PAXX is a novel target to overcome resistance to doxorubicin and cisplatin in osteosarcoma.
- 作者列表："Ma W","Yang L","Liu H","Chen P","Ren H","Ren P
:Osteosarcoma (OS) is the most common primary malignant bone tumor diagnosed in children and adolescents. Unfortunately, OS patients with metastatic or recurrent disease are highly resistant to front line chemotherapy that significantly limits the long-term survival rate. Since majority of chemotherapeutic agents used in OS work by generating DNA damages, enhanced DNA repair pathways are generally associated with chemoresistance in OS treatment. However, the exact mechanisms of chemoresistance in OS are not fully understood. Our study found that paralogue of XRCC4 and XLF (PAXX), which was identified recently as a novel factor of non-homologous end joining (NHEJ), is upregulated in chemoresistant OS cells. Importantly, PAXX deficiency re-sensitizes chemoresistant OS cells to doxorubicin and cisplatin. Mechanistically, chemoresistance to doxorubicin or cisplatin results in enhanced PAXX-Ku70 interaction and elevated NHEJ efficiency. We also identified a small molecule M11 that interrupts PAXX-Ku70 interaction and re-sensitizes chemoresistant OS cells to doxorubicin and cisplatin. Thus, our data provide evidence that PAXX could serve as a novel target to overcome chemoresistance in OS treatment.
: 骨肉瘤 (OS) 是儿童和青少年中最常见的原发性恶性骨肿瘤。不幸的是，具有转移或复发性疾病的OS患者对一线化疗高度耐药，这显著限制了长期生存率。由于OS中使用的大多数化疗药物通过产生DNA损伤起作用，因此增强的DNA修复途径通常与OS治疗中的化疗耐药相关。然而，OS化疗耐药的确切机制尚不完全清楚。我们的研究发现，XRCC4 和XLF (PAXX) 的副作用，最近被鉴定为非同源末端连接 (NHEJ) 的新因子，在化学抗性OS细胞中上调。重要的是，PAXX缺乏使化疗耐药OS细胞对多柔比星和顺铂重新敏感。从机制上讲，多柔比星或顺铂的耐药性导致PAXX-Ku70 相互作用增强，NHEJ效率升高。我们还发现了一种小分子M11，它能阻断PAXX-Ku70 的相互作用，使化疗耐药的OS细胞对多柔比星和顺铂重新敏感。因此，我们的数据提供了证据，表明PAXX可以作为克服OS治疗中化疗耐药的新靶点。
METHODS:OBJECTIVE:Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS: :Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS: :Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION:Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE: :This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.
METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.
METHODS:PURPOSE:Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. METHODS:The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. RESULTS:The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. CONCLUSIONS:Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.