An exciting new trial of a TEAD Inhibitor

node leader
15 December 2021

Over the past six years, the EHE Group has funded, and continues to fund, multiple EHE research projects that have many different objectives and deliverables. At the highest level however, all of these projects have a common goal, namely to answer key questions about the biology and natural history of EHE with the hope of identifying a new treatment for EHE that can at least help us to control the disease, and even possibly ‘kill’ it.

Of all of these objectives, a key focus has been on the role of the TAZ-CAMTA1 fusion protein. EHE occurs due to a chromosomal translocation that yields a WWTR1-CAMTA1 gene fusion that in turn encodes the TAZ-CAMTA1 fusion protein. Fusion proteins that result from chromosomal translocations are particularly good targets because the resulting cancer is typically “addicted" to the mutant protein, in this case, TAZ-CAMTA1. Indeed, the most effective cancer therapies developed to date target disease-driving mutant proteins that are required for cancer formation and growth.

Inhibiting TAZ-CAMTA1 function was therefore seen as a key to treating EHE. This was the focus of Dr Rubin’s drug screening research that the EHE Group funded in 2018, to identify compounds that may inhibit the EHE fusion protein. Of particular interest was to see if a means could be found to inhibit TAZ-CAMTA1 from binding to TEAD4, another protein in our cells. This is of particular interest as TAZ-CAMTA1 cannot bind to our DNA on its own, and so needs to bind to TEAD4 before it can influence the transcription process and so drive EHE. Blocking this process could allow us to halt or inhibit EHE progression.

In addition to finding ways to inhibit TEAD binding, another key missing element for EHE was an animal model or cell line of the disease that could allow testing of any such drug or compound. This fundamental requirement was met when Dr Rubin’s genetically engineered mice (GEM) finally presented with EHE. Not only did the mice present with EHE, but they presented with EHE that was an extraordinarily strong analogue to human EHE. The ability to test drug impact on EHE was further enhanced this year when INT in Milan were able to confirm that they had successfully created an EHE PDX mouse model. PDX mice have human tissue implanted in them which is then kept alive and grows thanks to the mouse.

So with Dr Rubin’s GEM and INT’s PDX models, we are now in a very strong position to test new drugs and compounds designed to inhibit TEAD. If successful, then the next step would be a potential clinical trial.

The EHE community were therefore very excited when news was posted of information from Precision Oncology News of just such a trial that was being promoted by Ikena Oncology, and which will be open to EHE patients.

“Ikena Oncology confirmed that the US Food and Drug Administration has cleared an investigational new drug application for its TEAD inhibitor IK-930, allowing it to begin evaluating the agent in cancer patients harboring genetic mutations in the Hippo signaling pathway.

Boston-based Ikena will therefore be launching a biomarker-guided Phase I trial of IK-930 in tumor types that have a high frequency of Hippo pathway alterations, including NF2-deficient malignant mesothelioma as well as certain soft tissue sarcomas with YAP/TAZ genetic fusions, such as epithelioid hemangioendothelioma. Additionally, Ikena will study the agent in combination with other targeted treatments in patients with solid tumors harboring EGFR and KRAS mutations.

IK-930 blocks TEAD-dependent transcription of genes that cause cancer progression, metastases, and treatment resistance. According to the firm, preclinical research supports further exploring the treatment as a monotherapy and in combination with targeted agents such as EGFR and MEK inhibitors.

"Our biomarker-driven approach will be key in determining which patient populations stand to benefit most from IK-930," Sergio Santillana, Ikena's chief medical officer, said in a statement.

Ikena hope to begin the Phase I trial in early 2022.”

It is also exciting that Ikena Oncology will be presenting at the EHE360 International Conference at the end of January at which they will provide further details. The EHE Group will be liaising closely with Ikena Oncology to understand and communicate timing and procedures for patient involvement in the trial.

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