EXTH-63 - MTA-cooperative PRMT5 inhibitors are efficacious in MTAP-deleted malignant peripheral nerve sheath tumor models

Friday, November 17, 2023

7:30 PM – 9:30 PM PT

Location: Exhibit Hall A/B

Author(s)

DB

Dana Borcherding

Washington University in St. Louis
St. Louis, Missouri, United States

Poster Presenter(s)

Xiaochun Zhang

Washington University in St. Louis
St. Louis, Missouri, United States

Author(s)

Minjie Zhang

Tango Therapeutics
Boston, Massachusetts, United States
HB

Himanshi Bhatia

Washington University in St. Louis
St. Louis, Missouri, United States
YL

Yang Lyu

Washington University in St. Louis
St. Louis, Missouri, United States
KH

Kevin He

Washington University in St. Louis
St. Louis, Missouri, United States
LY

Liuzhan Yang

Washington University in St. Louis
St. Louis, Missouri, United States
KY

Kuangying Yang

Washington University in St. Louis
St. Louis, Missouri, United States
HD

Heather DiBenedetto

Tango Therapeutics
Boston, Massachusetts, United States
AT

Alice Tsai

Tango Therapeutics
Boston, Massachusetts, United States
AH

Alan Huang

Tango Therapeutics
Boston, Massachusetts, United States
JM

John Maxwell

Tango Therapeutics
Boston, Massachusetts, United States
KC

Kevin Cottrell

Tango Therapeutics
Boston, Massachusetts, United States
KB

Kimberly Briggs

Tango Therapeutics
Boston, Massachusetts, United States
Angela C. Hirbe

Washington University in St. Louis
St. Louis, Missouri, United States

Objectives: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with limited treatment options and poor survival rates, necessitating the development of novel therapeutics. Approximately 25-50% of MPNST harbor loss of the enzyme methylthioadenosine phosphorylase (MTAP) due to a passenger deletion driven by loss of the proximal tumor suppressor gene, CDKN2A. PRMT5 was identified as a selective dependence in MTAP-deleted cells due to the accumulation of the substrate methylthioadenosine (MTA), which is itself an endogenous PRMT5 inhibitor. TNG908 and TNG462 are clinical stage MTA-cooperative PRMT5 inhibitors that demonstrate selectivity for MTAP-deleted cells over MTAP-intact cells of 15X and 45X, respectively. Previous reports show both molecules drive durable tumor regressions in xenograft models of various MTAP-deleted cancer histologies. Here, our objectives are to examine the activity of TNG908 and TNG462 in preclinical MPNST models.

Methods: The proliferation effects of MTA-cooperative PRMT5 inhibitors, TNG908 or TNG462, and a SAM-cooperative PRMT5 inhibitor, GSK3326595, on MTAP-deleted and MTAP-intact MPNST cell lines were determined using CellTiter-Glo (CTG) assays. TNG908 and TNG462 were further profiled in two MTAP-deleted MPNST patient-derived xenograft (PDX) models, WU-356 and WU-386.

Results: Incubation with the MTA-cooperative PRMT5 inhibitors, TNG908 and TNG462, selectively decreased the proliferation of MTAP-deleted MPNST cell lines relative to MTAP-intact MPNST cell lines. TNG908 and TNG462 drove dose-dependent antitumor activity including tumor regressions in the MTAP-deleted MPNST PDX models, WU-356 and WU-386, at well-tolerated doses.

Conclusions: The clinical stage MTA-cooperative PRMT5 inhibitors TNG908 (NCT05275478) and TNG462 (NCT05732831) are efficacious in MPNST models in vitro and in vivo and are therefore promising therapeutic agents for patients with MTAP-deleted MPNST.