胰腺癌免疫治疗的前沿与未来

胰腺癌仍然是最致命的恶性肿瘤之一，对传统疗法的抵抗使其生存率在过去几十年内几乎未有改善，而基于肿瘤免疫的胰腺癌治疗策略，如免疫检查点抑制剂、治疗性疫苗和联合免疫疗法正显示出新的治疗希望。尽管临床试验中探索的诸多免疫疗法尚未报道出显著的治疗效果，但毋庸置疑的是免疫治疗将是胰腺癌预后改善甚至治愈的重要希望。本文介绍了目前胰腺癌免疫疗法的相关进展及遇到的瓶颈，并提出了进一步的优化方向和解决方案，希望为胰腺癌免疫治疗发展提供参考。     

Treatments of pancreatic cancer from the standpoint of medical oncology

The early diagnosis of pancreatic cancer is difficult because of the lack of specific early symptoms,and surgery with curative intent can be performed in only 20% of patients. Chemotherapy for unresectable pancreatic cancer has been advancing ever since gemcitabine (GEM) was confirmed to provide a survival advantage in patients with advanced pancreatic cancer. For more than 20 years, the standard treatment for locally advanced diseases has been chemoradiotherapy using 5-FU, but more effective chemotherapy regimens are required. New standard treatments for locally advanced pancreatic cancer, including GEM chemotherapy and chemoradiotherapy using new agents, should be investigated. Several randomized clinical trials comparing GEM-based chemotherapy and GEM alone for the treatment of unresectable pancreatic cancer have been conducted, but a new standard chemotherapy regimen superior to GEM alone has not established. In Japan, phase II studies of S-1 or a combination of GEM and S-1 have produced promising survival rates, and a large phase III study using GEM and S-1 is necessary to establish the standard chemotherapy. Furthermore, second-line chemotherapy regimens for use after GEM chemotherapy should be investigated to improve the survival of patients with advanced pancreatic cancer.     

Biologic therapies for advanced pancreatic cancer

Patients with metastatic pancreatic cancer have poor prognosis and short survival due to lack of effective therapy and aggressiveness of the disease. Pancreatic cancer has widespread chromosomal instability, including a high rate of translocations and deletions. Upregulated EGF signaling and mutation of K-RAS are found in most pancreatic cancers. Therefore, inhibitors that target EGF receptor, K-RAS, RAF, MEK, mTOR, VEGF and PDGF, for example, have been evaluated in patients with pancreatic cancer. Although significant activities of these inhibitors have not been observed in the majority of pancreatic cancer patients, an enormous amount of experience and knowledge has been obtained from recent clinical trials. With a better inhibitor or combination of inhibitors, and improvement in the selection of patients for available inhibitors, better therapy for pancreatic cancer is on the horizon.     

Biologic therapies for advanced pancreatic cancer

Patients with metastatic pancreatic cancer have poor prognosis and short survival due to lack of effective therapy and aggressiveness of the disease. Pancreatic cancer has widespread chromosomal instability, including a high rate of translocations and deletions. Upregulated EGF signaling and mutation of K-RAS are found in most pancreatic cancers. Therefore, inhibitors that target EGF receptor, K-RAS, RAF, MEK, mTOR, VEGF and PDGF, for example, have been evaluated in patients with pancreatic cancer. Although significant activities of these inhibitors have not been observed in the majority of pancreatic cancer patients, an enormous amount of experience and knowledge has been obtained from recent clinical trials. With a better inhibitor or combination of inhibitors, and improvement in the selection of patients for available inhibitors, better therapy for pancreatic cancer is on the horizon.     

Novel advances in pancreatic cancer treatment

Little progress has been made on the treatment of advanced pancreatic cancer. Gemcitabine has been an acceptable standard for more than a decade. The benefit of single-agent gemcitabine in advanced and metastatic pancreatic cancer is small. Adding other chemotherapy agents to gemcitabine has not resulted in meaningful improvement in survival. The randomized trials studying the addition of molecular targeting agents (cetuximab, bevacizumab, farnesyl transferase inhibitors and metalloproteinase inhibitors) to gemcitabine compared with gemcitabine alone have been disappointing. A small gain in median survival by adding erlotinib to gemcitabine has recently been reported. We herein review novel agents in pancreatic cancer that may change the current nihilistic approach in the management of this challenging disease.     

胰腺癌:靶向治疗的前景

Pancreatic cancer is a devastating disease characterized by almost identical incidence and mortality rates. Since this tumour is mostly diagnosed in an advanced stage there is usually no option for a curative surgical resection. In addition, pancreatic cancers known to be resistant to conventional treatment modalities such as chemotherapy and radiotherapy. Therefore, novel strategies for targeting these tumors are urgently needed. The increasing knowledge on the underlying pathogenetic mechanisms has led to the identification of surface receptor molecules that initiate intracellular signalling cascades upon ligand binding, thus leading to tumor progression. Targeting these receptors or their secreted ligands is therefore an attractive new approach for cancer therapy. The epidermal growth factor receptor （EGFR） and the vascular endothelial growth factor receptor （VEGFR） are transmembrane tyrosine kinase receptors which can be targeted by various compounds such as antibodies or small molecule inhibitors. In addition, various molecules targeting proteins secreted by pancreatic cancers such as matrix metalloproteinases （MMP＇s） or intracellular oncogenic signalling components such as the farnesyltransferase have been proposed as potential new approaches for targeted cancer therapy. The use of these agents alone or in combination with conventional therapeutic regimens is currently being evaluated and shows first promising results for pancreatic cancer therapy.     

免疫检查点抑制剂治疗结直肠癌的疗效及肠道菌群对其疗效影响的研究进展

随着免疫治疗领域的快速发展,越来越多的免疫检查点抑制剂被应用于临床。免疫治疗为结直肠癌晚期转移患者提供了一种新的治疗选择。研究证实,错配修复缺陷/高度微卫星不稳定（dMMR/MSI-H）状态的晚期转移性结直肠癌患者对免疫治疗更敏感,有较为客观及持续的临床反应。在肿瘤免疫治疗的应答中,肠道菌群被证实有一定的调节作用,部分细菌可通过免疫系统或机体代谢功能来影响免疫检查点抑制剂的疗效。随着研究的进展,肠道菌群不仅有望成为结直肠癌免疫治疗的疗效预测性生物标志物,也可能成为影响结直肠癌免疫治疗结果的关键调控因素,在今后的临床治疗中,为更多的晚期结直肠癌患者使用免疫检查点抑制剂获益带来可能性。     

Angiogenesehemmung in der Onkologie

Targeted therapies against cancer have become more and more important. In particular, the inhibition of tumor angiogenesis has been the focus of new treatment strategies. Numerous new substances have been developed as angiogenesis inhibitors and evaluated in clinical trials for safety, tolerance and efficacy. With positive study results, some of these molecules have already been approved for clinical use. This is true for the VEGF neutralising antibody bevacizumab in metastatic colorectal cancer, as well as the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cancer, and, in the case of sunitinib, also for gastrointestinal stroma tumors. Specific toxicity profile and the high cost for these new therapeutics require a careful selection of patients, including consideration of possible benefits and risks on a individual basis.     

Targeting protein kinase C subtypes in pancreatic cancer

In preclinical studies, protein kinase C (PKC) enzymes have been implicated in regulating many aspects of pancreatic cancer development and progression. However, clinical Phase I or Phase II trials with compounds targeting classical PKC isoforms were not successful. Recent studies implicate that mainly atypical and novel PKC enzymes regulate oncogenic signaling pathways in pancreatic cancer. Members of these two subgroups converge signaling induced by mutant Kras, growth factors and inflammatory cytokines. Different approaches for the development of inhibitors for atypical PKC and novel PKC have been described; and new compounds include allosteric inhibitors and inhibitors that block ATP binding.     

A case of advanced pancreatic cancer with remarkable response to thalidomide, celecoxib and gemcitabine

Advanced human pancreatic cancer is considered a chemoresistant disease. To date, no treatments have had a significant efficacy on the disease. Patients with pancreatic cancer, however, experienced an improvement in the related symptoms with gemcitabine. Thalidomide has been shown to have antiangiogenic and immunomodulatory effects, including the inhibition of vascular endothelial growth factor, basic fibroblast growth factor and tumor necrosis factor alpha. The reported biological consequences of COX-2 up-regulation include inhibition of apoptosis, increased metastatic potential and promotion of angiogenesis. These events may contribute to cell transformation and tumor progression. Antiangiogenesis represents a significant new strategy for cancer treatment; however, most tumors are biologically heterogeneous, especially in endothelial cell diversity. As vessels of most solid tumors are structurally and functionally abnormal, tumor vessels differ from normal blood vessels in their responses to antiangiogenic agents. Therefore, it is important to accept a wide range of different inhibitors, such as thalidomide and selective COX-2 inhibitors, with conventional cytotoxic agents. Here we show a case of advanced pancreatic cancer with remarkable improvement in tumor shrinkage, CA19-9, and a cessation of dirty exudate from umbilicus.     

New Horizons in the Treatment of Metastatic Pancreatic Cancer: A Review of the Key Biology Features and the Most Recent Advances to Treat Metastatic Pancreatic Cancer

Only a limited number of therapeutic strategies are available for patients diagnosed with pancreatic adenocarcinoma, and disease recurrence and mortality are consequently high. For metastatic disease, two combinations are approved in the first line setting: a triplet with 5-fluoruracil, irinotecan, and oxaliplatin, and the combination of gemcitabine and nab-paclitaxel. In patients who have progressed on gemcitabine, a new nanoliposomal formulation of irinotecan has recently been approved. While these treatments have demonstrated some efficacy, there has been little increase in survival rates for metastatic pancreatic cancer patients. Consequently, there is an urgent need for research and development of new treatments. As there is now a deeper understanding of pancreatic cancer biology, new drugs targeting altered pathways are under research, including agents that target TGF-β, IGF, or NOTCH. Furthermore, taking into account the role of the tumor stroma in this disease, some stroma-targeting drugs are being developed, including PEGPH20, a pegylated recombinant human hyaluronidase. In the immunotherapy field, although checkpoint inhibitors have failed to demonstrate benefit as monotherapies, combinations with other drugs are being investigated, with promising preliminary results. Other strategies under research are targeting tumor metabolism or DNA repair deficiency.     

Raltitrexed (Tomudex) in combination treatment for colorectal cancer: new perspectives

In recent years, significant advances have been achieved in the treatment of colorectal cancer, including the use of adjuvant chemotherapy following surgery in patients with colon cancer and the use of palliative chemotherapy for metastatic disease. Further potential for improvements in outcome for patients with colorectal cancer is provided by the introduction of new agents in combined treatment modalities. Although some of these new agents, such as raltitrexed, oxaliplatin and irinotecan, are active in colorectal cancer, single-agent therapy as first-line treatment has failed to demonstrate a substantial increase in survival. However, preclinical studies have indicated that combination treatments have the potential benefit of enhanced response rates. One such agent, raltitrexed, is currently under investigation in combination with 5-FU (bolus and infusional), oxaliplatin, cisplatin, irinotecan and anthracyclines, principally in patients with advanced colorectal cancer, but also in patients with other tumours. Similarly, combinations of adjuvant or neo-adjuvant radiotherapy and chemotherapy are being investigated and can offer a benefit in the treatment of rectal, oesophageal, pancreatic and gastric cancer. Promise for the future, therefore, appears to lie in combined treatment modalities which are expected to provide superior alternatives to current standard treatments.     

The use of radiofrequency ablation in pancreatic cancer in the midst of the dawn of immuno-oncology

Despite significant improvement in treatment, the prognosis of pancreatic ductal adenocarcinoma remains poor as the biology of the tumour affects survival even when a radical resection has been performed. Pancreatic cancer remains resistant to currently available chemotherapeutic options. Recently, immunotherapy has achieved significant results in certain types of cancer. However, for pancreatic cancer, results were not initially encouraging as pancreatic cancer microenvironment is highly immunosuppressive. Radiofrequency ablation is currently used as treatment option especially for liver cancer with significant results. However, in pancreatic cancer, the use of radiofrequency ablation is relatively new. Radiofrequency ablation has been identified as a promising mechanism to induce antigen-presenting cell infiltration and enhance systemic antitumour T-cell immune response and tumour regression. In this short communication, we briefly review the role of radiofrequency ablation in pancreatic cancer and explore the idea that the combination of radiofrequency ablation with immunotherapy could represent a novel and promising treatment.     

Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells

The proteasome inhibitor bortezomib (formerly known as PS-341) recently received Food and Drug Administration approval for the treatment of multiple myeloma, and its activity is currently being evaluated in solid tumors. Bortezomib triggers apoptosis in pancreatic cancer cells, but the mechanisms involved have not been fully elucidated. Here, we show that pancreatic cancer cells exposed to bortezomib formed aggregates of ubiquitin-conjugated proteins ("aggresomes") in vitro and in vivo. Bortezomib-induced aggresome formation was determined to be cytoprotective and could be disrupted using histone deacetylase (HDAC) 6 small interfering RNA or chemical HDAC inhibitors, which resulted in endoplasmic reticulum stress and synergistic levels of apoptosis in vitro and in an orthotopic pancreatic cancer xenograft model in vivo. Interestingly, bortezomib did not induce aggresome formation in immortalized normal human pancreatic epithelial cells in vitro or in murine pancreatic epithelial cells in vivo. In addition, these cells did not undergo apoptosis following treatment with bortezomib, suberoylanilide hydroxamic acid, or the combination, showing tumor selectivity. Taken together, our study shows that inhibition of aggresome formation can strongly potentiate the efficacy of bortezomib and provides the foundation for clinical trials of bortezomib in combination with HDAC inhibitors for the treatment of pancreatic cancer.     

mTOR inhibitors in urinary bladder cancer

Despite the great scientific advances that have been made in cancer treatment, there is still much to do, particularly with regard to urinary bladder cancer. Some of the drugs used in urinary bladder cancer treatment have been in use for more than 30 years and show reduced effectiveness and high recurrence rates. There have been several attempts to find new and more effective drugs, to be used alone or in combination with the drugs already in use, in order to overcome this situation.The biologically important mammalian target of rapamycin (mTOR) pathway is altered in cancer and mTOR inhibitors have raised many expectations as potentially important anticancer drugs. In this article, the authors will review the mTOR pathway and present their experiences of the use of some mTOR inhibitors, sirolimus, everolimus and temsirolimus, in isolation and in conjunction with non-mTOR inhibitors cisplatin and gemcitabine, on urinary bladder tumour cell lines. The non-muscle-invasive cell line, 5637, is the only one that exhibits a small alteration in the mTOR and AKT phosphorylation after rapalogs exposure. Also, there was a small inhibition of cell proliferation. With gemcitabine plus everolimus or temsirolimus, the results were encouraging as a more effective response was noticed with both combinations, especially in the 5637 and T24 cell lines. Cisplatin associated with everolimus or temsirolimus also gave promising results, as an antiproliferative effect was observed when the drugs were associated, in particular on the 5637 and HT1376 cell lines. Everolimus or temsirolimus in conjunction with gemcitabine or cisplatin could have an important role to play in urinary bladder cancer treatment, depending on the tumour grading.     

Tyrosine kinase inhibitors in pediatric malignancies

Tyrosine kinase inhibitors have been used to treat adult cancers for over a decade. Since the discovery of imatinib mesylate (STI-571, Gleevec; Novartis), tyrosine kinase inhibitors have ushered in a new age of targeted therapy. Although the United States Food and Drug Administration has approved several kinase inhibitors for use in adult cancers, currently only imatinib mesylate is approved for use in children with cancer. This review highlights the mechanisms of tyrosine kinase inhibition, the potential role of tyrosine kinase pathways in the treatment of pediatric cancers, and the current status of pediatric clinical investigation of a spectrum of tyrosine kinase inhibitors for the treatment of childhood cancer.     

Suppression of Human Pancreatic Cancer Growth in BALB/c Nude Mice by Manumycin, a Farnesyl:protein Transferase Inhibitor

Activating mutations of Ki- ras have been detected in most human pancreatic adenocarcinomas. Since Ras protein requires farnesylation to function, we investigated the effects of manumycin, a potent farnesyl:protein transferase inhibitor, on the growth in nude mice of a human pancreatic cancer cell line, MIA PaCa-2, with a point mutation in the Ki- ras gene. Tumor-bearing mice received intraperitoneal injection of 1 or 5 mg/kg manumycin daily for 5 days, or 2 mg/kg manumycin daily for 2 weeks. Growth of inoculated tumors was significantly inhibited by the treatment. The treatment significantly (P<0.05) lowered the numbers of bromodeoxyuridine-incorporating tumor cells. Manumycin did not have apparent hepatotoxicity in vivo . Farnesyl:protein transferase inhibitors could offer a new approach for cancer chemotherapy.     

Lipoxygenase and cyclooxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer

The essential fatty acids, linoleic acid and arachidonic acid play an important role in pancreatic cancer development and progression. These fatty acids are metabolized to eicosanoids by cyclooxygenases and lipoxygenases. Abnormal expression and activities of both cyclooxygenases and lipoxygenases have been reported in pancreatic cancer. In this article, we aim to provide a brief summary of (1) our understanding of the roles of these enzymes in pancreatic cancer tumorigenesis and progression; and (2) the potential of using cyclooxygenase and lipoxygenase inhibitors for pancreatic cancer treatment and prevention.     

Inflammation and the development of pancreatic cancer

OBJECTIVE: Pancreatic cancer has an extremely poor prognosis and the cellular mechanisms contributing to pancreatic cancer are relatively unknown. The goals of this review are to present the epidemiological and experimental data that supports inflammation as a key mediator of pancreatic cancer development, to explain how inflammatory pathways may create an environment that supports tumor formation, and to discuss how the use of novel agents directed at these pathways may be used for the treatment of pancreatic malignancy. SUMMARY BACKGROUND DATA: Inflammation has been identified as a significant factor in the development of other solid tumor malignancies. Both hereditary and sporadic forms of chronic pancreatitis are associated with an increased risk of developing pancreatic cancer. The combined increase in genomic damage and cellular proliferation, both of which are seen with inflammation, strongly favors malignant transformation of pancreatic cells. Cytokines, reactive oxygen species, and mediators of the inflammatory pathway (e.g., NF-kappaB and COX-2) have been shown to increase cell cycling, cause loss of tumor suppressor function, and stimulate oncogene expression; all of which may lead to pancreatic malignancy. Anti-cytokine vaccines, inhibitors of pro-inflammatory NF-kappaB and COX-2 pathways, thiazolidinediones, and anti-oxidants are potentially useful for the prevention or treatment of pancreatic cancer. Redirection of experimental interests toward pancreatic inflammation and mechanisms of carcinogenesis may identify other novel anti-inflammatory agents or other ways to screen for or prevent pancreatic cancer. CONCLUSION: Pancreatic inflammation, mediated by cytokines, reactive oxygen species, and upregulated pro-inflammatory pathways, may play a key role in the early development of pancreatic malignancy.     

HGF/c-MET信号通路抑制剂在抗胰腺癌中的研究进展

胰腺癌是恶性程度较高的肿瘤之一.靶向治疗日渐成为胰腺癌治疗的重要组成部分.研究证实肝细胞生长因子及其受体(HGF/c-MET)信号通路在胰腺癌发生、发展过程中起重要作用,通过抑制该条信号通路能够起到显著的抗胰腺癌作用.因此,HGF/c-MET靶向抑制剂的研究为胰腺癌的治疗开辟了一条新的途径.