Sarcoma stratification by combined pH2AX and MAP17 (PDZK1IP1) levels for a better outcome on doxorubicin plus olaparib treatment

Abstract

Sarcomas constitute a rare heterogeneous group of tumors, including a wide variety of histological subtypes. Despite advances in our understanding of the pathophysiology of the disease, first-line sarcoma treatment options are still limited and new treatment approaches are needed. Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development. In this study, we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein, an inducer of DNA damage through ROS increase, as prognostic biomarkers in sarcoma tumors. Next, we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers. We evaluate retrospectively the levels of pH2AX (Ser139) and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features. We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival. Next, we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma. We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro, inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation, as a result of DNA damage. The synergism was corroborated in patient-derived xenografts (PDX) where the combination was effective in tumors with high levels of pH2AX and MAP17, suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.