PI3K, HDAC Inhibition With CUDC-907 Shows Promise in Thyroid Cancer

Dual inhibition of PI3K signaling and histone deacetylase 2 (HDAC2) enzymes with CUDC-907 slowed thyroid tumor cell proliferation, tumor progression, and metastasis, according to a preclinical study presented at the 86^th Annual Meeting of the American Thyroid Association (ATA), held September 21–25 in Denver, Colorado.[1]

“Our results show that CUDC-907 treatment leads to an upregulation of thyroid differentiation markers in thyroid cancer cells, and effectively inhibits growth and metastasis in vivo, by inhibiting PI3K signaling and HDAC2 expression,” said lead study author Shweta Kotian, PhD, a postdoctoral fellow at the National Cancer Institute in Bethesda, Maryland.

There is an urgent need for new treatments for anaplastic and poorly differentiated thyroid cancers, said Dr. Kotian. “The [US Food and Drug Administration] has approved sorafenib and lenvatinib for treating differentiated radioiodine-refractory thyroid cancer, but anaplastic thyroid cancer and poorly differentiated thyroid cancer account for two-thirds of all thyroid cancer deaths and we have no active or standard therapy for them.”

The PI3K signaling pathway and HDAC are key players in cell growth, differentiation, and survival. Previous research has shown that the PI3K-AKT pathway is activated, and that HDAC levels are higher in thyroid cancer than in benign neoplasms.

The investigational, first-in-class oral PI3K/HDAC inhibitor CUDC-907 prevents activation of the PI3K-AKT-mTOR signaling pathway and compensatory signaling molecules like RAF and MEK, potentially halting progression in PI3K- or HDAC-expressing tumors. Dual inhibition of P13K-AKT and HDACs has previously been shown to induce thyroid cancer cell differentiation. A phase I clinical trial of CUDC-907 was recently completed among patients with relapsed/refractory lymphoma and multiple myeloma.[2]

Using immunohistochemistry analysis of a thyroid tissue array, the study authors found that HDAC2 was significantly higher in anaplastic, papillary, and follicular thyroid cancer than in benign tumor or normal thyroid tissue.

“HDAC2 is overexpressed in aggressive thyroid cancer,” explained Dr. Kotian. “We found that HDAC2 was preferentially overexpressed in anaplastic, followed by papillary, followed by follicular thyroid cancer.” HDAC2 was typically not overexpressed in normal or benign tissue.

The study authors used six thyroid cancer cell lines and two mouse models of thyroid cancer metastasis to examine the CUDC-907’s effects on thyroid cancer cell differentiation biomarkers and in vivo growth, and metastasis.

They found that CUDC-907 “exerts significant cytotoxicity” and significantly decreases cellular proliferation among thyroid cancer cell lines, Dr. Kotian reported.

CUDC-907 also induced apoptosis and caused declines in survivin, an apoptosis-inhibiting protein. “We saw a decrease in survivin across cell lines in a dose-dependent manner,” Dr. Kotian said.

CUDC-907 also significantly increases sodium/iodide symporter (NIS) mRNA expression in all thyroid cancer cell lines, Dr. Kotian reported. “It increases NIS levels by several-hundred fold, which is very exciting because it suggests that it might be a treatment for radioiodine-refractory thyroid cancers.”

In two mouse models of metastatic thyroid cancer, in which the animals’ tail veins were injected with human thyroid cancer cells, CUDC-907 significantly reduced tumor growth and metastasis.

CUDC-907 warrants investigation in a clinical trial for advanced and metastatic thyroid cancer, the authors concluded.

References

1. Kotian S, Zhang L, Boufraqech M, et al. Oral abstract 18. Simultaneous inhibition of PI3K signaling and HDAC2 induces differentiation in thyroid cancer cells and suppresses tumorigenesis. Thyroid. 2016;26(suppl 1).

2. Younes A, Berdeja JG, Patel MR, et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncology. 2016;17:622–631.