SBIR-STTR Award

Direct to Phase II

TK216 is an investigational, potentially first-in-class, targeted small molecule that is designed to specificallyinhibit the biological activity of the ETS family of oncoproteins. Tumorigenic gene fusions involving ETS factorsare frequently found in tumors, such as Ewing sarcoma (ES) as well as childhood leukemias and prostatecancer. ETS factors are also often overexpressed in other tumors, such as neuroblastoma, lymphomas, acutemyeloid leukemia and high-grade glioma brain tumors. Based on work in the laboratory of our collaboratorJeffrey Toretsky (Georgetown University), Oncternal Therapeutics, Inc. created the novel ETS family inhibitorTK216. In preclinical models, TK216 inhibits the interaction between ETS family members and RNA helicaseA (RHA) leading to transcriptional changes and apoptosis. Oncternal is currently enrolling patients withrelapsed or refractory ES, a rare pediatric cancer that has historically been very challenging to treat effectively,in a Phase 1 clinical trial. Interim analysis has shown TK216 to be generally well-tolerated, with dose limitingtoxicity of manageable myelosuppression and no obvious off-target toxicity. Notably, the current dosingregimen demonstrated early exciting evidence of activity in seven evaluable patients with 1 surgical completeresponse (CR) and 1 very good partial response (PR; 90% tumor shrinkage). TK216 has received OrphanDrug and Fast Track Designations from the U.S. Food and Drug Administration (FDA) for treatment ofrelapsed/refractory ES. ES is driven by an EWS-ETS fusion protein, which occurs through a reciprocalchromosomal translocation. The EWS-ETS fusion protein was considered "˜undruggable'. However, themechanism of EWS-FLI1 is driven by its partnering with other proteins, thus TK216, similar to YK-4-279,targets the EWS-ETS by disrupting or preventing protein-protein interactions (PPI). Given the significant needfor an EWS-ETS targeted therapy, the clinical development is being accelerated by administering TK216 asa continuous infusion via ambulatory pump over 14 days. This allowed relapsed ES patients to gain accessand provide proof of efficacy. While this current form of administration is acceptable to patients suffering fromcancers with few or no other treatment options available, it poses a significant inconvenience hurdle for ESpatients as well as effectively prevents its clinical application in other unmet medical needs driven by ETS-dysregulation. Therefore, we propose 2 main objectives for our proposal to support the TK216-basedtherapies: a) delineation of the activity spectrum of TK216 against members of the ETS transcription factorfamily and b) development an oral dosing form of TK216, including GLP pharmacology/toxicology studies andGMP manufacturing. Our intent regarding ES is to offer a more convenient dosing form for ES patients andto allow for expansion of TK216 studies into other oncology indications. The overarching goal of this projectis to complete the development of an oral formulation and obtain preclinical data supportive of InvestigationalNew-Drug (IND) applications for indication expansion.

Public Health Relevance Statement:
Many oncology treatments often include using highly toxic drugs, often combined with surgery and radiation. The acute toxicities associated with these treatments, include nausea, vomiting, hair loss and fatigue. Survivors may have long-term cardio-pulmonary, musculoskeletal, and fertility/sterility complications, leaving room for improvement. Newer targeted cancer agents are often helpful, but only to very small groups of patients whose tumors possess specific mutations. To consider larger groups of patients, an out-of-the-box consideration would be to target master regulators, or transcription factors, that are critical for tumor growth. Our drug TK216 targets a transcription factor family of proteins. The studies proposed here will further illuminate the drug mechanism and develop a liquid or tablet dosage form to enable future clinical trials.

Project Terms: