Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer.

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. CONCLUSIONS: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

Continuous spectrum of periodically stationary pulses in a stretched-pulse laser.

A spectral method for determining the stability of periodically stationary pulses in fiber lasers is introduced. Pulse stability is characterized in terms of the spectrum (eigenvalues) of the monodromy operator, which is the linearization of the round trip operator about a periodically stationary pulse. A formula for the continuous (essential) spectrum of the monodromy operator is presented, which quantifies the growth and decay of continuous waves far from the pulse. The formula is verified by comparison with a fully numeric method for an experimental fiber laser. Finally, the effect of a saturable absorber on pulse stability is demonstrated.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer.

Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimen to prevent antagonistic effects. Thus, this work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

Mechanistic modeling of anti-microRNA-155 therapy combinations in lung cancer.

To improve treatment outcomes in non-small cell lung cancer (NSCLC), it is crucial to identify treatment strategies with the potential to exhibit drug synergism. This can lower the required effective dose, reducing exposure to drugs and associated toxicities, while improving treatment efficacy. In previous studies, drugs targeting the microRNA-155 or PD-L1 have been promising in restraining NSCLC tumor growth. We have developed a mathematical model that simulates the in vivo pharmacokinetics and pharmacodynamics of the novel nanoparticle-delivered anti-microRNA-155 for potential use with standard-of-care drug atezolizumab for NSCLC. Through modeling and simulation, we identified possible drug synergism between the two drugs that holds promise to improve tumor response at reduced drug exposure.Clinical Relevance-Identifying the possibility of drug synergism for an anti-microRNA-155 based nanotherapeutic with standard-of-care immunotherapy to improve lung cancer treatment outcomes.