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Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma.

ABSTRACT: Background Preclinical studies suggested synergistic anti-tumor activity when pairing mTOR inhibitors with histone deacetylase (HDAC) inhibitors. We completed a phase I, dose-finding trial for the mTOR inhibitor everolimus combined with the HDAC inhibitor panobinostat in advanced clear cell renal cell carcinoma (ccRCC) patients. We additionally investigated expression of microRNA 605 (miR-605) in serum samples obtained from trial participants. Patients and Methods Twenty-one patients completed our single institution, non-randomized, open-label, dose-escalation phase 1 trial. miR-605 levels were measured at cycle 1/day 1 (C1D1) and C2D1. Delta Ct method was utilized to evaluate miR-605 expression using U6B as an endogenous control. Results There were 3 dosing-limiting toxicities (DLTs): grade 4 thrombocytopenia (n = 1), grade 3 thrombocytopenia (n = 1), and grade 3 neutropenia (n = 1). Everolimus 5 mg PO daily and panobinostat 10 mg PO 3 times weekly (weeks 1 and 2) given in 21-day cycles was the recommended phase II dosing based on their maximum tolerated dose. The 6-month progression-free survival was 31% with a median of 4.1 months (95% confidence internal; 2.0-7.1). There was higher baseline expression of miR-605 in patients with progressive disease (PD) vs those with stable disease (SD) (p = 0.0112). PD patients' miR-605 levels decreased after the 1st cycle (p = 0.0245), whereas SD patients' miR-605 levels increased (p = 0.0179). Conclusion A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic pairing did not appear to improve clinical outcomes in our group of patients with advanced ccRCC. There was differential expression of miR-605 that correlated with treatment response. Clinical trial information: NCT01582009.

SUBMITTER: Wood A

PROVIDER: S-EPMC7182475 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionOf the more than one million global cases of breast cancer diagnosed each year, approximately fifteen percent are characterized as triple-negative, lacking the estrogen, progesterone, and Her2/neu receptors. Lack of effective therapies, younger age at onset, and early metastatic spread have contributed to the poor prognoses and outcomes associated with these malignancies. Here, we investigate the ability of the histone deacetylase inhibitor panobinostat (LBH589) to selectively target triple-negative breast cancer (TNBC) cell proliferation and survival in vitro and tumorigenesis in vivo.MethodsTNBC cell lines MDA-MB-157, MDA-MB-231, MDA-MB-468, and BT-549 were treated with nanomolar (nM) quantities of panobinostat. Relevant histone acetylation was verified by flow cytometry and immunofluorescent imaging. Assays for trypan blue viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation, and DNA fragmentation were used to evaluate overall cellular toxicity. Changes in cell cycle progression were assessed with propidium iodide flow cytometry. Additionally, qPCR arrays were used to probe MDA-MB-231 cells for panobinostat-induced changes in cancer biomarkers and signaling pathways. Orthotopic MDA-MB-231 and BT-549 mouse xenograft models were used to assess the effects of panobinostat on tumorigenesis. Lastly, flow cytometry, ELISA, and immunohistochemical staining were applied to detect changes in cadherin-1, E-cadherin (CDH1) protein expression and the results paired with confocal microscopy in order to examine changes in cell morphology.ResultsPanobinostat treatment increased histone acetylation, decreased cell proliferation and survival, and blocked cell cycle progression at G2/M with a concurrent decrease in S phase in all TNBC cell lines. Treatment also resulted in apoptosis induction at 24 hours in all lines except the MDA-MB-468 cell line. MDA-MB-231 and BT-549 tumor formation was significantly inhibited by panobinostat (10 mg/kg/day) in mice. Additionally, panobinostat up-regulated CDH1 protein in vitro and in vivo and induced cell morphology changes in MDA-MB-231 cells consistent with reversal of the mesenchymal phenotype.ConclusionsThis study revealed that panobinostat is overtly toxic to TNBC cells in vitro and decreases tumorigenesis in vivo. Additionally, treatment up-regulated anti-proliferative, tumor suppressor, and epithelial marker genes in MDA-MB-231 cells and initiated a partial reversal of the epithelial-to-mesenchymal transition. Our results demonstrate a potential therapeutic role of panobinostat in targeting aggressive triple-negative breast cancer cell types.

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Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma.

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