Biology subjects

Manne, U.

Publications and source records attributed to Manne, U..

5 recordsLinked to original sources

bioRxiv2025

UALCAN Mobile, an app for cancer proteogenomic data analysis.

Cancer is a complex disease affecting various organs and is a major cause of death worldwide. During cancer initiation, disease progression, and tumor metastasis, various genomic and proteomic alterations are observed. Recent technological advances have led to the generation of large amounts of molecular data, including genomics and transcriptomics. These large-scale datasets can be utilized to analyze and identify sub-class-specific cancer biomarkers and targets. However, there is a need for the development of user-friendly tools for large-scale data analysis, disseminating the analyzed data in a visualizable format to cancer researchers with no programming skills. We developed UALCAN, a comprehensive platform that allows users to integrate disparate data to better understand the genes, proteins, and pathways perturbed in cancer and make discoveries of potential biomarkers and targets. In the current study, we describe the development of the UALCAN Mobile application (app) that will provide cancer transcriptomic data obtained from The Cancer Genome Atlas (TCGA) project to evaluate protein-coding gene expression based on various stratifications, including stage, grade, race, gender, and molecular-subtypes across over 30 types of cancers. In addition, the UALCAN mobile provides data analysis options for epigenetic changes due to DNA promoter methylation and Clinical Proteomic Tumor Analysis Consortium (CPTAC) cancer proteomic data. The app provides access to large cancer molecular datasets on the go. To find changes in the expression of causative genes and proteins and to identify biomarkers and therapeutic targets, UALCAN mobile app will be extremely valuable. The "UALCAN Mobile" app is free to use and can be downloaded from both the iOS/Apple and the Android Play Store and has been downloaded over 100 times in each of iOS and android app stores. Key PointsO_LICancer, a complex disease affecting various organs, is a major cause of death worldwide. C_LIO_LIMany molecular alterations, gene and protein expression changes lead to the initiation of cancer, disease progression, and tumor metastasis. C_LIO_LIThe available large genomic and proteomics datasets can be utilized to analyze and identify sub-class-specific cancer biomarkers and targets with innovative tools. C_LIO_LIUALCAN Mobile application (app) will provide gene expression, promoter DNA methylation, and protein expression across cancers based on various stratifications, including stage, grade, and molecular subtypes across over 30 types of cancers. C_LIO_LIUALCAN Mobile app is free and can be downloaded from both iOS/Apple and the Android Play Store. C_LI

bioinformatics↗

bioRxiv2024

ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma

Here, we evaluated in vivo antitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations. ADT-1004 treatment increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRASG12C inhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RASWT PDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development. SignificanceADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

cancer biology↗

bioRxiv2021

ARID1A-mutant and deficient bladder cancer is sensitive to EZH2 pharmacologic inhibition

Metastatic urothelial carcinoma of the bladder is generally incurable by current systemic therapy. Molecular characterization of bladder cancer (BLCa) has revealed multiple candidate driver genes for BLCa tumorigenesis. Epigenetic/chromatin modifiers have been shown to be frequently mutated in BLCa, with ARID1A mutations highly prevalent in nearly 20% of early and late stage tumors. EZH2 is a histone methyltransferase that acts as an oncogene. The data herein show that ARID1A deficient tumors, but not ARID1A wild-type tumors are sensitive to EZH2 inhibition. Specifically, EZH2 inhibitor-treated ARID1A deficient bladder cancer cells show significantly reduced cell viability, colony formation, and in vivo tumor growth relative to ARID1A-wild type bladder cancer cells. Thus, our study suggests that a specific subset of bladder cancer patients with ARID1A mutations can be therapeutically treated with pharmacologic inhibitors targeting EZH2.

cancer biology↗

bioRxiv2020

Comparative transcriptome analyses reveal genes associated with SARS-CoV-2 infection of human lung epithelial cells

Understanding the molecular mechanism of SARS-CoV-2 infection (the cause of COVID-19) is a scientific priority for 2020. Various research groups are working toward development of vaccines and drugs, and many have published genomic and transcriptomic data related to this viral infection. The power inherent in publicly available data can be demonstrated via comparative transcriptome analyses. In the current study, we collected high-throughput gene expression data related to human lung epithelial cells infected with SARS-CoV-2 or other respiratory viruses (SARS, H1N1, rhinovirus, avian influenza, and Dhori) and compared the effect of these viruses on the human transcriptome. The analyses identified fifteen genes specifically expressed in cells transfected with SARS-CoV-2; these included CSF2 (colony-stimulating factor 2) and S100A8 and S100A9 (calcium-binding proteins), all of which are involved in lung/respiratory disorders. The analyses showed that genes involved in the Type1 interferon signaling pathway and the apoptosis process are commonly altered by infection of SARS-CoV-2 and influenza viruses. Furthermore, results of protein-protein interaction analyses were consistent with a functional role of CSF2 in COVID-19 disease. In conclusion, our analysis has revealed cellular genes associated with SARS-CoV-2 infection of the human lung epithelium; these are potential therapeutic targets.

bioinformatics↗

bioRxiv2019

Therapeutically actionable PAK4 is amplified, overexpressed and involved in bladder cancer progression

Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Disease incidence and survival rates vary based on aggressiveness and treatment options. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. For a minority ([~]20%) of patients, T-cell checkpoint inhibitors provide durable benefits following prior platinum therapy. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting heterogeneity in these tumors and pointing to the importance of molecular characterization of MIBCs to provide effective treatment. We have performed multi-omic profiling of the kinome to identify therapeutic targets that are overexpressed in a subset of BLCAs. Our analyses revealed amplification and overexpression of P21 (RAC1) activated kinase 4 (PAK4) in a subset of BLCAs. For these tumors, multiplex kinase assay profiling identified corresponding PAK4 target substrates. By performing experiments using cultured bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, our studies showed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, Protein Tyrosine Kinase 6 (PTK6), upon treatment with a PAK4 inhibitor. Similarly, RNA interference of PAK4 led to elevated expression of PTK6. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared to either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

cancer biology↗