On November 14, 2022 Rakovina Therapeutics Inc. (TSX-V: RKV) ("the Company"), reported publication of a scientific article on the anti-cancer activity of the Company’s novel dual PARP-HDAC inhibitor in models of Ewing sarcoma (Press release, Rakovina Therapeutics, NOV 14, 2022, View Source [SID1234624041]).

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The manuscript entitled "A bi-functional PARP-HDAC inhibitor with activity in Ewing sarcoma", indicate a benefit of dual PARP and HDAC inhibition and provide proof-of-concept for a bi-functional single-molecule therapeutic strategy in the treatment of Ewing sarcoma.

Ewing sarcoma is a highly aggressive bone and soft tissue tumor affecting mainly children and young adults, with a dismal 5-year survival rate of 15-30% for metastatic disease. Previous studies have demonstrated that Ewing sarcoma cells are sensitive to FDA-approved PARP inhibitors, but clinical trials have failed to produce a durable treatment response.

PARP inhibitors have been demonstrated to impact tumors that harbor BRCA mutations or other defects in homologous repair (HR). This concept is commonly referred to as "BRCAness".

Ewing sarcoma is characterized by the presence of a genetic fusion involving the EWSR1 gene. This fusion has been shown to impair HR activity indicating a level of "BRCAness" in Ewing sarcoma. The lack of clinical response in Ewing sarcoma to treatment with single-agent PARP inhibitors supports employing combination therapy strategies that further inhibit HR and increase BRCAness in Ewing sarcoma.

Recent studies in leukemia, breast cancer, liver cancer, glioblastoma, prostate cancer and anaplastic thyroid models demonstrated suppression of HR following treatment with HDAC inhibitors, supporting the synergistic potential of dual HDAC and PARP inhibition.

Rakovina Therapeutics researchers characterized and tested kt-3283, a novel dual-function single molecule of PARP and HDAC in Ewing sarcoma model systems. In these studies, kt-3283 demonstrated higher efficacy than treatment with single-agent PARP or HDAC inhibitors. These data indicate the dual activity of kt-3283 is 30- to 80-times more potent in Ewing sarcoma models than an FDA-approved PARP inhibitor, and 30- to 60-times more potent than an FDA-approved HDAC inhibitor. In an Ewing sarcoma metastasis model, kt-3283 prevented metastatic cancer growth in the lungs of mice inoculated with an aggressive Ewing sarcoma cell line.

"These results provide proof-of-concept for a novel single-molecule PARP-HDAC inhibitor in the treatment of Ewing sarcoma," stated Prof. Mads Daugaard Rakovina Therapeutics’ president and chief scientific officer. "This concept will likely be relevant in other cancer indications beyond Ewing sarcoma and potentially offer an opportunity to suppress therapeutic resistance to PARP-inhibitor treatment."

Development of Rakovina Therapeutics’ novel kt-3000 DNA-damage response inhibitors is supported, in part, by the St. Baldrick’s Foundation Martha’s BEST Grant for All, which is aimed at developing new treatments for Ewing sarcoma, an aggressive bone and soft tissue cancer in children and young adults.