driver of polyamine synthesis. We investigated the efficacy of polyamine pathway inhibitors as a therapeutic strategy against DIPG. We found high expression levels of synthetic enzymes in the polyamine pathway in primary patient samples and cultures. Using cytotoxicity and clonogenic assays, we found that DFMO inhibited the proliferation of DIPG neurospheres. However, DIPG cells compensated for DFMO inhibition by increasing expression of the polyamine transporter SLC3A2. Gene expression analysis showed that the polyamine transporter, SLC3A2, was significantly overexpressed in DIPG compared with all other high-risk childhood cancers. Addition of polyamine transporter inhibitor AMXT 1501 to DFMO led to synergistic inhibition of DIPG proliferation. Consistent with the in vitro results, the combination treatment significantly prolonged the survival of mice bearing 3 different DIPG orthografts with 2/3 of the animals surviving up to 160 days. Addition of irradiation further improved the survival of mice treated with DFMO and AMXT 1501. Our results suggest that DIPG tumours are exquisitely sensitive to polyamine inhibitors and that dual blockade of polyamine synthesis and transport is a promising novel therapeutic strategy. AMXT 1501 is currently in clinical development for adult cancers (NCT03536728). A clinical trial for DIPG patients is planned through the CONNECT consortium.

scholarly journals RARE-02. POLYAMINE PATHWAY INHIBITION IS A POTENT NOVEL THERAPEUTIC STRATEGY AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i40-i41
Author(s):  
Aaminah Khan ◽  
Laura Gamble ◽  
Dannielle Upton ◽  
Denise Yu ◽  
Ruby Pandher ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Phase 1 ◽  
Differential Expression Analysis ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Normal Brain ◽  
Pontine Glioma ◽  
Polyamine Synthesis ◽  
Polyamine Transporter ◽  
Novel Therapeutic

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour, with a median survival of less than 1 year. Polyamines are intracellular polycations that control important aspects of cell growth and are often upregulated in cancer. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is a key driver of polyamine synthesis. We investigated the efficacy of polyamine pathway inhibitors as a therapeutic strategy against DIPG. We found that there were high over-expression levels of polyamine synthetic enzymes from DIPG primary patient samples and neurosphere cultures. Using alamar blue cytotoxicity and soft-agar clonogenic assays, we found that DFMO inhibited the proliferation of DIPG neurospheres. However, DIPG cells compensated for DFMO inhibition by increasing expression of the polyamine transporter SLC3A2 and subsequently uptake of polyamines. Addition of polyamine transporter inhibitor AMXT 1501 to DFMO led to synergistic inhibition of DIPG proliferation in vitro. Consistent with the in vitro results, the combination of DFMO and AMXT 1501 significantly prolonged the survival of mice bearing 3 different DIPG orthografts with at least 2/3 of the animals surviving up to 160 days. Addition of irradiation further improved the survival of mice treated with DFMO and AMXT 1501. Differential expression analysis showed that the polyamine transporter, SLC3A2, was significantly overexpressed in DIPG and other paediatric brain tumours including high grade gliomas compared with normal brain tissue. Our results suggest that DIPG tumours are exquisitely sensitive to polyamine inhibitors, and that dual blockade of polyamine synthesis and transport is a promising novel therapeutic strategy. AMXT 1501 is currently in clinical development, and following completion of an adult Phase 1 trial, a clinical trial of AMXT 1501 + DFMO for DIPG patients is planned through the CONNECT consortium.

Endothelial cells respond to hyperglycemia by increasing the LPL transporter GPIHBP1

2014 ◽  
Vol 306 (11) ◽  
pp. E1274-E1283 ◽  
Author(s):  
Amy Pei-Ling Chiu ◽  
Fulong Wang ◽  
Nathaniel Lal ◽  
Ying Wang ◽  
Dahai Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Expression ◽  
Binding Sites ◽  
Therapeutic Strategy ◽  
Density Lipoprotein ◽  
Streptozotocin Diabetes ◽  
Gene And Protein Expression ◽  
Lipoprotein Binding ◽  
Rate Limiting

In diabetes, when glucose uptake and oxidation are impaired, the heart is compelled to use fatty acid (FA) almost exclusively for ATP. The vascular content of lipoprotein lipase (LPL), the rate-limiting enzyme that determines circulating triglyceride clearance, is largely responsible for this FA delivery and increases following diabetes. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein [GPIHBP1; a protein expressed abundantly in the heart in endothelial cells (EC)] collects LPL from the interstitial space and transfers it across ECs onto the luminal binding sites of these cells, where the enzyme is functional. We tested whether ECs respond to hyperglycemia by increasing GPIHBP1. Streptozotocin diabetes increased cardiac LPL activity and GPIHBP1 gene and protein expression. The increased LPL and GPIHBP1 were located at the capillary lumen. In vitro, passaging EC caused a loss of GPIHBP1, which could be induced on exposure to increasing concentrations of glucose. The high-glucose-induced GPIHBP1 increased LPL shuttling across EC monolayers. GPIHBP1 expression was linked to the EC content of heparanase. Moreover, active heparanase increased GPIHBP1 gene and protein expression. Both ECs and myocyte heparan sulfate proteoglycan-bound platelet-derived growth factor (PDGF) released by heparanase caused augmentation of GPIHBP1. Overall, our data suggest that this protein “ensemble” (heparanase-PDGF-GPIHBP1) cooperates in the diabetic heart to regulate FA delivery and utilization by the cardiomyocytes. Interrupting this axis may be a novel therapeutic strategy to restore metabolic equilibrium, curb lipotoxicity, and help prevent or delay heart dysfunction that is characteristic of diabetes.

scholarly journals PATH-24. CXCR4 IS A POTENTIAL THERAPEUTIC TARGET FOR GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi148-vi148
Author(s):  
Soheil Zorofchian ◽  
Ping Zhu ◽  
Takeshi Takayasu ◽  
Adan Rios ◽  
Martha Quezado ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Therapeutic Strategy ◽  
Statistical Significance ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Cxcr4 Expression ◽  
Egfr Expression ◽  
The Difference

Abstract Glioblastoma (GBM) is the most common adult malignant brain tumor with poor prognosis and Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric type of glioblastoma for which there is no effective therapy. CXCR4, a G-protein coupled receptor, has been shown to play a role in GBM invasion, cell survival, proliferation and angiogenesis. A CXCR4 inhibitor (AMD3100/Plerixafor) has been suggested as a potential therapeutic strategy for GBM with an isolated case report of a long-term survivor and an ongoing clinical trial evaluating its effects in GBM patients. However, there is a poor understanding of the expression of CXCR4 in GBM and DIPGs. In this study, we evaluated the expression of CXCR4 in 21-DIPG and 36-GBM cases. In GBMs, CXCR4 was expressed in 5.6% of cases in tumor cells and in 19.4% of cases in endothelial cells in blood vessels. In DIPGs, we observed expression of CXCR4 in 28.6% of cases in tumor cells and in 14.3% of cases in endothelial cells. We observed absence of CXCR4 expression in all IDH-mutant GBMs. There was no correlation between CXCR4 or EGFR expression, p53-mutations or H3F3A p.K27M mutations in DIPGs. There was a trend of poorer prognosis in CXCR4 positive DIPGs but the difference did not reach statistical significance. Furthermore, we evaluated the effects of Plerixafor in the survival of DIPG and U87-GBM cell lines and observed a dose-dependent reduction in cell viability. RT-PCR and immunohistochemistry of DIPG cells showed variable CXCR4 expression in the cell lines that did not correlate with sensitivity to Plerixafor. In conclusion, in vitro experiments show that the CXCR4 inhibitor Plerixafor is a potential therapeutic strategy for GBM and DIPGs. However, CXCR4 is not universally expressed in glioblastomas and its expression should be considered in clinical trials that evaluate the efficacy of CXCR4 inhibitors in GBM and DIPGs.

scholarly journals Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1278
Author(s):  
Caitlin Ung ◽  
Maria Tsoli ◽  
Jie Liu ◽  
Domenico Cassano ◽  
Salvador Pocoví-Martínez ◽  
...  
Keyword(s):  
Colony Formation ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Confocal Imaging ◽  
Therapeutic Approaches ◽  
Orthotopic Model ◽  
Cell Content ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
Paediatric Brain Tumours ◽  
In Vitro Treatment

Diffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease. We have developed non-persistent gold nano-architectures (NAs) functionalised with human serum albumin (HSA) for the delivery of doxorubicin. Doxorubicin has been previously reported to be cytotoxic in DIPG cells. In this study, we have preclinically evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoarchitectures (NAs-HSA-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and doxorubicin-loaded NAs. Colony formation assays demonstrated greater potency of NAs-HSA-Dox on colony formation compared to doxorubicin. Western blot analysis indicated increased apoptotic markers cleaved Parp, cleaved caspase 3 and phosphorylated H2AX in NAs-HSA-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of NAs-HSA-Dox into DIPG neurospheres compared to doxorubicin alone. Despite the potency of the NAs in vitro, treatment of an orthotopic model of DIPG showed no antitumour effect. This disparate outcome may be due to the integrity of the blood-brain barrier and highlights the need to develop therapies to enhance penetration of drugs into DIPG.

scholarly journals Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

2018 ◽  
Author(s):  
Amber N. Stratman ◽  
Olivia M. Farrelly ◽  
Constantinos M. Mikelis ◽  
Mayumi F. Miller ◽  
Zhiyong Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Therapeutic Strategy ◽  
Human Endothelial Cells ◽  
Anti Cancer ◽  
General Potential ◽  
Summary Statement ◽  
Rate Limiting

Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth (1-6). However, the ability of tumors to overproduce pro-angiogenic ligands and overcome targeted inhibitory therapies has hampered this approach (7, 8). A novel way to circumvent this problem might be to target the resynthesis of critical substrates consumed during intracellular transduction of pro-angiogenic signals in endothelial cells, thus harnessing the tumor’s own production of excess stimulatory ligands to deplete adjacent host endothelial cells of the capacity to respond to these signals (9-12). Here we show using zebrafish and human endothelial cellsin vitrothat endothelial cells deficient inCDP-diacylglycerol synthase 2are uniquely sensitive to increased VEGF stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol 4,5-bisphosphate (PIP2) a key substrate for VEGF signal transduction, resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling (9-22). Using murine tumor allograft models (23) we show that either systemic or endothelial cell specific suppression of phosphoinositide recycling results in reduced tumor growth and reduced tumor angiogenesis. Our results suggest that inhibition of phosphoinositide recycling may provide a useful anti-angiogenic approach, and highlights the general potential of targeting the resynthesis of rate limiting signaling substrates as a valuable therapeutic strategy.SUMMARY STATEMENTTargeting phosphoinositide recycling during tumor angiogenesis provides a potentially uniquely effective anti-cancer therapy.

scholarly journals Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma

Oncotarget ◽  
2018 ◽  
Vol 9 (7) ◽  
pp. 7541-7556 ◽  
Author(s):  
Maria Tsoli ◽  
Jie Liu ◽  
Laura Franshaw ◽  
Han Shen ◽  
Cecilia Cheng ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Therapeutic Strategy ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Mtor Pathway ◽  
Pontine Glioma ◽  
Dual Targeting

scholarly journals Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 176
Author(s):  
Hyunmin Lee ◽  
Feng Cai ◽  
Neil Kelekar ◽  
Nipun K. Velupally ◽  
Jiyeon Kim
Keyword(s):  
Lung Cancer ◽  
Therapeutic Strategy ◽  
Malignant Phenotype ◽  
Hexosamine Biosynthesis ◽  
Rate Limiting ◽  
Hexosamine Biosynthesis Pathway ◽  
Mutant Cells ◽  
Aggressive Subtype

In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and tumor suppressor STK11 (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a previous study, we showed that murine KRAS/LKB1 co-mutant tumors and human co-mutant cancer cells have an enhanced dependence on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP), which could be targeted to reduce survival of KRAS/LKB1 co-mutants. Here, we found that KRAS/LKB1 co-mutant cells also exhibit an increased dependence on N-acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced KRAS/LKB1 co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in KRAS/LKB1 co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC.

scholarly journals Dual Targeting of Endothelial and Cancer Cells Potentiates In Vitro Nanobody-Targeted Photodynamic Therapy

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2732
Author(s):  
Vida Mashayekhi ◽  
Katerina T. Xenaki ◽  
Paul M.P. van Bergen en Henegouwen ◽  
Sabrina Oliveira
Keyword(s):  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Dual Targeting ◽  
Cell Target ◽  
New Strategy ◽  
Tumor Specificity ◽  
Targeted Photodynamic Therapy ◽  
Optimal Tumor

Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer, although sub-optimal tumor specificity and side effects have hindered its clinical application. We introduced a new strategy named nanobody-targeted PDT in which photosensitizers are delivered to tumor cells by means of nanobodies. As efficacy of targeted PDT can be hampered by heterogeneity of target expression and/or moderate/low target expression levels, we explored the possibility of combined targeting of endothelial and cancer cells in vitro. We developed nanobodies binding to the mouse VEGFR2, which is overexpressed on tumor vasculature, and combined these with nanobodies specific for the cancer cell target EGFR. The nanobodies were conjugated to the photosensitizer IRDye700DX and specificity of the newly developed nanobodies was verified using several endothelial cell lines. The cytotoxicity of these conjugates was assessed in monocultures and in co-cultures with cancer cells, after illumination with an appropriate laser. The results show that the anti-VEGFR2 conjugates are specific and potent PDT agents. Nanobody-targeted PDT on co-culture of endothelial and cancer cells showed improved efficacy, when VEGFR2 and EGFR targeting nanobodies were applied simultaneously. Altogether, dual targeting of endothelial and cancer cells is a promising novel therapeutic strategy for more effective nanobody-targeted PDT.

scholarly journals Convection Enhanced Delivery for Diffuse Intrinsic Pontine Glioma: Review of a Single Institution Experience

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 660
Author(s):  
Umberto Tosi ◽  
Mark Souweidane
Keyword(s):  
Therapeutic Strategy ◽  
Initial Response ◽  
Systemic Circulation ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Direct Infusion ◽  
Pontine Glioma ◽  
Single Institution ◽  
Convection Enhanced Delivery ◽  
Infiltrative Growth Pattern ◽  
Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine gliomas (DIPGs) are a pontine subtype of diffuse midline gliomas (DMGs), primary central nervous system (CNS) tumors of childhood that carry a terrible prognosis. Because of the highly infiltrative growth pattern and the anatomical position, cytoreductive surgery is not an option. An initial response to radiation therapy is invariably followed by recurrence; mortality occurs approximately 11 months after diagnosis. The development of novel therapeutics with great preclinical promise has been hindered by the tightly regulated blood–brain barrier (BBB), which segregates the tumor comportment from the systemic circulation. One possible solution to this obstacle is the use of convection enhanced delivery (CED), a local delivery strategy that bypasses the BBB by direct infusion into the tumor through a small caliber cannula. We have recently shown CED to be safe in children with DIPG (NCT01502917). In this review, we discuss our experience with CED, its advantages, and technical advancements that are occurring in the field. We also highlight hurdles that will likely need to be overcome in demonstrating clinical benefit with this therapeutic strategy.

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