Rational biomarker-guided PARP inhibitor combination therapy in pediatric sarcomas
The overall survival for recurrent and metastatic Ewing sarcoma (EWS) is dismal (15% and 10-30%, respectively). We previously showed that EWS has a defect in double-strand DNA (dsDNA) repair, and that the addition of Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi) to the existing standard of care (SOC) therapy of irinotecan (IRN) and temozolomide (TMZ) is remarkably successful at treating in vivo mouse models of recurrent EWS, resulting in >80% complete response compared to 100% mortality with SOC alone. Our EWS pre-clinical studies prompted several new questions. First, why is EWS sensitive to PARPi combination therapy, and could other pediatric sarcomas share this sensitivity? EWS does not appear to have obvious defects in BRCA1 or BRCA2 – two genes closely associated with PARPi sensitivity. Second, what is the optimal combination strategy for PARPi in tumors with defective dsDNA repair, and how does PARP trapping potential effect this strategy? Although all clinical PARPi strongly suppress PARP1 enzyme activity, they diverge widely with respect to PARP trapping potential.
Our preliminary data suggests the following: (a) the protein SLFN11 is strongly expressed in most EWS and a subset of other sarcomas; (b) high levels of SLFN11 correlate with PARPi sensitivity as single-agent or in combination; (c) PARPi with strong trapping potential may be more efficacious in tumors with defects in dsDNA repair when combined with Topoisomerase 1 inhibitors such as IRN. To confirm these hypotheses, we propose the following specific aims: (1) determine the extent to which SLFN1 is expressed in sarcomas, and whether high SLFN11 levels predict sensitivity to PARPi in different tumor types; (2) determine the relative contributions of PARP trapping and PARP catalytic inhibition to PARPi efficacy in sensitive sarcoma cell lines; and (3) determine the extent to which SLFN11 knockdown reduces the efficacy of PARPi in vitro and in vivo.
St. Jude is currently conducting the BMNIRN phase I clinical trial to explore the tolerability of combining the PARPi talazoparib and IRN with dose-escalating TMZ in patients with recurrent solid tumors. The biomarker hypothesis explored in aims 1 and 3 may help identify and stratify sensitive patients in subsequent clinical trials. The studies outlined in aim 2 may suggest that PARP trapping potential should be taken into account when designing drug combinations to target specific DNA repair defects. Finally, in the process of assessing PARPi sensitivity, our work may also help identify subsets of pediatric sarcoma that may respond dramatically to combination therapy with PARPi and radiotherapy (RT). In summary, our proposal lays the groundwork for translational efforts focused on maximizing both: (a) the potential for PARPi combination chemotherapy; and (b) the therapeutic window of RT via RT-drug sensitization and rational RT dose de-escalation.