Biology subjects

Jalal, S. I.

Publications and source records attributed to Jalal, S. I..

3 recordsLinked to original sources

bioRxiv2026

Effects of the Hypomethylating Agent Guadecitabine on Peripheral Blood Mononuclear Cell Methylomes and Immune Cell Populations in Small-Cell Lung Cancer Patients

BackgroundSmall-cell lung cancer (SCLC) represents 15% of lung cancers and with a 5-year survival rate under 7% remains one of the deadliest malignancies. Although initially responsive to chemotherapy, rapid recurrence and resistance are common. Epigenetic modifications, particularly DNA methylation, contribute to tumor progression and therapy resistance. Guadecitabine, a hypomethylating agent (HMA), has shown promising clinical activity when combined with carboplatin in preclinical models. We evaluated the combination of guadecitabine with carboplatin as a second-line treatment for extensive-stage SCLC (NCT03913455). Here we report methylome changes in peripheral blood mononuclear cell (PBMCs) collected at baseline and during treatment from patients on the trial. ResultsPMBC DNA was analyzed using Infinium HumanMethylationEPIC v1.0 bead chips. Data were processed and differentially methylated positions (DMPs) were identified and analyzed for pathway enrichment using bioinformatic approaches and immune deconvolution analyses were conducted to investigate the impact on immune cell composition. Direct comparison of PBMCs between cycle 2 day 5 (C2D5; post-treatment) vs cycle 1 day 1 (C1D1; pre-treatment) revealed a greater number of hypomethylated DMPs (380 DMPs in C2D5 vs C1D1 PBMCs; p < 0.05, |{beta}| > 20%). Moreover, when first compared with normal PBMCs from cancer-free controls, the number of hypomethylated DMPs was even greater in C2D5 than in C1D1 (1,771 vs 237 DMPs, respectively; p < 0.05, |{beta}| > 20%). Long interspersed nucleotide elements-1 (LINE-1) were also significantly hypomethylated in PBMCs after HMA treatment (C2D5), compared to C1D1. Pathway analysis of hypomethylated DMPs revealed significant alterations in key signaling pathways including NF-{kappa}B, Rho GTPase, pulmonary fibrosis, and p75 NTR in C1D1 vs C2D5. When normal PBMCs were compared to C1D1 PBMCs, changes in IL-3 signaling, Fc{gamma} receptor-mediated phagocytosis, and molecular mechanisms of cancer were observed. Deconvolution analysis revealed a significantly higher percentage of monocytes in C1D1 PBMCs vs normal PBMCs. However, after HMA treatment, percentages of monocytes and B cells decreased, while eosinophil percentage increased in C1D1 compared to C2D5 PBMCs. ConclusionIn the first study on the global impact of HMA treatment on PBMC methylomes in SCLC patients, DNA methylation changes associated with biological pathways related to PBMC function reveal shifts in distinct immune cell populations. SummaryMethylome changes in peripheral blood mononuclear cell (PBMCs) from small cell lung cancer (SCLC) patients treated with an epigenetic therapy revealed global hypomethylation and altered cancer signaling processes associated with tumor progression, immune response, therapy resistance and significant change in the proportion of immune cells. Integrating blood-based methylation biomarkers into clinical trials of epigenetic therapy and methylomic analysis of PBMCs provides direct monitoring of treatment effects in cancer patients, which may improve patient selection and enable real-time response assessment in patients receiving hypomethylating agents.

genomics↗

bioRxiv2025

Potentiation of EGFR mutant lung cancer treatment targeting replication stress.

Background/ObjectivesOncogene-targeted therapies against growth factor receptors are effective treatment options for driver mutation-positive non-small cell lung cancer (NSCLC). The third-generation EGFR-Tyrosine Kinase inhibitor (TKI) osimertinib, is a standard first-line therapy for patients with EGFR-mutated NSCLC cancer. Acquired resistance to osimertinib is a significant problem that limits survival. In addition to that clinical data show approximately 15% of EGFR mutant non-small cell lung cancer patients have innate resistance to Osimertinib. Tumor heterogeneity and multiple resistance mechanisms add to the complexity of EGFR-mutated NSCLC. Tumor cells that acquire resistance, independent of the mechanism, experience replication stress (RS) as proliferation resumes. MethodsWe have employed a series of non-small cell lung cancer models to assess the efficacy of combining osimertinib with NERx-329, targeting RS via inhibiting RPA, and the impact of these treatments on growth and damage signaling pathways. ResultsWe demonstrate that targeting RS with RPAi treatment induces cell death in multiple EGFR-mutant cell lines alone and when combined with osimertinib. Dissection of signaling pathways revealed that RPAi treatment does not block osimertinib inhibition of EGFR signaling. Analysis of DNA damage response (DDR) signaling reveals that NERx329 potentiates the osimertinib-dependent downregulation of Chk1 activity and expression. The Chk1 loss was shown to be dependent on proteasome degradation as proteasome inhibitor MG-132 restores Chk1 activity and expression. ConclusionsFrom these data, we infer that targeting RS via RPAi NERx-329 in combination with osimertinib is an effective strategy and represents a promising drug combination targeted therapy to enhance efficacy and limit the development of resistance. Simple SummaryThis research aims to assess a new mechanism to potentiate osimertinib treatment of EGFR-mutated non-small cell lung cancer. Targeting replication stress with the small molecule Replication proteins A inhibitor (RPAi), NERx-329, induces cancer cell death and enhance the effectiveness of osimertinib. The findings suggest that combining NERx-329 with osimertinib could be a promising strategy to improve treatment outcomes and reduce resistance. Importantly, we demonstrate that neither RPAi or osimertinib alter the anticancer mechanism of each single agent, providing a new approach to increase therapeutic efficacy and delay or eliminate the development of drug resistance.

cancer biology↗

bioRxiv2020

Chemical exhaustion of RPA in cancer treatment

Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination and the DNA-damage response (DDR). We have developed second generation RPA inhibitors (RPAis) that block the RPA-DNA interaction. These DNA-binding inhibitors (DBis) can elicit a state of cellular RPA exhaustion resulting in single agent in vitro anticancer activity across a broad spectrum of cancers and in vivo activity in two non-small cell lung cancer models. The cellular response to RPAi treatment suggests a threshold exists before RPA inhibition induces cell death. Chemical RPA exhaustion potentiates the anticancer activity of other DDR inhibitors as well as traditional DNA damaging cancer therapeutics. Consistent with the chemical RPA exhaustion model, we demonstrate that the effects of RPAi on replication fork dynamics and DNA damage signaling are similar to other known DDR inhibitors. In accordance with the RPA threshold model, retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. These data demonstrate a unique mechanism of action of RPAis eliciting a state of RPA exhaustion that impacts the DDR and may provide an effective therapeutic option for difficult to treat lung cancers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/404640v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@d662e4org.highwire.dtl.DTLVardef@f68b11org.highwire.dtl.DTLVardef@241c0corg.highwire.dtl.DTLVardef@ad7398_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗