CXCR1/2 dual-inhibitor ladarixin reduces tumour burden and promotes immunotherapy response in pancreatic cancer

Piro, Geny; Carbone, Carmine; Agostini, Antonio; Esposito, Annachiara; Pizzol, Maria De; Novelli, Rubina; Allegretti, Marcello; Aramini, Andrea; Caggiano, Alessia; Granitto, Alessia; Sanctis, Francesco De; Ugel, Stefano; Corbo, Vincenzo; Martini, Maurizio; Lawlor, Rita T.; Scarpa, Aldo

doi:10.1038/s41416-022-02028-6

Cited by 17 publications

(12 citation statements)

References 49 publications

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“…This includes, for example, ladarixin (CXCR1/2 inhibitor) and resminostat (HDAC-6 inhibitor). Both classes of drugs are investigated for synergistic effects with other anticancer agents, including taxanes, , and are considered, e.g., for combination therapies against pancreatic cancer. , IOWH-032 is a CFTR inhibitor that also suppresses SARS-CoV-2 replication and GS-6620 is a precursor of the antiviral drug remdesivir and assessed as treatment against the Ebola virus . These compounds might be tested in future experimental studies to extend the available data for QSPR modeling and establish pOx/pOzi-based DDS for more therapeutic fields.…”

Section: Resultsmentioning

confidence: 99%

POxload: Machine Learning Estimates Drug Loadings of Polymeric Micelles

Kehrein,

Bunker,

Luxenhofer

2024

Mol. Pharmaceutics

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Block copolymers, composed of poly(2-oxazoline)s and poly(2-oxazine)s, can serve as drug delivery systems; they form micelles that carry poorly water-soluble drugs. Many recent studies have investigated the effects of structural changes of the polymer and the hydrophobic cargo on drug loading. In this work, we combine these data to establish an extended formulation database. Different molecular properties and fingerprints are tested for their applicability to serve as formulation-specific mixture descriptors. A variety of classification and regression models are built for different descriptor subsets and thresholds of loading efficiency and loading capacity, with the best models achieving overall good statistics for both cross-and external validation (balanced accuracies of 0.8). Subsequently, important features are dissected for interpretation, and the DrugBank is screened for potential therapeutic use cases where these polymers could be used to develop novel formulations of hydrophobic drugs. The most promising models are provided as an open-source software tool for other researchers to test the applicability of these delivery systems for potential new drug candidates.

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Section: Resultsmentioning

confidence: 99%

POxload: Machine Learning Estimates Drug Loadings of Polymeric Micelles

Kehrein,

Bunker,

Luxenhofer

2024

Mol. Pharmaceutics

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“…There is no approved CXCR1/2 inhibitor, but several agents are under investigation ( 71 ). Ladarixin is one of the CXCR1/2 inhibitors, and in combination with a PD-1 inhibitor, it showed effectiveness in cell line- and patient-derived xenograft models of PDAC ( 72 ). A phase I clinical trial combining ladarixin and adagrasib for advanced NSCLC is currently ongoing (NCT05815173).…”

Section: Discussionmentioning

confidence: 99%

KRAS G12C inhibitor combination therapies: current evidence and challenge

Miyashita,

Kato,

Hong

2024

Front. Oncol.

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Although KRAS G12C inhibitors have proven that KRAS is a “druggable” target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

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“…Blocking CXCR2 enhances the quantity of CD3, CD4, and CD8 T lymphocytes and decreases suppressive regulatory T cells, resulting from the impediment of TAN recruitment [33]. Furthermore, suppression of CXCR1 [133, 134] and CXCR8 [135, 136] further enhances the efficacy of PC ICI treatment. Table 2 provides a comprehensive overview of ongoing clinical trials involving CXCR inhibitor drugs, such as LY2510924, SX‐682, BL‐8040, AMD3100, BMS‐813160, and NOX‐A12.…”

Section: Tans and Pc Immunotherapymentioning

confidence: 99%

Tumour‐associated neutrophils: Potential therapeutic targets in pancreatic cancer immunotherapy

Wu,

Mao,

Jiang

et al. 2024

Immunology

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Pancreatic cancer (PC) is a highly malignant tumour of the digestive system with poor therapeutic response and low survival rates. Immunotherapy has rapidly developed in recent years and has achieved significant outcomes in numerous malignant neoplasms. However, responses to immunotherapy in PC are rare, and the immunosuppressive and desmoplastic tumour microenvironment (TME) significantly hinders their efficacy in PC. Tumour‐associated neutrophils (TANs) play a crucial role in the PC microenvironment and exert a profound influence on PC immunotherapy by establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current status of PC immunotherapy. The present review aims to offer a comprehensive summary of the latest progress in understanding the involvement of TANs in PC desmoplastic and immunosuppressive functions and to emphasise the potential therapeutic implications of focusing on TANs in the immunotherapy of this deleterious disease. Finally, we provide an outlook for the future use of TANs in PC immunotherapy.

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CXCR1/2 dual-inhibitor ladarixin reduces tumour burden and promotes immunotherapy response in pancreatic cancer

Cited by 17 publications

References 49 publications

POxload: Machine Learning Estimates Drug Loadings of Polymeric Micelles

POxload: Machine Learning Estimates Drug Loadings of Polymeric Micelles

KRAS G12C inhibitor combination therapies: current evidence and challenge

Tumour‐associated neutrophils: Potential therapeutic targets in pancreatic cancer immunotherapy

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