Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study.

BACKGROUND: Histone deacetylase (HDAC) inhibitors have shown radiosensitising activity in preclinical tumour models. This phase 1 study assessed the use of vorinostat combined with pelvic palliative radiotherapy for gastrointestinal carcinoma. METHODS: Between Feb 14, 2007, and May 18, 2009, eligible patients with histologically confirmed carcinoma, scheduled to receive pelvic palliative radiation to 30 Gy in 3 Gy daily fractions over 2 weeks, were enrolled into cohorts of escalating vorinostat dose. Vorinostat was administered orally once daily, 3 h before each radiotherapy fraction, at the following dose levels: 100 mg (n=1), 200 mg (n=4), 300 mg (n=6), and 400 mg (n=6). Endpoints included safety, tolerability, and biological activity (tumour histone acetylation). This study is registered with ClinicalTrials.gov, number NCT00455351. FINDINGS: One patient withdrew consent after one treatment day, leaving 16 patients evaluable for tolerability. Most recorded adverse events were grade 1 and 2, among which fatigue (all patients) and gastrointestinal events (all patients) were most common. Grade 3 adverse events included fatigue (n=5), anorexia (n=3), diarrhoea (n=2), hyponatraemia (n=1), hypokalaemia (n=1), and acneiform rash (n=1). Of these, treatment-related grade 3 events (ie, dose-limiting toxicities) were observed in one of six patients at vorinostat 300 mg once daily (fatigue and anorexia), and in two of six patients at vorinostat 400 mg once daily (two events of diarrhoea and one each of fatigue, anorexia, hyponatraemia, and hypokalaemia). The maximum-tolerated dose of vorinostat in combination with palliative radiotherapy was thus determined to be 300 mg once daily. Histone hyperacetylation was detected, indicating biological activity of vorinostat. INTERPRETATION: Vorinostat can be safely combined with short-term pelvic palliative radiotherapy. This study highlights the potential use of HDAC inhibitors with radiation, and suggests investigation of vorinostat in long-term curative pelvic radiotherapy--eg, as a component of preoperative chemoradiotherapy for rectal cancer. FUNDING: Merck & Co, Inc, Norwegian Cancer Society, Norwegian Health and Rehabilitation Foundation.

Anti-Angiogenic Treatment in Pseudomyxoma Peritonei-Still a Strong Preclinical Rationale.

Pseudomyxoma peritonei (PMP) is a rare, slow-growing cancer characterized by progressive accumulation of intraperitoneal mucinous tumor deposits. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) cures approximately 50% of patients, but in unresectable and recurrent cases, treatment options are limited. Anti-angiogenic treatment is being explored as a potential therapeutic option. Using PMP patient samples, microvessel densities (immunostaining for CD31 and CD105) and pro-angiogenic factors were analyzed, and the proliferative response upon incubation with human umbilical cord vascular endothelial cells (HUVEC) was determined. Growth inhibition by anti-angiogenic drugs was analyzed in patient-derived xenograft models of PMP. PMP tumor tissues were found to be highly vascularized and contained key pro-angiogenic factors, in particular related to vascular endothelial growth factor (VEGF) signaling, but interestingly, high levels of fibroblast growth factor 2 were also detected. HUVEC proliferation was stimulated upon incubation with fresh tumor samples and the observed proliferation could be inhibited by VEGF pathway inhibitor bevacizumab. In xenograft models the two VEGF pathway inhibitors, bevacizumab and aflibercept, inhibited tumor growth. This work reemphasizes the importance of angiogenesis as a major driver in PMP and strengthens the preclinical rationale for continued exploration of angiogenesis inhibition in the hope of providing novel treatment to a group of patients that have few other treatment options.

Integrative genomic analysis of peritoneal malignant mesothelioma: understanding a case with extraordinary chemotherapy response.

Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothelioma who had a remarkable response to palliative chemotherapy (platinum/pemetrexed). Tumor samples collected at surgery before and after treatment were analyzed on the genomic and transcriptional levels (exome sequencing, RNA-seq, and smallRNA-seq). Integrative analysis of single nucleotide and copy-number variants, mutational signatures, and gene expression was performed to provide a comprehensive picture of the disease. LATS1/2 were identified as the main mutational drivers together with homozygous loss of BAP1 and PBRM1, which also may have contributed to the extraordinary chemotherapy response. The presence of the S3 mutational signature is consistent with homologous recombination DNA repair defects due to BAP1 loss. Up-regulation of the PI3K/AKT/mTOR pathway after treatment, supported by deactivated PTEN through miRNA regulation, is associated with cancer progression and could explain chemotherapy resistance. The molecular profile suggests potential benefit from experimental targeting of PARP, EZH2, the PI3K/AKT/mTOR pathway and possibly also from immune checkpoint inhibition. In addition to providing the molecular background for this unusual case of peritoneal mesothelioma, the results show the potential value of integrative genomic analysis in precision medicine.

Individual tumor volume responses to short-course oxaliplatin-containing induction chemotherapy in locally advanced rectal cancer - Targeting the tumor for radiation sensitivity?

BACKGROUND: Neoadjuvant treatment of locally advanced rectal cancer (LARC) involves chemoradiotherapy (CRT), which may cause significant toxicity, and the potential role and sequential placement of neoadjuvant chemotherapy (NACT) relative to CRT is under debate. PATIENTS AND METHODS: In a non-randomized study of 72 LARC patients, short-course oxaliplatin-containing NACT was administered prior to CRT. Tumor volumes were calculated from magnetic resonance images before and after NACT, and four weeks after CRT, and associations between tumor volume responses and outcome were analyzed. Additionally, the impact of oxaliplatin exposure on radiosensitivity was examined in colorectal carcinoma cell lines. RESULTS: All tumors except one responded to NACT, with better responses in T3 than T4 cases, and 69/72 patients obtained additional tumor volume reduction after subsequent CRT. However, no associations were found between tumor volume reduction and long-term outcome. Of note, oxaliplatin-resistant cells were significantly more radiosensitive than the oxaliplatin-sensitive counterparts. CONCLUSIONS: Oxaliplatin-containing NACT led to substantial tumor volume reduction with particularly good responses in T3 cases. NACT did not impede subsequent CRT response, and experimental results rather suggested enhanced radiosensitivity in oxaliplatin-exposed cells, encouraging studies to explore the administration of NACT prior to CRT. Data are still lacking to support omitting radiation in LARC management.

BRAF mutation detection and identification by cycling temperature capillary electrophoresis.

BRAF mutations are found in many human tumors, namely melanomas ( approximately 70%) and colon carcinomas ( approximately 15%). This paper presents a method for identification of exon 15 BRAF mutations by denaturant capillary electrophoresis (CE), an analysis method that is sensitive, cost-effective (involving only polymerase chain reaction (PCR) and electrophoresis) and capable of high-throughput screening. In total, we found 21 (70%) out of 30 melanoma cell lines with BRAF mutations in exon 15: two of which were the p.Val600Asp (c.1799-800TG>AT) mutation, one cell line contained the p.Val600Arg (c.1798-99GT>AG) mutation, and 18 cell lines contained the p.Val600Glu (c.1799T>A) mutation. Of the nine cell lines that did not contain a BRAF mutation, five contained an NRAS mutation at exon 2, and no mutations were detected in NRAS exon 1. There was no overlap of NRAS and BRAF mutations in the same cell line. In addition, we looked at 221 colon biopsy samples and identified one further BRAF mutation, the p.Asp594Gly (c.1781A>G) mutation, in seven samples. The p.Val600Glu mutation was identified in 11 of the colon biopsy samples. Using the four mutations of BRAF exon 15, we then constructed a denaturing CE standard capable of distinguishing between each of the mutations; therefore, sequencing does not need to be performed to confirm the mutation. In conclusion, this sensitive, cost-effective mutation assay for BRAF (and RAS) will provide the opportunity to detect and determine mutations without the need to purify samples for sequencing. Future large-scale studies will provide the clinical usefulness of such mutations.