A Potentially Effective Way of Targeting Ewing Sarcoma

A study led by researchers at Nationwide Children’s Hospital has found no biomarkers of sensitivity in Ewing sarcoma cell lines for the proposed therapeutic agent SP-2509, for the simple and surprising reason that every cell line tested had sensitivity to SP-2509.

This is promising for the newly opened Phase 1 clinical trial of the clinical formulation of the agent – called SP-2577, or Seclidemstat – and appears to be a step toward finding a more targeted therapy for the aggressive bone tumors.

“I guess you could say that we failed to find what we were looking for. We actually haven’t found a patient-derived cell line that is resistant to the agent,” says Stephen Lessnick, MD, PhD, director of the Center for Childhood Cancer and Blood Diseases at Nationwide Children’s and senior author of the recent study. “Of course, that gives us great hope about the agent’s effectiveness against Ewing sarcoma.”

The study, published in Molecular Cancer Therapeutics, is part of an effort among Ewing sarcoma researchers and clinicians to move beyond traditional chemotherapies, which appear to have reached a “therapeutic ceiling” for the disease.

Those efforts have focused on the EWS/FLI chromosomal translocation, common to virtually every form of Ewing sarcoma and the driver of tumor development. While that mutation has proven difficult to target, the companion protein KDM1A (also known as lysine specific demethylase 1, or LSD1) can be targeted. KDM1A/LSD1 is overexpressed in a number of solid and hematological malignancies. The agent used in the recent study, SP-2509, is a KDM1A/LSD1 inhibitor.

The authors introduced SP-2509 to 17 Ewing sarcoma cell lines, and sensitivity was found in all of them. Of note, many cell lines were resistant to another KDM1A/LSD1 inhibitor, GSK-LSD1, suggesting that future Ewing sarcoma therapies based on GSK-LSD1 would be ineffective.

The publication also investigated how SP-2509 targets KDM1A/LSD1; it seems to engage the endoplasmic reticulum stress response, leading to apoptosis.

A clinical trial of a therapy based on the inhibitor began recruiting patients this summer (Dr. Lessnick is a scientific advisor to Salarius Pharmaceuticals, the company behind the trial).

Pishas KI, Drenberg CD, Taslim C, Theisen ER, Johnson KM, Saund RS, Pop IL, Crompton BD, Lawlor ER, Tirode F, Mora J, Delattre O, Beckerle MC, Callen DF, Sharma S, Lessnick SL.  Therapeutic targeting of KDM1A/LSD1 in Ewing sarcoma with SP-2509 engages the endoplasmic reticulum stress response.  Molecular Cancer Therapeutics. 2018 July 11. [Epub ahead of print]