Table 4

Current agents in clinical trials combined with radiotherapy

ClassMechanismPotential synergy with radiation therapyStatus in gynecologic oncology
ImmunotherapyCTLA-4 inhibitorsInterrupts T-cell (particularly T-regulatory cells) inhibitory CTLA-4 signaling, resulting in increased T-cell activation at the early induction phase after antigen stimulationEnhanced release, uptake, and cross-presentation of tumor antigens by dendritic cells and increased secretion of lymphocyte stimulating cytokines and chemokinesPhase I/II monotherapy trials performed; phase I trials of dual checkpoint inhibition and concurrent RT underway
PD-1/PD-L1 inhibitorsImpedes inhibitory PD-1/PD-L1 interactions, resulting in increased T-cell activation, particularly cytotoxic CD8 T-cells in the late effector phaseEnhanced effector-to-regulatory T-cell ratio and T-cell infiltration after RTSeveral phase I/II monotherapy trials completed and underway; phase I trials with dual checkpoint inhibitors and concurrent RT underway; monotherapy phase III trials underway; phase III trials with concurrent RT underway
DNA-damage response InhibitorPARP inhibitorsInhibit PARP’s essential role in single-stranded DNA repair; “trap” DNA resulting in replication fork collapse and DNA damageDirect DNA-damage effects and increase in overall genomic instabilityMultiple phase I–III monotherapy trials; phase I/II trials with concurrent RT underway
WEE1 inhibitorsRegulation of cell cycle progression, decreasing time for DNA repair to occurPhase I trial with concurrent RT underway
ATR inhibitorsInhibits ATR’s regulation of cell cycle progression and DNA repairPre-clinical data; no pending clinical trials
TriapineInhibits ribonucleotide reductase decreasing DNA repair timePhase III trial with concurrent RT underway
Cell signaling modulatorsNelfinavirProteasome inhibition; inhibition of the PI3K/Akt signaling pathway central in cellular growth and survival; reduction of hypoxia-induced HIF-1 α and subsequent reduction in angiogenesisDirect cytotoxic effect; increased oxygenation and thus increased generation of free radical productsPhase I and III trials with concurrent RT underway/about to open
MetforminIndirect inhibition of the PI3K/Akt signaling pathway central in cellular growth and survival; reduction of tumor hypoxiaPhase II trial with concurrent RT
EndostarAlters energy metabolism primarily in the tumor micro-environment through hypoxia modification; inhibits angiogenesisPhase III trial with concurrent RT
  • ATR, ataxia telangiectasia and Rad3-related; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PARP, poly(ADP-ribose) polymerase; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; RT, radiation therapy.