Biology subjects

D'Souza, J.

Publications and source records attributed to D'Souza, J..

5 recordsLinked to original sources

bioRxiv2025

Acute Myeloid Leukemia Relapse after Bromodomain Inhibitor Treatment or Chemotherapy is Characterized by Myc-Ras Transcriptional Remodeling

Adult and pediatric acute myeloid leukemias (AMLs) harbor distinct mutational profiles, including a higher incidence of RAS and other signaling mutations in young patients. Here we show that the BET inhibitor PLX51107 potently suppresses the growth of NRAS-mutant AML cell lines, and that these activities are enhanced by co-treatment with the MEK inhibitor PD0325901. Controlled preclinical trials in primary mouse Nras-mutant AMLs revealed single agent efficacy of PLX51107 that was enhanced by PD0325901. Leukemias that relapsed during treatment developed intrinsic drug resistance characterized by transition to a more primitive state, up-regulation of Myc target genes, and down-regulation of Ras-associated transcriptional programs. AMLs that relapsed after frontline chemotherapy showed similar transcriptional remodeling. These studies demonstrate transcriptional plasticity in primary AMLs that relapse following in vivo treatment with either targeted agents or chemotherapy, and support evaluating BET inhibition in leukemias with monocytic differentiation and RAS mutations.

cancer biology↗

bioRxiv2025

DeepResearch_Eco: A Recursive Agentic Workflow for Complex Scientific Question Answering in Ecology

We introduce DeepResearchEco, a novel agentic LLM-based system for automated scientific synthesis that supports recursive, depth- and breadth-controlled exploration of original research questions--enhancing search diversity and nuance in the retrieval of relevant scientific literature. Unlike conventional retrieval-augmented generation pipelines, DeepResearch enables user-controllable synthesis with transparent reasoning and parameter-driven configurability, facilitating high-throughput integration of domain-specific evidence while maintaining analytical rigor. Applied to 49 ecological research questions, DeepResearch achieves up to a 21-fold increase in source integration and a 14.9-fold rise in sources integrated per 1,000 words. High-parameter settings yield expert-level analytical depth and contextual diversity. Source code available at: https://github.com/sciknoworg/deep-research.

ecology↗

bioRxiv2025

TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with KMT2A-rearrangements or NPM1 mutations. However, mechanisms of de novo resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of TP53 mutations on the response of AML cells to revumenib. TP53 mutations are associated with de novo resistance to revumenib, impaired induction of TP53 transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53-mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A-rearranged leukemias with TP53 mutations.

cancer biology↗

bioRxiv2021

A new drug candidate for glycogen storage disorders enhances glycogen catabolism: Lessons from Adult Polyglucosan Body Disease models

This work employs Adult Polyglucosan Body Disease (APBD) models to explore the efficacy and mechanism of action of 144DG11, a new polyglucosan-reducing lead compound discovered by a high-throughput screen (HTS). APBD is an adult onset glycogen storage disorder (GSD) manifesting as a debilitating progressive axonopathic leukodystrophy. APBD is caused by glycogen branching enzyme (GBE) deficiency leading to poorly branched and insoluble glycogen inclusions, which precipitate as neuropathogenic polyglucosans (PG). 144DG11 led to prolonged survival and improved motor parameters in a GBE knockin (Gbeys/ys) APBD mouse model. Histopathologically, 144DG11 reduced PG and glycogen levels in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic PG. These results were also reflected at the cellular level by increased glycolytic, mitochondrial and total ATP production. Mechanistically, we show that the molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. Enhanced mitochondrial activity and lysosomal modifications were also the most pronounced effects of 144DG11 in APBD patient fibroblasts as discovered by image-based multiparametric phenotyping analysis and corroborated by proteomics. In summary, this work presents a broad mechanistic and target-based characterization of 144DG11 in in vivo and cell models of the prototypical GSD APBD. This investigation warrants development of 144DG11 into a safe and efficacious GSD therapy. One Sentence SummaryA new compound, demonstrated to ameliorate APBD in vivo and ex vivo by autophagic catabolism of glycogen, may potentially become a universal drug for glycogen storage disorders.

neuroscience↗

bioRxiv2020

Kinome Profiling of Gastrointestinal Stromal Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies Wee1 as Candidate Therapeutic Target

Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA, and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical problem. Development of effective treatment strategies for refractory GIST subtypes requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes and identified kinases that are universally activated in all GIST, as well as kinases that are unique to each subtype. Kinome profiling in combination with loss-of-function assays identified a significant role for the G2-M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT and PDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

cancer biology↗