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NIMG-30. ASSESSING TREATMENT RESPONSE OF GLIOBLASTOMA TO AN HDAC INHIBITOR, BELINOSTAT (PXD101)

ABSTRACT: Abstract The current standard of care for glioblastoma (GBM; WHO grade IV glioma) is maximal safe resection followed by radiation therapy (RT) with concurrent and adjuvant chemotherapy. Despite this aggressive treatment, the median survival remains only 15 months. Thus, there is a need for better treatment options. Histone deacetylases (HDAC) are proteins with broad impact on many cellular functions implicated in oncogenesis. Belinostat (PXD101; Spectrum Pharmaceuticals) is a pan-HDAC inhibitor (HDACi) with increased blood-brain barrier uptake compared to the previous HDACi’s. In this work, we evaluate the mechanism of belinostat in vitro and its anti-tumor effect in an in vivo orthotic rat glioma model. The data show that belinostat has an excellent dose-dependent anti-tumor effect as evaluated by behavioral changes and tumor volume, and that it restores MR-spectroscopy-detectable metabolism of N-acetylaspartate and myo-insolitol in vitro better than other HDACi’s. We also present data from several representative cases of patients treated with belinostat in addition to standard chemoradiation as part of an ongoing clinical trial (NCT02137759), assessing their metabolic response on spectroscopic MRI (sMRI) using the ratio of choline to N-acetylaspartate (Cho/NAA). It is observed that a patient who weakly stained acetyl H4 immunohistochemical analysis (IHC) showed an increase in metabolically-active tumor volume (as measured by Cho/NAA > twice contralateral white matter) at one month post-radiation, indicative of tumor proliferation, whereas two patients with strong acetylated H4 IHC showed sMRI signal decrease, indicative of tumor reduction. A patient with intermediate acetyl H4 IHC showed a small decrease in tumor volume. In summary, the preclinical data and these cases suggest that acetyl H4 can be a good biomarker for predicting HDACi treatment efficacy, and that its early response can be reliably monitered non-invasively using sMRI.

SUBMITTER: Gurbani S

PROVIDER: S-EPMC5692314 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Project description:Two classes of novel agents, NEDD8-activating enzyme (NAE) and histone deacetylase (HDAC) inhibitors, have shown single-agent activity in acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS). Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat coadministration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3-internal tandem duplication (ITD), whereas p53 short hairpin RNA (shRNA) knockdown or enforced FLT3-ITD expression significantly sensitized cells to the regimen. MLN4924 blocked belinostat-induced antiapoptotic gene expression through nuclear factor-κB inactivation. Each agent upregulated Bim, and Bim knockdown significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual vs combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/downregulation, cotreatment downregulated multiple homologous recombination and nonhomologous end-joining repair proteins, triggering robust double-stranded breaks, chromatin pulverization, and apoptosis. Consistently, Chk1 or Wee1 shRNA knockdown significantly sensitized AML cells to MLN4924. MLN4924/belinostat displayed activity against primary AML or MDS cells, including those carrying next-generation sequencing-defined poor-prognostic cancer hotspot mutations, and CD34(+)/CD38(-)/CD123(+) populations, but not normal CD34(+) progenitors. Finally, combined treatment markedly reduced tumor burden and significantly prolonged animal survival (P < .0001) in AML xenograft models with negligible toxicity, accompanied by pharmacodynamic effects observed in vitro. Collectively, these findings argue that MLN4924 and belinostat interact synergistically by reciprocally disabling the DDR in AML/MDS cells. This strategy warrants further consideration in AML/MDS, particularly in disease with unfavorable genetic aberrations.

Project description:Abstract BACKGROUND Healthy brain tissue responses to radiotherapy (pseudoprogression/radiation necrosis) may bias MRI-based tumor response evaluations. To understand these changes specifically after high doses of radiotherapy, we analyzed MRIs of patients of the INTRAGO study, a phase I/II dose-escalation trial on intraoperative radiotherapy in glioblastoma. METHODS Patients enrolled in INTRAGO (NCT02104882) received an intraoperative boost of 20-40 Gy followed by standard adjuvant radiochemotherapy and maintenance chemotherapy. In the present analyses, only patients who received per-protocol therapy and those, who underwent standardized serial MRI follow-ups including DSC-PWI, were included and assessed with special focus on perilesional enhancement pattern, volume, and mean rCBV. Mean leakage-corrected rCBV within enhancing lesions was computed for all MRI follow-ups. RESULTS Overall, 12/15 (80%) patients (median age 60.5 [range 46-73] years) were included in the analysis. Distant failure was the predominant failure pattern (7/12 [58.3%]) leading to salvage therapy after a median follow-up of 372.5 days (range: 72-991 days), while local tumor recurrence was observed in one case (8.3%). On the first follow-up MRI all patients demonstrated perilesional enhancement of varying extent: in 3/12 (25%) patients thin linear, in 1 (8.3%) nodular, in 7 (58.3%) combined linear and nodular, and in 1 (8.3%) voluminous, indistinct, mesh-like. In the course, most patients developed the latter two patterns (8/11 [72.2%]). Three different patterns of enhancing lesion volume were observed: in 3/10 (30%) an early (<200 days) continuous decrease, in 2/10 (20%) a marked early increase, and in 5 (50%) a marked late (≥200 days) increase. The overall linear trend in rCBV was negative in most patients (8/11 (72.2%)). CONCLUSIONS High doses to the tumor cavity result in characteristic perilesional enhancement patterns. These results will be useful for the response evaluation of patients exposed to high doses of radiotherapy in future studies, such as the multicenter randomized INTRAGO II trial (NCT02685605).

Project description:PurposeCurrent melphalan-based regimens for intravitreal chemotherapy for retinoblastoma vitreous seeds are effective but toxic to the retina. Thus, alternative agents are needed. Based on the known biology of histone deacetylases (HDACs) in the retinoblastoma pathway, we systematically studied whether the HDAC inhibitor belinostat is a viable, molecularly targeted alternative agent for intravitreal delivery that might provide comparable efficacy, without toxicity.MethodsIn vivo pharmacokinetic experiments in rabbits and in vitro cytotoxicity experiments were performed to determine the 90% inhibitory concentration (IC90). Functional toxicity by electroretinography and structural toxicity by optical coherence tomography (OCT), OCT angiography, and histopathology were evaluated in rabbits following three injections of belinostat 350 µg (2× IC90) or 700 µg (4× IC90), compared with melphalan 12.5 µg (rabbit equivalent of the human dose). The relative efficacy of intravitreal belinostat versus melphalan to treat WERI-Rb1 human cell xenografts in rabbit eyes was directly quantified. RNA sequencing was used to assess belinostat-induced changes in RB cell gene expression.ResultsThe maximum nontoxic dose of belinostat was 350 µg, which caused no reductions in electroretinography parameters, retinal microvascular loss on OCT angiography, or retinal degeneration. Melphalan caused severe retinal structural and functional toxicity. Belinostat 350 µg (equivalent to 700 µg in the larger human eye) was equally effective at eradicating vitreous seeds in the rabbit xenograft model compared with melphalan (95.5% reduction for belinostat, P < 0.001; 89.4% reduction for melphalan, P < 0.001; belinostat vs. melphalan, P = 0.10). Even 700 µg belinostat (equivalent to 1400 µg in humans) caused only minimal toxicity. Widespread changes in gene expression resulted.ConclusionsMolecularly targeted inhibition of HDACs with intravitreal belinostat was equally effective as standard-of-care melphalan but without retinal toxicity. Belinostat may therefore be an attractive agent to pursue clinically for intravitreal treatment of retinoblastoma.

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NIMG-30. ASSESSING TREATMENT RESPONSE OF GLIOBLASTOMA TO AN HDAC INHIBITOR, BELINOSTAT (PXD101)

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