Abstract 4780: RXDX-107 exhibits multiple mechanisms of intracellular delivery and results in extensive drug-induced interstrand crosslinks in solid tumor preclinical models

2016 ◽  
Author(s):  
Leenus Martin ◽  
Roopal Patel ◽  
Michael Johnson ◽  
Jerry Cao ◽  
Peter Chua ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Intracellular Delivery ◽  
Preclinical Models ◽  
Drug Induced ◽  
Interstrand Crosslinks

A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10556-10556
Author(s):  
Anang Shelat ◽  
Christopher Tinkle ◽  
Elizabeth Stewart ◽  
Sara Michele Federico ◽  
Brandon Bianski ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tumor Cells ◽  
Dna Adducts ◽  
Solid Tumor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Drug Induced ◽  
Potent Inducer ◽  
Pediatric Solid Tumors ◽  
Pediatric Solid Tumor

10556 Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric solid tumors and a potent inducer of DNA damage. Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included: talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay. Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric solid tumor lines, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2Gy IR and 1-10nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations < 10nM in tumor cells expressing detectable levels of SLFN11. Conclusions: SLFN11 is present in select pediatric solid tumors and may induce a DNA repair defect that is best exploited by combining low-doses of TAL and irinotecan with IR.

scholarly journals Differential introduction of DNA damage and repair in mammalian genes transcribed by RNA polymerases I and II.

1991 ◽  
Vol 11 (4) ◽  
pp. 2245-2252 ◽  
Author(s):  
J M Vos ◽  
E L Wauthier
Keyword(s):  
Chinese Hamster Ovary Cells ◽  
Mammalian Species ◽  
Chinese Hamster ◽  
Rrna Genes ◽  
Dhfr Gene ◽  
Drug Induced ◽  
Dna Damage And Repair ◽  
Ovary Cells ◽  
Interstrand Crosslinks ◽  
Mammalian Genes

We have developed a general quantitative method for comparing the levels of drug-induced DNA crosslinking in specific mammalian genes. We observed a dramatic difference between the efficiency of the removal of both psoralen monoadducts and interstrand crosslinks from the rRNA genes and the efficiency of their removal from the dihydrofolate reductase (DHFR) gene in cultured human and hamster cells. While 90% of the interstand crosslinks were removed from the human DHFR gene in 48 h, less than 25% repair occurred in the rRNA genes. Similarly, in Chinese hamster ovary cells, 85% repair of interstrand crosslinks occurred within 8 h in the DHFR gene versus only 20% repair in the rRNA genes. The preferential repair of the DHFR gene relative to that of the rRNA genes was also observed for psoralen monoadducts in cells from both mammalian species. In human-mouse hybrid cells, the active mouse rRNA genes were five times more susceptible to psoralen modification than are the silent rRNA human genes, but adduct removal was similarly inefficient for both classes. We conclude that the repair of chemical damage such as psoralen photoadducts in an expressed mammalian gene may depend upon the class of transcription to which it belongs.

scholarly journals The Road of Solid Tumor Survival: From Drug-Induced Endoplasmic Reticulum Stress to Drug Resistance

2021 ◽  
Vol 8 ◽  
Author(s):  
Shulong Cao ◽  
Jingyi Tang ◽  
Yichun Huang ◽  
Gaofeng Li ◽  
Zhuoya Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
T Cells ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Tumor Cells ◽  
Solid Tumor ◽  
Noncoding Rna ◽  
Signal Pathway ◽  
Drug Induced ◽  
Apoptosis Inhibition

Endoplasmic reticulum stress (ERS), which refers to a series of adaptive responses to the disruption of endoplasmic reticulum (ER) homeostasis, occurs when cells are treated by drugs or undergo microenvironmental changes that cause the accumulation of unfolded/misfolded proteins. ERS is one of the key responses during the drug treatment of solid tumors. Drugs induce ERS by reactive oxygen species (ROS) accumulation and Ca2+ overload. The unfolded protein response (UPR) is one of ERS. Studies have indicated that the mechanism of ERS-mediated drug resistance is primarily associated with UPR, which has three main sensors (PERK, IRE1α, and ATF6). ERS-mediated drug resistance in solid tumor cells is both intrinsic and extrinsic. Intrinsic ERS in the solid tumor cells, the signal pathway of UPR-mediated drug resistance, includes apoptosis inhibition signal pathway, protective autophagy signal pathway, ABC transporter signal pathway, Wnt/β-Catenin signal pathway, and noncoding RNA. Among them, apoptosis inhibition is one of the major causes of drug resistance. Drugs activate ERS and its downstream antiapoptotic proteins, which leads to drug resistance. Protective autophagy promotes the survival of solid tumor cells by devouring the damaged organelles and other materials and providing new energy for the cells. ERS induces protective autophagy by promoting the expression of autophagy-related genes, such as Beclin-1 and ATG5–ATG12. ABC transporters pump drugs out of the cell, which reduces the drug-induced apoptosis effect and leads to drug resistance. In addition, the Wnt/β-catenin signal pathway is also involved in the drug resistance of solid tumor cells. Furthermore, noncoding RNA regulates the ERS-mediated survival and death of solid tumor cells. Extrinsic ERS in the solid tumor cells, such as ERS in immune cells of the tumor microenvironment (TME), also plays a crucial role in drug resistance by triggering immunosuppression. In immune system cells, ERS in dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) influences the antitumor function of normal T cells, which results in immunosuppression. Meanwhile, ERS in T cells can also cause impaired functioning and apoptosis, leading to immunosuppression. In this review, we highlight the core molecular mechanism of drug-induced ERS involved in drug resistance, thereby providing a new strategy for solid tumor treatment.

scholarly journals Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

2021 ◽  
Author(s):  
Antonio Segovia-Zafra ◽  
Daniel E. Di Zeo-Sánchez ◽  
Carlos López-Gómez ◽  
Zeus Pérez-Valdés ◽  
Eduardo García-Fuentes ◽  
...  
Keyword(s):  
Liver Injury ◽  
Preclinical Models ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Differential introduction of DNA damage and repair in mammalian genes transcribed by RNA polymerases I and II

1991 ◽  
Vol 11 (4) ◽  
pp. 2245-2252
Author(s):  
J M Vos ◽  
E L Wauthier
Keyword(s):  
Chinese Hamster Ovary Cells ◽  
Mammalian Species ◽  
Chinese Hamster ◽  
Rrna Genes ◽  
Dhfr Gene ◽  
Drug Induced ◽  
Dna Damage And Repair ◽  
Ovary Cells ◽  
Interstrand Crosslinks ◽  
Mammalian Genes

We have developed a general quantitative method for comparing the levels of drug-induced DNA crosslinking in specific mammalian genes. We observed a dramatic difference between the efficiency of the removal of both psoralen monoadducts and interstrand crosslinks from the rRNA genes and the efficiency of their removal from the dihydrofolate reductase (DHFR) gene in cultured human and hamster cells. While 90% of the interstand crosslinks were removed from the human DHFR gene in 48 h, less than 25% repair occurred in the rRNA genes. Similarly, in Chinese hamster ovary cells, 85% repair of interstrand crosslinks occurred within 8 h in the DHFR gene versus only 20% repair in the rRNA genes. The preferential repair of the DHFR gene relative to that of the rRNA genes was also observed for psoralen monoadducts in cells from both mammalian species. In human-mouse hybrid cells, the active mouse rRNA genes were five times more susceptible to psoralen modification than are the silent rRNA human genes, but adduct removal was similarly inefficient for both classes. We conclude that the repair of chemical damage such as psoralen photoadducts in an expressed mammalian gene may depend upon the class of transcription to which it belongs.

scholarly journals Targeting Angiogenesis for Controlling Neuroblastoma

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Subhasree Roy Choudhury ◽  
Surajit Karmakar ◽  
Naren L. Banik ◽  
Swapan K. Ray
Keyword(s):  
Clinical Trials ◽  
Combination Therapy ◽  
Tumor Progression ◽  
Solid Tumor ◽  
Therapeutic Strategies ◽  
Preclinical Models ◽  
Malignant Phenotype ◽  
Clinical Challenge ◽  
Genetic Abnormalities ◽  
Tumor In Childhood

Neuroblastoma, a progressive solid tumor in childhood, continues to be a clinical challenge. It is highly vascular, heterogeneous, and extracranial tumor that originates from neural crest. Angiogenesis, genetic abnormalities, and oncogene amplification are mainly responsible for malignant phenotype of this tumor. Survivability of malignant neuroblastoma patients remains poor despite the use of traditional therapeutic strategies. Angiogenesis is a very common and necessary pre-requisite for tumor progression and metastasis. Angiogenesis is also a major factor in making malignant neuroblastoma. Thus, prevention of angiogenesis can be a highly significant strategy in the treatment of malignant neuroblastoma. Here, we summarize our current understanding of angiogenesis in malignant neuroblstoma and describe the use of experimental anti-angiogenic agents either alone or in combination therapy. This review will clearly indicate the importance of angiogenesis in the pathogenesis of malignant neuroblastoma, its prevention as a promising therapy in preclinical models of malignant neuroblastoma, and prospective clinical trials.

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