A novel strategy for combination of clofarabine and pictilisib is synergistic in gastric cancer

Khalafi, Shayan; Zhu, Shoumin; Khurana, Rimpi; Giordano, Silvia; Corso, Simona; Hassan, Abdulaziz; Wahlestedt, Claes; Schürer, Stephan C.; El–Rifai, Wael

doi:10.1016/j.tranon.2021.101260

Cited by 7 publications

(3 citation statements)

References 49 publications

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“…Unfortunately, when used to treat multiple sclerosis, cladribine can lead to acute, specific liver harm in individuals ( 42 ). Additionally, clofarabine is employed as an anticancer therapy for several solid tumors, including bladder ( 43 ), stomach ( 44 ), and breast malignancies ( 45 ). Since fludarabine dramatically reduces the release of HBV progenitor DNA, it has been used to treat HBV infection and enhance the prognosis of HCC that is related to HBV ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma

Zhang

Yuan

2023

Front. Immunol.

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IntroductionNatural killer (NK) cells play an irreplaceable and important role as a subtype of innate immune cells in the contemporary setting of antitumor immunity.MethodsWe chose a total of 1,196 samples for this analysis from the public dataset’s six separate cohorts. To identify 42 NK cell marker genes, we first carried out a thorough study of single-cell RNA sequencing data from the GSE149614 cohort of hepatocellular carcinoma (HCC).ResultsUsing the NK cell marker genes in the TCGA cohort, we next created a seven-gene prognostic signature, separating the patients into two categories with distinct survival patterns. This signature’s prognostic prediction ability was well verified across several validation cohorts. Patients with high scores had higher TIDE scores but lower immune cell infiltration percentages. Importantly, low-scoring patients had superior immunotherapy response and prognosis than high-scoring patients in an independent immunotherapy cohort (IMvigor210). Finally, we used CD56 and TUBA1B antibodies for immunohistochemical labeling of HCC tissue sections, and we discovered a lower number of CD56+ cells in the HCC tissue sections with high TUBA1B expression.DiscussionIn summary, our research created a unique prognostic profile based on NK cell marker genes that may accurately predict how well immunotherapy would work for HCC patients.

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Section: Discussionmentioning

confidence: 99%

Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma

Zhang

Yuan

2023

Front. Immunol.

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“…Similarly, analysis of apoptosis with Annexin V/FITC and western blot indicated GPC-1 knockdown sensitized ESO-26 and OE-33 cells to Pictilisib induced apoptosis which is in agreement with previous reports which have shown that apoptosis response in PI3K/Akt inhibition is mediated by increased mitochondrial membrane damage and caspase 3 activation. 37 , 38 Collectively, the results indicate that by introducing GPC-1 blockade to chemotherapy regimens, the number of cells that are immune to the drug could be reduced, thereby improving the outcomes of therapy. The findings of the in vitro study were corroborated by the in vivo investigation conducted on murine xenograft model.…”

Section: Discussionmentioning

confidence: 99%

Silencing Glypican-1 enhances the antitumor effects of Pictilisib via downregulating PI3K/Akt/ERK signaling in chemo-resistant esophageal adenocarcinoma

Pratap,

Qualman,

Garrett

et al. 2023

Molecular & Cellular Oncology

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Poorly differentiated esophageal adenocarcinoma (PDEAC) has a dismal prognosis. Glypican-1(GPC-1) is known to be upregulated in several cancer types in contrast to healthy tissues, rendering it as a biomarker. Nevertheless, the potential therapeutic targeting of GPC-1 has not been explored in PDEAC. There is accumulating evidence that GPC-1, via upregulation of PI3K/Akt/ERK signaling, plays a crucial role in the progression and chemoresistance in cancer. Pictilisib, a class I pan PI3K inhibitor, has shown promising antitumor results in clinical trials, however, has not gained widespread success due to acquired drug resistance. This study investigated the role of GPC-1 in chemo-resistant PDEAC and appraises the impact of targeted silencing of GPC-1 on the antitumor effects of Pictilisib in PDEAC cell lines. Immunohistochemistry assays in PDEAC tissue specimens demonstrated a pronounced intensity of staining with GPC-1. Upregulation of GPC-1 was found to be correlated with advanced stage and poor prognosis. In-vitro studies examined the influence of GPC-1 knockdown and Pictilisib, both as individual agents and in combination, on cytotoxicity, cell cycle distribution, apoptosis, and gene expression profiles. Silencing GPC-1 alone showed significantly reduced cell viability, migration, colony formation, epithelial-mesenchymal transition, and stemness in PDEAC cells. Significantly, knockdown of GPC-1 combined with low-dose Pictilisib led to enhancement of cytotoxicity, cell cycle arrest, and apoptosis in ESO-26 and OE-33 cells. In the xenograft mouse model, the combination of Pictilisib and GPC-1 knockdown exhibited synergy. These findings suggest that GPC-1 represents a promising target to augment chemosensitivity in esophageal adenocarcinoma.

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“…However, our analysis has some limitations. Recent studies have reported new strategies for combining two drugs to treat tumors; therefore, further mining of data available in databases for assessing the sensitivity exhibited by patients after combining two or more drugs is needed in our subsequent studies (73). In addition, Schürer and his concurrent report that the Clinical Kinase Index can be used as a method to prioritize understudied kinases as drug targets for cancer therapy, providing great value for the development of clinical biomarkers or drug targets (74).…”

Section: Discussionmentioning

confidence: 99%

Elucidating the Influence of MPT-driven necrosis-linked LncRNAs on immunotherapy outcomes, sensitivity to chemotherapy, and mechanisms of cell death in clear cell renal carcinoma

Huang,

Liu,

Chen

et al. 2023

Front. Oncol.

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BackgroundClear cell renal carcinoma (ccRCC) stands as the prevailing subtype among kidney cancers, making it one of the most prevalent malignancies characterized by significant mortality rates. Notably,mitochondrial permeability transition drives necrosis (MPT-Driven Necrosis) emerges as a form of cell death triggered by alterations in the intracellular microenvironment. MPT-Driven Necrosis, recognized as a distinctive type of programmed cell death. Despite the association of MPT-Driven Necrosis programmed-cell-death-related lncRNAs (MPTDNLs) with ccRCC, their precise functions within the tumor microenvironment and prognostic implications remain poorly understood. Therefore, this study aimed to develop a novel prognostic model that enhances prognostic predictions for ccRCC.MethodsEmploying both univariate Cox proportional hazards and Lasso regression methodologies, this investigation distinguished genes with differential expression that are intimately linked to prognosis.Furthermore, a comprehensive prognostic risk assessment model was established using multiple Cox proportional hazards regression. Additionally, a thorough evaluation was conducted to explore the associations between the characteristics of MPTDNLs and clinicopathological features, tumor microenvironment, and chemotherapy sensitivity, thereby providing insights into their interconnectedness.The model constructed based on the signatures of MPTDNLs was verified to exhibit excellent prediction performance by Cell Culture and Transient Transfection, Transwell and other experiments.ResultsBy analyzing relevant studies, we identified risk scores derived from MPTDNLs as an independent prognostic determinant for ccRCC, and subsequently we developed a Nomogram prediction model that combines clinical features and associated risk assessment. Finally, the application of experimental techniques such as qRT-PCR helped to compare the expression of MPTDNLs in healthy tissues and tumor samples, as well as their role in the proliferation and migration of renal clear cell carcinoma cells. It was found that there was a significant correlation between CDK6-AS1 and ccRCC results, and CDK6-AS1 plays a key role in the proliferation and migration of ccRCC cells. Impressive predictive results were generated using marker constructs based on these MPTDNLs.ConclusionsIn this research, we formulated a new prognostic framework for ccRCC, integrating mitochondrial permeability transition-induced necrosis. This model holds significant potential for enhancing prognostic predictions in ccRCC patients and establishing a foundation for optimizing therapeutic strategies.

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A novel strategy for combination of clofarabine and pictilisib is synergistic in gastric cancer

Cited by 7 publications

References 49 publications

Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma

Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma

Silencing Glypican-1 enhances the antitumor effects of Pictilisib via downregulating PI3K/Akt/ERK signaling in chemo-resistant esophageal adenocarcinoma

Elucidating the Influence of MPT-driven necrosis-linked LncRNAs on immunotherapy outcomes, sensitivity to chemotherapy, and mechanisms of cell death in clear cell renal carcinoma

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