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Is ONC-201 limited to H3K27M tumors?

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  • Is ONC-201 limited to H3K27M tumors?

    Is ONC-201 limited to H3K27M tumors? Or does it also show effectiveness with other mutations, such as IDH-Mutant Anaplastic Astrocytomas? Most of what I've read about ONC-201 seems to be related to H3K27M tumors.

    Thanks!

  • #2
    This is not the official explanation - just my thoughts. Ask the company for the official response..
    We really do not know yet. I am not sure H3K27M has anything to do with it really. Onc-201 is an antagonist of dopamine receptor D2, which is highly concentrated in the midline structures of the brain. Really bad tumors of the midline structure of the brain have a high chance of having the H3K27M mutation. And tumors with the H3K27m mutation have a high chance of having the DRD2, and a good chance of having a low DRD5 and EGFR. Tumors with a high DRD5 won't respond to Onc-201 while those with a high DRDR2 should. They recently found that if you had an overexpression of EGFR or have the EGFRvIII mutation, you have much less chance of responding to Onc-201. In other words, H3K27M might just be a marker for tumors that have the right combination of EGFR, DRD2 and DRD5. - but perhaps not the only marker. This is why all tumors should get a complete genomic profiling.
    SO - bottom line: If a tumor has high D2, Low D5, Low EGFR, no EGFRvIII, it is probably worth trying the drug even if they do not have H3K27m mutation. I proposed a trial of onc-201 in any glioblastoma, and add an EGFR inhibitor - but they did not want to try. We have to wait until it is approved before we can try combinations like that but I think combinations like that will have a chance of making a major impact on a large variety of tumors. The EGFR inhibitors by themselves did not work, possibly because the dopamine pathways took over. Onc-201 by itself only works in about 1/2 of the patients, possibly because the EGFR pathway takes over. We have to stop both pathways at the same time and possible a third and 4th.
    Having said all of that, it will be impossible right now to get Onc-201 until it is approved unless you fit one of the trials or the expanded access program. The expanded access program is for DMG with H3K27M or DIPG (do not need biopsy). I do not think (check clinicaltrials.gov to make sure) anaplastic astrocytomas are eligable now.

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