Biology subjects

Mazumder, S.

Publications and source records attributed to Mazumder, S..

8 recordsLinked to original sources

bioRxiv2026

Dual inhibition of p38α MAPK and Casein kinase δ/ϵ as a novel treatment strategy for AR-independent and taxane-resistant advanced prostate cancer

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer death among US men. Metastatic castration-resistant PCa (mCRPC) is a clinically advanced form of PCa, often associated with increased aggressiveness, metastatic potential, morbidity, and a higher risk of developing resistance to taxanes (TX), the first-line chemotherapy for mCRPC. Furthermore, cancer stemness and epithelial to mesenchymal trans-differentiation (EMT) potentially contribute to aggressiveness and the development of drug resistance in mCRPC. Here, we applied our drug development pipeline, secDrug, which utilizes a pharmacogenomics data-driven computational algorithm, to demonstrate that TAK-715 - a dual inhibitor of p38 MAPK and Casein kinase {delta}/{epsilon}, is a promising treatment for these advanced/lethal variants of PCa. Using in vitro cytotoxicity assays followed by cell-based functional assays in a panel of mCRPC cell lines representing TX-sensitive mCRPC, clonally derived TX-resistant lines, and a highly aggressive metastatic variant of mCRPC, we demonstrated the efficacy of TAK-715 treatment as a single agent and in combination with TX, including cancer stem-like cells. Further, we showed that the apoptotic effects of TAK-715 occur via a mitochondrial-mediated pathway. Bulk tumor RNA sequencing followed by pathway analysis identified genes associated with mitochondrial dysfunction and cell cycle arrest as the top molecular networks associated with TAK-715 single-treatment. HES1, a gene associated with nodal metastasis and PCa progression, was the top differentially expressed gene. Single-cell transcriptomics analysis revealed that TAK-715 treatment erodes the subclonal populations responsible for cancer stemness, metastasis, and drug resistance. The clinical significance of these findings was validated in silico using multiple patient datasets. Our results suggest that TAK-715 treatment has the potential to decrease oncogenic progression and cancer stem cell-like activity in drug-resistant, aggressive, and stem-like mCRPC cells.

cancer biology↗

bioRxiv2026

A functional genomics screen of human B-cell differentiation reveals convergent mechanisms of inherited childhood leukemia predisposition

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer, yet the mechanisms by which inherited risk variants predispose to leukemia development remain poorly understood. A major challenge to studying these mechanisms has been the lack of model systems that faithfully capture the transient developmental states in which predisposition alleles are thought to act. Here, we establish a human B-cell differentiation platform from hematopoietic stem/progenitor cells that enables CRISPR-based engineering, recapitulates early B-cell lymphopoiesis, and enriches for rare developmental intermediates. By applying systematic perturbations with multiplexed single-cell transcriptomic profiling to mimic the effects of mutations in nine familial B-ALL predisposition genes, we decipher mechanisms by which B-cell development can be altered by such inherited variation to predispose to B-ALL. Through these studies, we identify convergent delays in B-cell differentiation at progenitor stages characterized by high-level RAG1/2 recombination activity. We propose that these delays at progenitor stages increase the likelihood that cells can undergo illegitimate RAG-mediated recombination to promote transformation, a finding consistent with similar rates of illegitimate RAG-associated genomic alterations in those with B-ALL associated with familial predisposition variants compared to sporadic cases.

cancer biology↗

bioRxiv2024

Distance between miRNA responsive elements selectively enhances target specificity with reduced cellular toxicity by miRNA-mediated synergism

Despite the emergence of miRNAs as promising therapeutic tools in cancer management, most clinical trials have not been successful due to their cytotoxic effects. Here, we have investigated the factors regulating the effect of miRNA-mimic pairs in enhancing target gene specificity while reducing cellular toxicity. Synergistic reductions by the miRNA-mimic pairs were observed for the 3-UTRs of common target genes with miRNA-responsive elements (MREs) preferentially located at a distance of 200-800bp. Deletion of either of the miRNA seed sequences resulted in a loss of synergism. Furthermore, we performed small RNA-sequencing to identify significantly downregulated miRNAs in Oral cancer. Consequently, we transfected let-7c-5p and miR-125b-5p miRNA mimics either alone or in combination at half-dose concentrations and determined the expression levels of their common and unique target genes in oral cancer cells. Significant reductions in target gene expression were observed for genes containing MREs for both miRNA mimics within the preferential distance. Proteomic data revealed that the let-7c-5p and miR-125b-5p miRNA-mimic pairs synergistically reduced the expression of their common target genes, hexokinase 2 (HK2) and branched-chain amino acid transaminase 1 (BCAT1), in cancer cells. However, unique target genes did not exhibit any significant alterations in their protein levels. The effect of HK2 and BCAT1 downregulation was also reflected in the metabolomic profiling of cancer cells, specifically affecting glycolysis and the BCAA degradation pathways. As a result of the metabolic impairment caused by the synergistic effect of miRNA mimic pairs, oral cancer cells showed a significant reduction in proliferation, migration, and spheroid formation compared to cells treated with either single miRNA. The synergistic effect of these miRNA mimics was lost in normal keratinocytes, possibly due to low expression levels of the target oncogenes, suggesting a cancer cell-specific effect of this mechanism.

cancer biology↗

bioRxiv2022

Integrating pharmacogenomics data-driven prediction with bulk and single-cell RNAseq to demonstrate the efficacy of an NAMPT inhibitor against aggressive, taxane-resistant, and stem-like cells in lethal prostate cancer

Metastatic prostate cancer is the second leading cause of cancer deaths in US men. Resistance to standard medical castration and secondary taxane-based chemotherapy is nearly universal. Further, presence of cancer stem-like cells (EMT/epithelial to mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/advanced/lethal variants of PCa (AVPC). In this study, first we used single-cell RNA sequencing (scRNAseq) analysis to demonstrate that ARlow PCa cells in metastatic prostate cancer, including castration-sensitive tumors, harbored signatures of EMT, and cancer stemness. Next, we introduced a novel pharmacogenomics data-driven computational approach and identified several potential agents that can be re-purposed as novel secondary drugs ("secDrugs") to treat advance variants of Prostate cancer. Using scRNAseq as a biomarker-based drug screen, we demonstrated that a majority of the single-cell subclones in mCRPC and mCSPC cell lines also showed significantly high expression of the NAMPT pathway genes, indicating that the secDrug FK866, which targets NAMPT, is potentially effective against drug-resistant and stem-cell-like subpopulation cluster. Next, we showed significant in vitro cytotoxicity of FK866 as single-agent and in combination with the taxanes or Enzalutamide against models of clinically-advanced PCa. We performed bulk- and single-cell RNAseq to identify several pathways underlining FK866 mechanism of action and found that in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness-related genes HES1 and CD44. Further, we performed a microfluidic chip-based cell migration assay that demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using multiple PCa patient datasets, we showed that FK866 is potentially capable of reversing expression of several genes associated with biochemical recurrence and inter-ethnic differences, including IFITM3 and LTB4R. Thus, using FK866 as a proof-of-concept drug, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa.

molecular biology↗

bioRxiv2020

Recapitulating tumor microenvironment using preclinical 3D tissueoids model for accelerating cancer research and drug screening

The formation of three-dimensional spheroid tumor model using the scaffold-based platforms has been demonstrated over many years now. 3D tumor models are generated mainly in non-scalable culture systems, using synthetic and biological scaffolds. Many of these models fail to reflect the complex tumor microenvironment and do not allow long-term monitoring of tumor progression. This has resulted in inconsistent data in drug testing assays during preclinical and clinical studies. To overcome these limitations, we have developed 3D tissueoids model by using novel AXTEX-4D platform. Cancer 3D tissueoids demonstrated the basic features of 3D cell culture with rapid attachment, proliferation, and longevity with contiguous cytoskeleton and hypoxic core. This study also demonstrated greater drug resistance in 3D-MCF-7 tissueoids in comparison to 2D monolayer cell culture and the collagen-based 3D system. In conclusion, 3D-tissueoids are more responsive than 2D-cultured cells in simulating important tumor characteristics, anti-apoptotic features, and their resulting drug resistance.

cancer biology↗

bioRxiv2020

AXTEX-4D™: A Novel 3D ex vivo platform for preclinical investigations of immunotherapy agents

The latest advancements in oncology are majorly focused on immuno-oncology (I-O) therapies. However, only ~7% of drugs are being approved from the preclinical discovery phase to phase 1. The most challenging issues in I-O is the problem of developing active and efficient drugs economically and on time. This mandates an urgent need for better preclinical screening models that closely mimic the in vivo tumor microenvironment. The established and most common methods for investigating the tumoricidal activity of I-O drugs are either two-dimensional (2D) systems or primary tumor cells in standard tissue culture vessels. However, they do not mimic the tumor microenvironment. Therefore, the more in vivo-like three-dimensional (3D) multicellular tumor spheroids are quickly becoming the favored model to examine immune cell-mediated responses in reaction to the administration of I-O drugs. Accordingly, we have demonstrated the utility of the three-dimensional ex vivo oncology model, developed on our novel AXTEX-4D platform to assess therapeutic efficacies of I-O drugs by investigating immune cell proliferation, migration, infiltration, cytokine profiling, and cytotoxicity of tumor tissueoids. The platform eliminates the need for additional biomolecules such as hydrogels and instead relies on the cancer cells themselves to create their own gradients and microenvironmental factors. In effect, the more comprehensive and in vivo like immune-oncology model developed on AXTEX-4D platform can be utilized for high-throughput screening of immunotherapeutic drugs.

immunology↗

bioRxiv2020

PRAK-03202: A triple antigen VLP vaccine candidate against SARS CoV-2

The rapid development of safe and effective vaccines against SARS CoV-2 is the need of the hour for the coronavirus outbreak. Here, we have developed PRAK-03202, the worlds first triple antigen VLP vaccine candidate in a highly characterized S. cerevisiae-based D-CryptTM platform, which induced SARS CoV-2 specific neutralizing antibodies in BALB/c mice. Immunizations using three different doses of PRAK-03202 induces antigen specific (Spike, envelope and membrane proteins) humoral response and neutralizing potential. PBMCs from convalescent patients, when exposed to PRAK-03202, showed lymphocyte proliferation and elevated IFN-{gamma} levels suggestive of conservation of epitopes and induction of T helper 1 (Th1)-biased cellular immune responses. These data support the clinical development and testing of PRAK-03202 for use in humans.

immunology↗

bioRxiv2019

Neural Mediators of Altered Perceptual Choice and Confidence Using Social Information

Understanding how individuals utilize social information while making perceptual decisions and how it affects their decision confidence is crucial in a society. Till date, very little is known about perceptual decision making in humans under the influence of social cues and the associated neural mediators. The present study provides empirical evidence of how individuals get manipulated by social cues while performing a face/car identification task. Subjects were significantly influenced by what they perceived as decisions of other subjects while the cues in reality were manipulated independently from the stimulus. Subjects in general tend to increase their decision confidence when their individual decision and social cues coincide, while their confidence decreases when cues conflict with their individual judgments often leading to reversal of decision. Using a novel statistical model, it was possible to rank subjects based on their propensity to be influenced by social cues. This was subsequently corroborated by analysis of their neural data. Neural time series analysis revealed no significant difference in decision making using social cues in the early stages unlike neural expectation studies with predictive cues. Multivariate pattern analysis of neural data alludes to a potential role of frontal cortex in the later stages of visual processing which appeared to code the effect of social cues on perceptual decision making. Specifically medial frontal cortex seems to play a role in facilitating perceptual decision preceded by conflicting cues.

neuroscience↗