Comparison of Proliferation Marker Expression in Napabucasin and APX2009 Treated Malignant Peripheral Nerve Sheath Tumors

Emily L. Hulsey1, Silpa Gampala2, Fenil Shah2, D. Wade Clapp2, Andrew R. Tee3, Karen E Pollok2,4, Mark R. Kelley2,4, Melissa L. Fishel2,4, George E. Sandusky1 1Department of Pathology and Laboratory Medicine, 2Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University, School of Medicine, Indianapolis, IN, 3Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff, Wales, UK, 4Department of Pharmacology and Toxicology, Indiana University, School of Medicine, Indianapolis, IN 46202, USA

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma that affects the nerves, starting in the major nerve trunks. MPNST accounts for 5-10% of all soft tissue sarcomas. MPNST usually occurs between 20 and 50 years of age and occurs in 1 in 100,000 people. Around 50% of all MPNSTs occur in people with neurofibromatosis-1. These tumors are highly refractory to treatment

New data suggests STAT3 as a driver in the MPNST phenotype1; we tested the efficacy of Napabucasin (Napa) a reported STAT3 / stemness inhibitor2 in MPNST tumors. Napa is a cancer stem cell inhibitor with potential antineoplastic activity. APX2009 is a second generation inhibitor of the redox activity of APE1 and exhibits potent antitumor activity. The MPNST cell line ST88-14 was implanted into mice and treated with both reagents.

We evaluated the effect of Napa on tumor growth and proliferation. The tumors were stained with cell proliferation markers, Phosphorylated Histone H3 (pH3) and Ki67 using the DAKO Flex system. pH3 stains cells in the late G2 phase and mitosis while Ki67 stains cells in any stage of the cell cycle except for G0. 

Slides were imaged with the Aperio Scanscope and analyzed with the Aperio ImageScope system using the positive pixel algorithm to determine the expression of the markers.

Napa and APX2009 both decreased tumor volume with a corresponding decrease in tumor weight at the end of study. In the Napa-treated tumors, Ki67 was significantly decreased and pH3 increased significantly. IHC staining in the APX2009 tumors had expected decreases in proliferation in pH3 and Ki67. Although the tumor growth reduction was significant, we did not observe complete regression indicating combination therapy may be necessary. In the future, we will use orthotopic or PDX models to look at relevant combination therapies to pair with Napa treatment.

Additional Abstract Information

Presenter: Emily Hulsey

Institution: Indiana University School of Medicine

Type: Poster

Subject: Biology

Status: Approved

Time and Location

Session: Poster 2
Date/Time: Mon 3:00pm-4:00pm
Session Number: 2643