Establishing combination PAC-1 and TRAIL regimens for treating ovarian
cancer based on patient-specific pharmacokinetic profiles using in
silico clinical trials
Abstract
Ovarian cancer is commonly diagnosed in its late stages, and new
treatment modalities are needed to improve patient outcomes and
survival. We have recently established the synergistic effects of
combination tumour necrosis factor-related apoptosis-inducing ligand
(TRAIL) and procaspase activating compound (PAC-1) therapies in
granulosa cell tumours (GCT) of the ovary, a rare form of ovarian
cancer, using a mathematical model of the effects of both drugs in a GCT
cell line. Here, to understand the mechanisms of combined TRAIL and
PAC-1 therapy, study the viability of this treatment strategy, and
accelerate preclinical translation, we leveraged our mathematical model
in combination with population pharmacokinetics (PopPK) models of both
TRAIL and PAC-1 to expand a realistic heterogeneous cohort of virtual
patients and optimize treatment schedules. Using this approach, we
investigated treatment responses in this virtual cohort and determined
optimal therapeutic schedules based on patient-specific pharmacokinetic
characteristics. Our results showed that schedules with high initial
doses of PAC-1 were required for therapeutic efficacy. Further analysis
of individualized regimens revealed two distinct groups of virtual
patients within our cohort: one with high PAC-1 elimination, and one
with normal PAC-1 elimination. In the high elimination group, high
weekly doses of both PAC-1 and TRAIL were necessary for therapeutic
efficacy, however virtual patients in this group were predicted to have
a worse prognosis when compared to those in the normal elimination
group. Thus, PAC-1 pharmacokinetic characteristics, particularly
clearance, can be used to identify patients most likely to respond to
combined PAC-1 and TRAIL therapy. This work underlines the importance of
quantitative approaches in preclinical oncology.