ABSTRACT
Ovarian cancer (OvCA) ranks fifth in cancer deaths among women, accounting for more deaths than any other
gynecologic cancer. Each year, ~22,240 women in the United States will be diagnosed with OvCA, and
~14,070 will die. Ovarian epithelial cancer represents ~90% of all ovarian malignant tumors. The typical pattern
of spread and probably the earliest kind of metastasis of OvCA is intraperitoneal spread, ovarian peritoneal
carcinomatosis (OPC). OPC is a frequent terminal evolution of OvCA and is considered a lethal condition. In
this grant application, we hypothesize that a multimodal approach (a combination of the biochemical
agent Fc-TRAIL (immunoglobulin Fc domain fused tumor necrosis factor-related apoptosis-inducing
ligand), the chemotherapeutic agent mitomycin C, and mild hyperthermia) will effectively prevent
recurrence of OPC by promoting apoptotic death. The specific aims of this project are to: (1) investigate the
mechanism of synergistic induction of cytotoxicity by the combinatorial treatment of Fc-TRAIL, mitomycin C,
and hyperthermia in OPC organoids; and (2) establish a humanized PDX (patient-derived xenograft) mouse
model of OPC and examine the preclinical tumoricidal efficacy of the multimodal approach. In the first aim, we
will employ biochemical and molecular techniques to investigate the mechanism of apoptotic death during the
combinatorial treatment in OPC organoids. In the second aim, we will establish PDX tumor models with
humanized triple transgenic NSGTM-SGM3 mice (nonobese diabetic/severe combined immunodeficiency
NOD/SCID gamma mice expressing human interleukin-3, granulocyte-macrophage colony-stimulating factor,
and stem cell factor) and assess the response to the combinatorial treatment. We believe that since NSG™-
SGM3 mice are a proven host for engraftment of human tumors as well as the establishment of human
immunity following hematopoietic stem cell transplantation, we expect that humanized PDX mouse models will
retain most of the characteristics of the original tumors and reconstituted human immune system. We believe
that the successful outcome of this study will support the useful application of the humanized PDX mouse
model to assess this novel chimeric TRAIL-based therapy in combination with HIPEC therapy to patients with
OPC.
