Scientists at Roswell Park Cancer Institute have demonstrated that entinostat (Syndax Pharmaceuticals, Inc.), a class I benzamide histone deacetylase inhibitor also known as SNDX-275 and MS-275, has novel immunomodulatory properties that contribute to the enhanced activity of cancer immunotherapies in models of renal and prostate cancer.
Histone deacetylases (HDAC)are key enzymes that alter the structure of chromatin to control gene expression by removing acetyl groups (O=C-CH3) from an ?-N-acetyl lysine amino acid on a histone. Because DNA is wrapped around histones and DNA expression is regulated by acetylation and de-acetylation, increased DNA binding condenses DNA structure, preventing transcription. This aberrant gene expression can result in reversible, epigenetically-based drug tolerance. Designed to selectively target the HDAC isoforms most relevant to the biology of tumors, entinostat can normalize dysregulated gene expression in cancer cells.
Unique selectivity profile
Entinostat, which has been studied in more than 600 cancer patients where objective tumor responses have been observed in both solid and hematologic malignancies, is differentiated from other members of its class through its unique selectivity profile, pharmacokinetic properties and safety profile.
“The results…” published in the January 23rd of PLoS ONE, “…. demonstrate a novel immunomodulatory effect of entinostat and provide a rationale for the clinical testing of entinostat to enhance cancer immunotherapy,” said Roberto Pili, MD, professor of oncology, chief, genitourinary section and co-leader, genitourinary program, department of medicine, Roswell Park Cancer Institute. “We are interested in testing whether entinostat could improve the benefit seen with immunotherapies in the advanced disease population where oncology treatments are limited.”
Suppressing anti-tumor activity
Entinostat inhibits the function of T regulatory cells that are involved in suppressing the anti-tumor activity of immune based therapies. Importantly entinostat maintained the activity of the T effector cell population. The study showed that a low dose of entinostat (5 mg/kg) reducedFoxp3 gene and protein levels in regulatory T cells (Tregs) which wasassociated with enhanced tumor growth inhibition in combination with either Interleukin-2/rIl-2 (Proleukin?/Aldesleuking) or a survivin-based vaccine therapy (SurVaxM vaccine). Entinostat down-regulated Foxp3 expression transcriptionally and blocked Tregs suppressive function without affecting T effector cells (Teffs). In vitro low dose entinostat (0.5 ?M) inducedSTAT3 acetylation and a specific inhibitor of STAT3 partially rescued entinostat-induced down-regulation of Foxp3, suggesting that STAT3 signaling is involved in Foxp3 down-regulation by entinostat.
“This exciting pre-clinical data provides new information about entinostat’s mechanism of action, expanding the potential for entinostat in new combinations in solid tumors,” said Joanna Horobin, MD, president and chief executive officer of Syndax. “Because of collaborations like this one with the Roswell Park Cancer Institute(RPCI), we are able to continue to investigate new combinations that could ultimately change the clinical outcomes for oncology patients who need new treatment options.”
Proof of concept
A proof-of-concept clinical study testing this hypothesis is underway with entinostat combined with rIL-2 in renal cell cancer. Additional studies in combination with recently approved immunotherapies are planned. Entinostat has shown effect in Phase II clinical testing in other solid tumors including with the aromatase inhibitor exemestane in advanced breast cancer and with the epidermal growth factor receptor inhibitor erlotinib in advanced lung cancer.
Randomized, placebo-controlled phase II studies with entinostat have demonstrated promising results in combination with aromatase inhibitors in breast cancer (ENCORE 301) and with the EGFR-TKI erlotinib in non-small cell lung cancer (ENCORE 401). Results from the ENCORE clinical program have provided the basis for moving entinostat into pivotal, phase III testing across a platform of breast and lung cancer indications.
For more information:
Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, Sotomayor P, Shrikant P, Fenstermaker R, Pili R. Class I Histone Deacetylase Inhibitor Entinostat Suppresses Regulatory T Cells and Enhances Immunotherapies in Renal and Prostate Cancer Models.PLoS One. 2012;7(1):e30815. Epub 2012 Jan 27.
– Study to Evaluate Exemestane With and Without SNDX-275 in Treatment of Postmenopausal Women With Advanced Breast Cancer (NCT00676663)
– Interleukin 2, Aldesleukin and Entinostat for Kidney Cancer (NCT01038778)
– Azacitidine and MS-275 in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer (NCT00387465)
– A Phase 2 Exploratory Study of Erlotinib and SNDX-275 in Patients With Non-small Cell Lung Carcinoma Who Are Progressing on Erlotinib (NCT00750698)