PAR-4 as a possible new target for pancreatic cancer therapy

Importance of the field: Pancreatic cancer (PC) is a deadly disease that is intractable to currently available treatment regimens. Although well described in different tumors types, the importance of apoptosis inducer prostate apoptosis response-4 (Par-4) in PC has not been appreciated. PC is an oncogenic kras driven disease, which is known to downregulate Par-4. Therefore, this review highlights its significance and builds a strong case supporting the role of Par-4 as a possible therapeutic target in PC.

Areas covered in this review: Literature-based evidence spanning the last 15 years on Par-4 and its significance in PC.

What the reader will gain: This review provides comprehensive knowledge of the significance of Par-4 and its association with kras status in PC, along with the crosstalk with crucial resistance and survival molecules NF-κB and Bcl-2 that ultimately are responsible for the overall poor outcome of different therapeutic approaches in this disease.

Take home message: Par-4 holds promise as a potential therapeutic target that can be induced by chemopreventive agents and small-molecule inhibitors either alone or in combination with standard chemotherapeutics leading to selective apoptosis in PC cells. It also acts as a chemosensitizer and therefore warrants further clinical investigations in this disease.     

胰腺癌的化学治疗

胰腺癌早期诊断较困难 ,一旦发现多属晚期 ,此时手术切除率低、平均生存时间短、死亡率高 ,因此给予综合治疗十分重要 ,其中化学治疗占有一定位置 ;本文将对胰腺癌化疗方法、常用化疗药物、疗效及各家对胰腺癌使用化疗的评价 ,做一简要介绍     

胰腺癌药物治疗研究进展

吉西他滨是目前晚期胰腺癌化疗的一线药物,未发现其他化疗药物与吉西他滨联合治疗胰腺癌能显著延长患者生存期,因此针对胰腺癌生物学特性进行治疗是改善预后的关键。分子靶向药物成为目前研究的焦点,将VEGF和EGFR单克隆抗体,酪氨酸激酶抑制药,COX-2抑制药及其他免疫治疗方法用于临床,有着较良好的研究前景。     

Management of pancreatic cancer

Each year in the UK, pancreatic cancer is diagnosed in around 7,000 people. At least 80% of these present with locally advanced inoperable or metastatic disease and most patients with pancreatic cancer die within a year of diagnosis. Here, we review treatment options, dealing exclusively with adenocarcinoma (the commonest tumour type), focusing on whether they cure the disease, prolong survival, alleviate symptoms or improve quality of life.     

人胰腺癌变组织中血管内皮生长因子微血管密度CXCR-4的表达及其意义

目的探讨血管内皮生长因子(VEGF)、微血管密度(MVD)和趋化因子受体CXCR-4基因在胰腺恶性病变中的表达及意义。方法收集经手术切除且病理证实的胰腺癌患者65例,所有患者术前均未经放疗或化疗,记录各患者肿瘤部位、组织学类型、病理分期等临床资料,采用免疫组织化学法检测标本中VEGF、CXCR-4和MVD的表达。结果 VEGF、CXCR-4和MVD表达与患者的分化程度、组织学类型无关(P>0.05)。VEGF、CXCR-4和MVD表达与胰腺癌临床分期和淋巴结转移差异有统计学意义(P<0.05)。结论三者联合检测可能有助于胰腺癌的病理学分期诊断。     

Adjuvant therapy for pancreatic cancer

Ductal adenocarcinoma of the pancreas is one of the leading causes of cancer death in the UK, Europe and US, with incidence closely paralleling mortality. Until recently, enthusiasm for treating these patients was limited for a number of reasons: the majority of patients undergoing surgery would relapse early, adjuvant treatment was of unproven value and systemic therapy in advanced disease had only a small chance of a short-term benefit. More recently, however, it has become recognised that specialist surgery can improve results and there is evidence that adjuvant chemotherapy has a significant advantage in terms of 5-year survival. In particular adjuvant systemic 5-fluorouracil with folinic acid can result in 5-year survival of < or = 29% (compared with 11% for controls) and adjuvant gemcitabine can improve disease-free survival to 13.4 months from a median of 6.9 months in controls, but not overall survival. In contrast the role of adjuvant chemoradiation in addition to chemotherapy remains unproven and the survival results appear to be inferior to systemic chemotherapy alone. New agents, such as capecitabine and erlotinib, are emerging with some activity in this dismal disease signalling hope for the future.     

胰腺癌的超声诊断

目的:探讨胰腺癌的超声诊断价值及漏误诊原因.方法:结合手术病理结果,分析胰腺癌的声像图特点,总结其超声漏误诊的原因.结果:32例胰腺癌,位于胰头的占21例,其中超声诊断准确16例,漏误诊5例,超声正确率76.1%;胰体尾癌的11例,超声诊断正确7例,漏误诊4例,诊断准确率63.6%.结论:超声对胰腺癌有较高的诊断价值,但需结合其他影像学、实验室检查及临床特征 诊断.     

胰腺癌的手术治疗

在胰腺癌的治疗中 ,早期诊断、及时手术探查和正确作出切除决断都具有关键意义。对疑诊病例不要轻易放弃探查机会 ,术中根据综合判断诊断为胰腺癌 ,即使缺乏术中病理诊断 ,也不要轻易放弃切除机会。要争取使手术达到根治性的效果 ,包括合理的扩大淋巴结清扫。为了达到阴性切缘的目的 ,有血管侵犯的病例 ,一定要做连同血管的整块切除 ,这是提高远期疗效的有力手段。针对丧失治愈性切除手术机会的病人 ,要根据全身和局部条件 ,选择手术治疗或非手术治疗 ,以达到延长生命或改善生存质量的效果。     

胰腺癌的病因因素

胰腺癌的病因并未确定。其病因因素有多种 :吸烟是最强有力的因素 ,且与吸烟的量有关 ,为学者所公认 ;其次有慢性胰腺炎、糖尿病、过度肥胖、遗传 ,支气管哮喘和酒精中毒等。新鲜蔬菜饮食和(或 )体力活动有减少胰腺癌发生的作用。饮用咖啡尚无足够证据列为病因因素     

Adjuvant therapy for pancreatic cancer

Ductal adenocarcinoma of the pancreas is one of the leading causes of cancer death in the UK, Europe and US, with incidence closely paralleling mortality. Until recently, enthusiasm for treating these patients was limited for a number of reasons: the majority of patients undergoing surgery would relapse early, adjuvant treatment was of unproven value and systemic therapy in advanced disease had only a small chance of a short-term benefit. More recently, however, it has become recognised that specialist surgery can improve results and there is evidence that adjuvant chemotherapy has a significant advantage in terms of 5-year survival. In particular adjuvant systemic 5-fluorouracil with folinic acid can result in 5-year survival of ≤ 29% (compared with 11% for controls) and adjuvant gemcitabine can improve disease-free survival to 13.4 months from a median of 6.9 months in controls, but not overall survival. In contrast the role of adjuvant chemoradiation in addition to chemotherapy remains unproven and the survival results appear to be inferior to systemic chemotherapy alone. New agents, such as capecitabine and erlotinib, are emerging with some activity in this dismal disease signalling hope for the future.     

胰腺癌的临床表现

胰腺的临床表现因病变而异。腹痛、黄疸及体重减轻是胰腺癌的主要临床表现。部分病人同时可表现为发热、焦虑、抑郁、胆囊肿大及血栓性静脉炎等。     

Emerging drugs in pancreatic cancer

Improving survival in patients with pancreatic cancer remains a formidable challenge. For the few patients with localised stages of the disease, intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies remain non-validated and the survival benefit conferred by 5-fluorouracil-folinic acid adjuvant chemotherapy over radical surgery alone is still a matter of debate. Gemcitabine has recently emerged as the standard single agent in advanced stages of the disease and pharmacokinetic refinements such as the use of a fixed-dose infusion rate may further improve still rather modest result figures. At present, most efforts deal with the development of more effective doublet or triplet therapies, combining gemcitabine with either conventional cytotoxic drugs--the most promising being oxaliplatin--or more innovative, targeted therapeutic agents. Among these agents, matrix metalloprotease inhibitors and farnesyltransferase inhibitors have already undergone Phase III trials, alone or in combination with gemcitabine, with rather disappointing results. However, preclinical and Phase I and II studies of cyclooxygenase-2 or lipoxygenase inhibitors, various immunotherapeutic approaches and several tyrosine kinase inhibitors or monoclonal antibodies against growth factors or their receptors are encouraging and may provide some hope for patients with pancreatic cancer.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4–6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4-6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

Mucin-based targeted pancreatic cancer therapy

The prognosis of pancreatic cancer (PC) patients is very poor with a five-year survival of less than 5%. One of the major challenges in developing new therapies for PC is the lack of expression of specific markers by pancreatic tumor cells. Mucins are heavily Oglycosylated proteins characterized by the presence of short stretches of amino acid sequences repeated several times in tandem. The expression of several mucins including MUC1, MUC4, MUC5AC, and MUC16 is strongly upregulated in PC. Recent studies have also demonstrated a link between the aberrant expression and differential overexpression of mucin glycoproteins to the initiation, progression, and poor prognosis of the disease. These studies have led to increasing recognition of mucins as potential diagnostic markers and therapeutic targets in PC. In this focused review we present an overview of the therapies targeting mucins in PC, including immunotherapy (i.e. vaccines, antibodies, and radioimmunoconjugates), gene therapy, and other novel therapeutic strategies.     

Novel approaches to target pancreatic cancer

Despite remarkable progress that has been made in the recent years in the treatment of gastrointestinal tumors, in particular colorectal cancer, the prognosis of pancreatic cancer remains dismal. Five years after diagnosis almost all patients have died. At early stages of the disease surgery is the only modality to achieve long term survival. In the palliative setting gemcitabine confers some benefit to patients with advanced pancreatic cancer. A large number of chemotherapy combinations has been tested in patients with advanced pancreatic cancer. Only one combination showed significant improvement of survival, however also increased toxicity. The introduction of targeted therapies raised hopes for a better treatment of pancreatic cancer. However, most of the compounds tested so far failed to improve the survival of patients with pancreatic cancer. This review summarizes molecular targets examined so far in pancreatic cancer including matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, vascular endothelial growth factor and epidermal growth factor receptor inhibitors and points out novel promising strategies for this difficult-to-treat tumor.     

Conventional chemotherapy of advanced pancreatic cancer

The vast majority of patients with pancreatic cancer present with locally advanced unresectable or metastatic disease, and in this setting only a palliative treatment can be offered. Single-agent gemcitabine has been considered the standard chemotherapy for patients with advanced pancreatic cancer since the results of a pivotal phase III trial showing superior clinical benefit compared to bolus 5-fluorouracil were published in 1997. In recent years, many randomized trials have attempted to improve results obtained with gemcitabine exploring a different schedule (fixed dose rate) of its administration, or testing the addition of one or more drugs to gemcitabine. Unfortunately, none of these trials produced a statistically significant and clinically relevant improvement in overall survival compared to the standard. A randomized phase III trial has recently shown a survival advantage using a combination of more drugs (FOLFIRINOX: irinotecan, oxaliplatin, folinic acid and 5-fluorouracil) compared to single-agent gemcitabine, suggesting that regimens without gemcitabine can be successfully used in patients with advanced pancreatic cancer. FOLFIRINOX was associated with worse toxicity than gemcitabine, and the available data suggest that this regimen may be considered for patients with metastatic pancreatic cancer who are fit enough to withstand potential side effects. The best option for these patients remains the enrolment in prospective clinical trials. Improvements in the treatment of the advanced disease will possibly derive from new combinations or from new drugs, but certainly from a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis and in invasion and metastasis.