Biology subjects

Azzoli, C. G.

Publications and source records attributed to Azzoli, C. G..

5 recordsLinked to original sources

bioRxiv2026

Next-Generation Imipridones ONC206 and ONC212 Synergize with Lurbinectedin in Killing Pancreatic Ductal Adenocarcinoma Cells

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a five-year survival rate of approximately 13%, underscoring the urgent need for novel therapeutic strategies. Next-generation imipridones ONC206 and ONC212 are potent anticancer agents that activate the mitochondrial ClpP protease and the integrated stress response. Lurbinectedin, an FDA-approved therapy for metastatic small cell lung cancer, inhibits transcription by binding the DNA minor groove and has demonstrated preclinical efficacy in PDAC models. Here, we show that ONC206 and ONC212 are highly cytotoxic against PDAC cell lines as monotherapies and in combination with lurbinectedin. Both ONC206 and ONC212 achieved sub-micromolar seventy-two-hour IC values in BxPC-3, PANC-1, and HPAF-II PDAC cells, with ONC212 exhibiting greater potency across all lines. Mechanistically, ONC206 and ONC212 induce apoptosis through ClpX depletion, ATF4 induction, and caspase-mediated PARP cleavage. Combination treatment of lurbinectedin with both imipridones produced robust synergy, with ONC212 generally exhibiting stronger synergy at lower concentrations and HSA synergy scores up to 29.5. Importantly, these combinations showed minimal toxicity in CCD 841 CoN non-malignant colon epithelial cells, indicating selective tumor cell killing. Western blot analysis revealed that synergy between lurbinectedin and ONC212 is associated with upregulation of DR5 and downregulation of Bcl-2 and ClpX. These findings provide mechanistic and preclinical support for combining lurbinectedin with next-generation imipridones as a therapeutic strategy in PDAC.

cancer biology↗

bioRxiv2026

Synergistic cytotoxicity with Chk1/Chk2-inhibitor prexasertib in small cell lung cancer following lurbinectedin-induced G2/M-checkpoint activation

Small cell lung cancer (SCLC) is an aggressive thoracic malignancy with a 5-year survival rate under 7%. Lack of meaningful improvement of survival rates despite advances in treatment highlights the need for novel therapeutic approaches to improve patient outcomes. Currently, carboplatin + etoposide chemotherapy is the backbone of treatment for most patients. Lurbinectedin is a cytotoxic drug with unique activity against small cell lung cancers in patients with extensive disease and acquired resistance to carboplatin + etoposide. Our preliminary experiments in human SCLC cell lines treated with lurbinectedin demonstrated a dose-dependent increase in Chk1 and Chk2 protein phosphorylation. A consequence of the frequent TP53 inactivation in SCLC is tumor cell reliance on G2/M cell cycle checkpoints involving Chk1/Chk2 to maintain genomic integrity and allow cell survival following DNA damage. We hypothesised that inhibition of Chk1/Chk2-dependent responses with dual-inhibitor prexasertib (ACR-368), would potentiate tumor cell killing by lurbinectedin potentially in a synergistic manner. SCLC cells underwent cell death following single agent prexasertib exposure and this further increased with prexasertib + lurbinectedin combination. Highest Single Agent (HSA) synergy score calculations based on cell viability measurements suggested synergistic action between prexasertib and lurbinectedin at select dose combinations. Western blot analysis of intracellular proteins from SCLC cells treated with both drugs demonstrate dynamic, dose-dependent effects on Chk2, Chk1 and downstream effector Wee1, with lurbinectedin increasing intracellular levels of pChk1 and pChk2, while co-treatment with prexasertib deregulates this process across multiple human-derived cell lines. Synergistic killing was associated with elevated {psi}-H2AX levels indicative of DNA double strand breaks and PARP-cleavage due to apoptotic caspase activation. Despite some heterogeneity among treated SCLC cells, the increased phosphorylation of Chk1 was noted at several kinase-activating sites including Serine 296, 317, and 345 while Chk2 Tyrosine 68 phosphorylation was consistently upregulated by lurbinectedin. The results provide a preclinical mechanistic rationale for overcoming a pro-survival, drug resistance-promoting checkpoint pathway to enhance the unique efficacy of single-agent lurbinectedin in patients with SCLC.

cancer biology↗

bioRxiv2026

A Multimodal Neural Network Model for Early Recurrence Prediction in Lung Adenocarcinoma

Lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), is the most common primary lung cancer worldwide. Despite advancements in early detection and treatment, up to 39% of patients develop recurrent tumors following complete resection. Currently, no widely available models exist for reliably predicting early recurrence of LUAD, which is a significant prognostic factor of post-recurrence survival. Models leveraging deep learning (DL) techniques have demonstrated notable utility in cancer recurrence prediction, particularly when used in combination with both clinical and genomic data. We developed a DL-based model, Predicting Lung Adenocarcinoma recurrence via Selective Multimodal Attention (PLASMA), to predict early recurrence using clinical, mRNA expression, and mutation data from patients with primary stage I-III LUAD. Trained on The Cancer Genome Atlas (TCGA) dataset, PLASMA outperformed traditional machine learning models in predicting early recurrence in both the TCGA test set and an external validation set (TRACERx Lung), achieving area under the receiver operating characteristic curve (AUROC) scores of 85.0% and 76.5%, respectively. Our results support the potential of multimodal DL for early LUAD recurrence prediction and risk stratification.

bioinformatics↗

bioRxiv2023

Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer

Pancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin stalls and degrades RNA Polymerase II and introduces breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedins highly efficient killing of human-derived pancreatic tumor cell lines PANC-1, BxPC-3, and HPAF-II as a single agent. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of {gamma}H2AX, a DNA damage marker, and the Chk1/ATR pathway, involved in replicative stress and DNA damage response. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-fluorouracil (5-FU) results in highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer.

cancer biology↗

bioRxiv2023

TRAIL agonists rescue mice from radiation-induced lung injury

Cancer therapy is often limited by toxicity from pneumonitis. This often-lethal side effect is known to be impacted by innate immunity, and in particular the pathways regulated by the TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from the lethal effects of radiation. We found that two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound #10 (TIC10/ONC201), could achieve this goal. Both compounds could completely protect mice from lethality by reducing pneumonitis, alveolar-wall thickness, and oxygen desaturation. At the molecular level, this protection appeared to be due to the inhibition of CCl22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from high doses of radiation exposure has important translational implications. One Sentence SummaryPrevention of lethality, pneumonitis, lung fibrosis and skin dermatitis post-{psi}-irradiation by short- term treatment with innate immune TRAIL pathway agonists

pathology↗