Expert Discusses Preclinical Data Supporting Investigational Small Molecule in Medullary Thyroid Cancer

Rozita Yarmand, PhD

Rozita Yarmand, PhD

Preclinical data presented during the 2019 AACR Annual Meeting suggest that the investigational small molecule ONC201 alone or in combination with a tyrosine kinase inhibitor (TKI) can reverse RET-mediating signaling through its effect on Activating Transcription Factor-4 (ATF4) in patients with medullary thyroid cancer (MTC).

While RET suppresses expression of many tumor suppressor genes, it also inhibits ATF4, which prevents cell death. ONC201 was shown to inhibit the kinase activity of RET while increasing the transcription of ATF4 to enhance cell death. The agent also showed synergy in combination with a TKI.

“The standard of care for MTC right now is multi-TKIs, cabozantinib (Cabometyx) and vandetanib (Caprelsa), but with those drugs, the patients will have resistance and their response is partial, so we need novel compounds that have less toxicity with durable response,” said lead study author Rozita Yarmand, PhD.

In an interview withTargeted Oncology, Yarmand, an assistant professor in the department of endocrine neoplasia and hormonal disorders at The University of Texas MD Anderson Cancer Center, discussed the rationale for investigating ONC201 in patients with MTC and the toxicity profile that has been seen with this small molecule in mouse models and in other tumor types.

TARGETED ONCOLOGY: Can you discuss the background for this study?

Yarmand:In the majority of MTC, there is an activating resistance mutation in the RET tyrosine kinase receptor, and RET is considerably active in the neuroendocrine tissues that normally express this protein, such as C cells of the thyroid gland, in which MTC originates. Basically, RET is a survival factor and an oncogene in MTC. The standard of care for MTC right now is multi-TKIs, cabozantinib and vandetanib, but with those drugs, the patients will have resistance and their response is partial, so we need novel compounds that have less toxicity with durable response.

We think that RET suppresses the expression of many tumor suppressor genes. We found that 1 of those tumor suppressor genes in MTC is ATF4, which is repressed by RET. Our interest was to find a drug that actually inhibits the kinase activity of RET but also increases the transcription of ATF4 to enhance cell death. We found this drug, ONC201, which is an orally active small molecule that is right now in clinical trials for many types of cancer, especially gliomas, but not in MTC.

Our preclinical study shows that ONC201 inhibits tumor growth and also inhibits the expression of RET, which is very important for MTC. The imaging also shows that if you combine ONC201 with a TKI, we will see a synergistic effect. We think that ONC201 could be an efficient therapy for MTC, especially in combination with TKIs in the clinic.

TARGETED ONCOLOGY: What have we learned from previous research regarding what causes resistances to TKI-mediated cell death?

Yarmand:They found that RET repressed the transcription of ATF4, which will actually allow integrated stress response (ISR), and ATF4 actually increased the transcription of pro-aptotic genes, which causes cell death. RET, through ATF4, prevents apoptosis.

TARGETED ONCOLOGY: What was the rationale for looking at ONC201 in MTC?

Yarmand:ONC201 actually increases the expression of ATF4. In previous studies, ATF4 was a tumor-suppresser gene that was very important in MTC, and it was repressed by RET, so we thought that was rational to use ONC201 to increase the transcription of ATF4.

TARGETED ONCOLOGY: What did you set out to do in your investigation of ONC201 in MTC?

Yarmand:ONC201, in other preclinical studies, is very efficient in inhibiting tumor growth in mice without any toxicity. Also, in the culture, it’s synergized with TKIs, which are already being used in the clinic for MTC. The use of ONC201 could decrease the dose issues in the clinic and it could be more efficient even as a single agent.

TARGETED ONCOLOGY: What is the key takeaway from these data?

Yarmand:We think that because MTC is actually a cancer that secretes a lot of hormones and then is very sensitive to assess response, we think that ONC201 could be especially efficient in this type of cancer that actually secretes hormones and are sensitive to ISR.

TARGETED ONCOLOGY: Where do you see future research with ONC201 in MTC heading?

Yarmand:The future of this could be using as a single agent in MTC because it’s very efficient in the preclinical studies, but also in combination with TKI that are already FDA approved for MTC.

TARGETED ONCOLOGY: What does the safety profile look like?

Yarmand:Right now, it’s in a phase II clinical trial, and the toxicity of this drug is really very low, much less compared to other drugs that are being used right now in the clinic. Basically, the phase II trial looks very promising for ONC201 in other types of cancer, especially gliomas.

TARGETED ONCOLOGY: What do you hope oncologists take away from this research?

Yarmand:The take home message is that we need more novel compounds that are actually less toxic and the response is durable. Novel compounds are needed for MTC, and we think ONC201 could be a drug that is very efficient in MTC, especially compared to other types of tumors.

The response to TKIs is partial, so we need a drug that will actually have a durable response and less toxicity, so I think [ONC201] could have a potential [role] for use in the clinic.

TARGETED ONCOLOGY: If this drug was eventually approved for MTC, what kind of impact do you think it will have on this patient population?

Yarmand:I think ONC201, if approved for MTC, could be a drug with no toxicity, and it could be a lesser regimen. Multi-TKIs are usually taken every day, but ONC201 could be taken only once a week.