We set out to create a drug that targeted an ideal Achilles' heel in Ewing sarcoma. This target was EWS-FLI1, which is only found in Ewing sarcoma tumor cells and had been called 'undruggable'. Now, TK216 demonstrates that not only is EWS-FLI1 druggable, but that the potential of TK216 inhibiting a broader range of tumors driven by similar oncogenes is an unexpected benefit.

— Dr. Jeffrey Toretsky, Georgetown University —

ONCT-216 (formerly called TK216) is a first-in-class small molecule inhibiting the biological activity of ETS-family (E26 Transformation Specific) transcription factor oncoproteins in a variety of tumor types. It is currently being evaluated in the Phase 2 portion of a study in patients with relapsed or refractory Ewing sarcoma, a serious pediatric bone cancer. 

Targeting Known Oncogenes

The ETS-transcription factor family (E26 Transformation - Specific) of genes includes nine members (FLI1, ERG, ETV1, ETV4, ETV5, ETV6, ETS1, ETS2, and SPIB) implicated as oncogenes, or genes that have been identified as important for the development or progression of cancer. While they are important in embryogenesis, these ETS-family proteins are not commonly expressed after birth, presenting an ideal target for researchers hoping to selectively affect cancer cell growth. In Ewing sarcoma, the cancer is caused by a single and well-characterized genetic mutation that leads to a chimeric ETS protein, usually EWS-FLI1, which enables patients to be easily identified with DNA-based testing. The ETS-family proteins are also over-expressed in various other cancers, including acute myeloid leukemia, aggressive lymphoma, and prostate cancer.

Ewing Sarcoma Has High Unmet Medical Need

We are initially developing ONCT-216 for Ewing sarcoma because of the tremendous need for new, targeted therapies for this devastating disease and the hope that it can be made available for patients with an expedited approval pathway. Ewing sarcoma is the second most common pediatric bone tumor. Patients with metastatic Ewing sarcoma have a five-year survival between 18% and 30%, and patients with recurrent Ewing sarcoma have a five-year survival after recurrence of approximately 10% to 15%. In the last 30 years, no new therapies have been approved by the FDA specifically for Ewing sarcoma. There is no standard treatment available to use after a combination regimen of five chemotherapy drugs is given. We are planning subsequent studies to investigate ONCT-216 in patients with other cancers whose tumors carry mutant or overexpressed levels of ETS- family oncogenes.

Collaboration with Georgetown University

ONCT-216 was developed based on the discoveries of Jeff Toretsky, MD, at Georgetown University, who identified a small molecule that was shown to kill Ewing sarcoma cells and inhibit growth of tumors in preclinical studies. Oncternal scientists developed and tested a large series of derivatives of the research molecule and after extensive evaluation, ONCT-216 was selected as our lead product candidate. ONCT-216 has been extensively evaluated in preclinical studies, where it has been confirmed to kill Ewing sarcoma cells and inhibit Ewing sarcoma tumors in animal models. We continue to collaborate with Dr. Toretsky and his colleagues in order to advance the research underlying the molecular pathways of ONCT-216 and optimize its development across multiple tumor types. 

We are enrolling patients:

  • With relapsed/refractory mantle cell lymphoma (MCL) for a Phase 1b/2 study of zilovertamab in combination with ibrutinib
  • With chronic lymphocytic leukemia (CLL) for a Phase 2 clinical study of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor 
  • With Ewing sarcoma for a Phase 1 study of ONCT-216, our small-molecule inhibitor of ETS-family transcription factor oncoproteins, in combination with vincristine
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