Yungan Tao

Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152

Overexpression of the Aurora-B kinase correlates with oncogenic transformation and poor prognosis. We evaluated the effects of the bona fide Aurora-B kinase inhibitor AZD1152 on tumor responses to ionizing radiation (IR). When p53wt HCT116 and A549 cells were pretreated with AZD1152-HQPA prior to IR, additive effects were observed. Interestingly, more pronounced tumoricidal effects were observed in p53-deficient HCT116 and HT29 cells, as well as A549 cells treated with the p53 inhibitor cyclic pifithrin-α. In vivo studies on xenografted mice confirmed enhanced tumor growth delay after the combination of IR plus AZD1152-IR as compared to IR alone. Again, this effect was more pronounced with p53−/− HCT116 and p53-mutant xenografts. The AZD1152-mediated radiosensitization was mimicked by knockdown of Aurora-B with a short interference RNA or by inhibition of Aurora-B by transfection with an inducible kinase-dead Aurora-B. The radiosensitizing effect of AZD1152 was lost in CHK2−/− and 14-3-3−/− HCT116 cells. Altogether, these data indicate that AZD1152 can radiosensitize tumor cell lines in vitro and in vivo, the fact that these effects are exacerbated in p53-deficient cancer cells is of potential interest for further clinical development.

Radiosensitization by Chir-124, a selective CHK1 inhibitor: effects of p53 and cell cycle checkpoints.

Checkpoint kinase-1 (CHK1) is a key regulator of the DNA damage-elicited G2-M checkpoints. The aim of the present study was to investigate the effects of a selective CHK1 inhibitor, Chir124, on cell survival and cell cycle progression following ionizing radiation (IR). Treatment with Chir-124 resulted in reduced clonogenic survival and abrogated the IR- induced G2-M arrest in a panel of isogenic HCT116 cell lines after IR. This radiosensitizing effect was relatively similar between p53-/- and p53-sufficient wild type (WT) HCT116 cells. However, the number of mitotic cells (as measured by assessing the phosphorylation of mitotic proteins) increased dramatically in p53-/- HCT116 cells after concomitant Chir-124 exposure, compared to IR alone, while no such effect was observed in p53-sufficient WT HCT116 cells. In p53-/- cells, Chir-124 treatment induced a marked accumulation of polyploid cells that were characterized by micronucleation or multinucleation. p21-/- HCT116 cells displayed a similar pattern of response as p53-/- cells. Chir-124 was able to radiosensitize HCT116 cells that lack checkpoint kinase-2 (CHK2) or that were deficient for the spindle checkpoint protein Mad2. Finally, Chir-124 could radiosensitize tetraploid cell lines, which were relatively resistant against DNA damaging agents. Altogether these results suggest that Chir-124-mediated radiosensitization is profoundly influenced by the p53 and cell cycle checkpoint system.

Current concepts of management in radiotherapy for head and neck squamous-cell cancer

Radiotherapy plays a key role in the management of early stage and locally advanced head and neck squamous-cell carcinomas (HNSCC) either alone or, more frequently combined with surgery and/or chemotherapy. Several approaches have been developed to improve its efficacy while maintaining acceptable toxicities, such as altered fractionated radiotherapy or concomitant chemoradiotherapy which have both improved the anti-tumor efficacy of radiotherapy. Of particular interest is concomitant chemoradiotherapy (CT-RT) which is the most commonly used approach in locally advanced disease. Taxanes and platinum-based induction chemotherapy could constitute an option in the treatment of locally advanced HNSCC and its contribution before concomitant RT-CT is currently under investigation. More recently, epidermal growth factor receptor (EGFr) molecular targeting with cetuximab combined with radiotherapy has been successfully tested in a large randomized trial and this combination constitutes a new option, especially for patients with medical co-morbidities. Finally management of treatment related acute or late toxicity remains an important issue and in the last decade major achievements have been obtained in this field especially using intensity modulated radiotherapy (IMRT).

Randomized phase III trial (GORTEC 98-03) comparing re-irradiation plus chemotherapy versus methotrexate in patients with recurrent or a second primary head and neck squamous cell carcinoma, treated with a palliative intent

PURPOSE This randomized phase III trial investigated the potential benefit of concurrent re-irradiation, fluorouracil and hydroxyurea versus methotrexate for patients treated with palliative intent for recurrent or second primary head and neck squamous cell carcinoma (HNSCC) in previously irradiated area. PATIENTS AND METHODS Patients with recurrent HNSCC or a second primary not amenable to curative-intent treatment were randomized to the R-RT arm (concurrent re-irradiation, fluorouracil and hydroxyurea) or to the Ch-T arm (methotrexate). The primary endpoint was overall survival (OS). Due to a very slow accrual, the trial was closed after inclusion of 57 patients. RESULTS Fifty-seven patients were included. All patients died in the two arms with a maximal follow-up of 5years. Although four complete responses were achieved in R-RT arm, (none in Ch-T arm) re-irradiation did not improve OS compared with methotrexate (23% versus 22% at 1year, NS). Sixteen patients experienced clinical grade ⩾3 late toxicities (>6months), 11 in R-RT arm and five in Ch-T arm. CONCLUSIONS Premature discontinuation of the trial did not allow us to draw firm conclusions. However, there was no suggestion that concurrent re-irradiation, fluorouracil and hydroxyurea improved OS compared to methotrexate alone in patients treated with palliative intent for a recurrent or second primary HNSCC.

The Aurora B kinase inhibitor AZD1152 sensitizes cancer cells to fractionated irradiation and induces mitotic catastrophe

AZD1152, an Aurora kinase inhibitor with selectivity for Aurora B kinase, can enhance the effect of ionizing radiation (IR). The aim of this study was to evaluate and to mechanistically explore scheduling effects of AZD1152 on tumor responses to IR, in three different settings: neoadjuvant (AZD1152 before IR), adjuvant (IR before AZD1152), or concomitant treatments (AZD1152 plus one single IR dose). A more pronounced tumor growth delay was observed in the neoadjuvant and adjuvant schedules as compared to the concomitant schedule. However, AZD1152 enhanced the efficacy of IR when concomitant IR was fractionated over several days. Histopathological examination revealed that AZD1152 + IR induced polyploidy, multinucleation and micronuclei in vivo. Time-lapse videomicroscopy confirmed that cell death induced by AZD1152 + IR was preceded by multinucleation and the formation of micronuclei, which both are hallmarks of mitotic catastrophe. Caspase inhibition or removal of the pro-apoptotic protein Bax did not ameliorate the long-term cell survival of AZD1152-treated cancer cells. In contrast, a chemical inhibitor of CHK1, Chir124, sensitized cancer cells to the lethal effect of AZD1152. Altogether, these data support the contention that AZD1152 mediates radiosensitization in vivo by enhancing mitotic catastrophe, which can be used as a biomarker of treatment efficacy.

Increased radiosensitivity of HPV-positive head and neck cancers: Molecular basis and therapeutic perspectives

Human papillomavirus driven head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), are characterized by a significant survival advantage over their HPV-negative counterparts. Although the reasons behind this are still not fully elucidated, it is widely accepted that these tumors have a higher response to ionizing radiation that might explain their favorable outcomes. Potential underlying intrinsic mechanisms include impaired DNA repair abilities, differences in activated repopulation-signaling pathways and cell cycle control mechanisms. The role of the microenvironment is increasingly highlighted, particularly tumor oxygenation and the immune response. Recent studies have shown a distinct pattern of intratumoral immune cell infiltrates, according to HPV status, and have suggested that an increased cytotoxic T-cell based antitumor immune response is involved in improved prognosis of patients with HPV-positive OPSCC. These significant milestones, in the understanding of HPV-induced HNSCC, pave the way to new therapeutic opportunities. This article reviews the current evidence on the biological basis of increased radiosensitivity in HPV-positive HNSCC and discusses potential therapeutic implications.

Oral cavity squamous cell carcinoma in 260 patients aged 80 years or more

PURPOSE We report the experience of two French cancer centers in the treatment of oral cavity squamous cell carcinoma (SCC) in patients aged 80 years. MATERIALS AND METHODS Two hundred and sixty patients aged 80 years with a primary oral cavity SCC were included in this retrospective analysis. RESULTS Sex ratio was near to 1. Tobacco or alcohol intoxication was the main risk factor for 66% of men and 16% of women and leukoplakia, lichen planus, or oral traumatism for 55% of women and 11% of men (p<0.0001). Two hundred patients received a loco-regional (LR) treatment with a curative intent (surgery and/or radiotherapy), 29 with a palliative intent and 31 did not receive a LR treatment. Curative treatments were initially planned to be adapted to age in 118 patients (59%). The median disease-specific survival (DSS) was 29 months. In multivariate analysis, the independent prognostic factors for DSS were stage (HR=0.42 [0.24-0.72]), age (HR=0.43 [0.24-0.75]) and performance status (HR=0.50 [0.27-0.95]). The median overall survival (OS) was 14 months. In multivariate analysis, the independent prognostic factors for OS were age (HR=0.52 [0.35-0.79]), stage (HR=0.56 [0.38-0.84]), tumor differentiation (HR=0.60 [0.33-0.93]) and performance status (HR=0.6 [0.37-0.97]). In patients treated with a curative intent, treatment adapted to age was not associated with a decreased overall survival or disease-specific survival as compared with the standard treatment. However, prophylactic lymph node treatment in stages I-II tumors decreased the rate of nodal recurrence from 38% to 6% (p=0.01). CONCLUSION This study emphasizes the need for prospective evaluation of standard and adapted schedules in elderly patients with oral cavity cancer.

Caspase independence of radio-induced cell death.

Colon carcinoma cells subjected to γ-irradiation (4 Gy) manifest signs of apoptosis (caspase activation, chromatin condensation, phosphatidylserine (PS) exposure on the cell surface, sub-diploid DNA content), correlating with their radiosensitivity, which is increased in cells lacking the 14-3-3σ protein as compared to wild-type controls. Inhibition of caspases by addition of Z-Val-Ala-DL-Asp (OMe)-fluoromethylketone, by stable transfection with the Baculovirus gene coding for p35, or by Bax knockout reduced all signs of apoptosis, yet failed to suppress radio-induced micro- and multinucleation. Moreover, pharmacological caspase inhibition, p35 expression or Bax knockout had no effect on the clonogenic survival that was reduced by γ-irradiation and caspase inhibition failed to abolish the increased radiosensitivity of 14-3-3σ-deficient cells. Micro- and multinucleation was detectable among non-apoptotic cells lacking PS exposure, as well as among cells undergoing apoptosis. Moreover, a fraction of micro- or multinucleated cells manifested caspase activation, and videomicroscopic analyses revealed that such cells could succumb to caspase-dependent apoptosis. Altogether, these results suggest that genomic instability induced by γ-irradiation can trigger apoptosis, although apoptosis is dispensable for radio-induced clonogenic death.

Advances in radiotherapy of head and neck cancers.

Purpose of review Radiation therapy plays a key role in the management of head and neck cancers (HNCs). We reviewed the recent advances in radiotherapy of HNCs and the role of imaging in treatment planning. Recent findings As shown in a recent update of meta-analysis of chemotherapy in head and neck cancer (MACH-NC), concurrent chemoradiotherapy was confirmed to be a standard of care in the management of locally advanced HNCs. Two recent large-scale randomized trials [Groupe d’Oncologie Radiothérapie Tête et Cou (GORTEC) and Radiation Therapy Oncology Group (RTOG)] failed to show additional benefit when combining accelerated radiotherapy with concurrent chemoradiotherapy. Updated 5-year results of a phase III pivotal trial confirmed the benefit of targeting epidermal growth factor receptor with cetuximab when combined with radiotherapy. Taxane–platinum–fluorouracil-based induction chemotherapy has been established as a reference induction regimen and has been explored as a possible part of the treatment of locally advanced HNCs, which was particularly successful in larynx preservation. The superiority of intensity-modulated radiation therapy compared with conventional radiotherapy for parotid protection has been shown in a prospective phase III trial. PET-based treatment planning is still to be validated in the HNCs. Summary Concurrent chemoradiotherapy could still be considered as a standard of care; several new treatment combinations and new radiation technologies have been recently successfully evaluated in clinical trials.

Distant Metastasis of Undifferentiated Carcinoma of Nasopharyngeal Type

Positron emission tomography (PET) using fluorine-18-labeled fluorodeoxyglucose (18F-FDG) which is a promising method for the early detection of DM of NPC [7] was not mentioned in this case report, although early detection of further liver metastasis might not have changed the clinical practice nor improved patient’s survival [8]. It would be interesting to know the intensity of fixation in PET images of this kind of metastatic cystic lesions. The prognosis of patients with liver metastasis is considered to be poorer than lung or bone metastasis [5, 9]. For some kind of solitary liver metastasis, however, surgical resection, radiofrequency ablation or stereotactic body radiotherapy could be valuable treatment options, especially when loco-regional disease has been controlled. Long-term survival has been reported with partial hepatectomy [10]. The authors claim that concurrent chemo-radiotherapy is the standard treatment for metastatic NPC. We may consider this statement with caution. For selected patients with few metastatic sites, additional radiotherapy can provide extended disease control as shown in previous reports. Poly-chemotherapy can be considered as standard of care in patients with metastatic NPC [11]. Cisplatin-based combination chemotherapy is the most effective standard treatment for metastatic NPC. The combination of cisplatin and infusional 5-FU remains the most commonly used in first-line treatment with a 66–76% response rate. More intensive combinations give a higher response rate, but are also usually associated with increased toxicities. None of these combinations has yet been compared with the combination of cisplatin and 5-FU [1]. Treatment of metastatic NPC is essentially palliative and survival is usually poor. However, a small percentage of patients may be cured by systemic therapy, long-term survival may be obtained in some cases [5, 12]. 20 long-term (more than 36 months) disease-free survivors of metastatic NPC (bone, lung, or liver) from the Institut Gustave-Roussy have been reported using 4 different intensive chemotherapy protocols including cisplatin, bleomycin, 5-FU, epirubicin, or mitomycin. This suggests a potential curative role for chemotherapy in metastatic Nasopharyngeal carcinoma (NPC) is endemic in southern China, south-east Asia and north Africa, where the undifferentiated carcinoma of nasopharyngeal type (UCNT; WHO type 2 and 3) is most frequent [1]. UCNT is an Epstein-Barr virus (EBV)-related carcinoma [2]. NPC has distinctive features from other head and neck squamous cell cancers (HNSCC). These include early subclinical dissemination, with most of distant metastases (DM) appearing within 18 months of first symptoms [3]. The incidence of DM is reported to be more than 30% in one large series based on 5,037 cases of NPC [4]. Bone is the most frequent metastatic site, followed by lung, and liver [3, 5]. In this issue of ONKOLOGIE, Kao et al. [6] report an unusual case of cystic liver metastases form of NPC. The patient has been treated initially by chemo-radiotherapy based on cisplatin and 5-fluorouracil (5-FU) for NPC with bone metastases. The suspicion of liver metastases was found 1 year after the beginning of treatment and confirmed finally by histological examination of liver aspiration with fluid cytology 6 months later. The treatment had been switched to docetaxel and cisplatin as soon as liver metastases were suspected. There are few published studies concerning liver metastasis of NPC although they are not rare, and cystic liver metastasis from NPC is exceptional. This report provides an example of this kind of rare characteristic of NPC metastasis, and may suggest that a special aspect of liver metastases with a cystic form does exist for NPC. The limitations of this report are obvious, and it is unlikely to provide us with strong clinical practice assistance because of a case study characteristic of this kind of report (Evidence Based Medicine level 5). In fact, cystic lesions in liver could be induced by many factors, such as infectious or congenital diseases, liver injuries, benign tumors or liver metastasis of other malignant tumors (e.g. carcinoid, ovary, pancreas). For the diagnosis, histological confirmation is necessary as shown in the figure of this case study. We may point out that metastases are sometimes more differentiated than primitive nasopharyngeal carcinoma, as shown in this case.