Smarter drugs emerging in pancreatic cancer therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death in the Western world. Owing to a lack of specific symptoms and no accessible precursor lesions, primary diagnosis is commonly delayed, resulting in only 15%–20% of patients with potentially curable disease. The standard of care in advanced pancreatic cancer has improved. Apart from gemcitabine (plus erlotinib), FOLFIRINOX and the combination of gemcitabine plus nab-paclitaxel are novel and promising therapeutic options for patients with metastatic PDAC. A better molecular understanding of pancreatic cancer has led to the identification of a variety of potential molecular therapeutic targets. Many targeted therapies are currently under clinical evaluation in combination with standard therapies for PDAC. This review highlights the current status of targeted therapies and their potential benefit for the treatment of advanced PDAC.     

Immunotherapy as a treatment for biliary tract cancers: A review of approaches with an eye to the future

Biliary tract cancers (BTC) are aggressive malignancies associated with resistance to chemotherapy and poor prognostic rates. Therefore, novel treatment approaches are in need. Immunotherapy represents a promising breakthrough that uses a patient’s immune system to target a tumor. This treatment approach has shown immense progress with positive results for selected cancers such as melanoma and nonsmall cell lung cancer. Initial preclinical data and preliminary clinical studies suggest encouraging mechanistic effects for immunotherapy in BTC offering the hope for an expanding therapeutic role for this disease. These approaches include targeted tumor antigen therapy via peptide and dendritic cell-based vaccines, allogenic cell adoptive immunotherapy, and the use of inhibitory agents targeting the immune checkpoint receptor pathway and multiple components of the tumor microenvironment. At this time demonstrating efficacy in larger clinical trials remains imperative. A multitude of ongoing trials aim to successfully translate mechanistic effects into antitumor efficacy and ultimately aim to incorporate immunotherapy into the routine management of BTC. With further research efforts, the optimization of dosing and therapeutic regimens, the identification of novel tumor antigens and a better understanding of alternative checkpoint pathway receptor expression may provide additional targets for rational combinatorial therapies which enhance the effects of immunotherapy and may offer hope for further advancing treatment options. Ultimately, the challenge remains to prospectively identify the subsets of patients with BTC who may respond to immunotherapy, and devising alternative strategies to sensitize those that do not with the hopes of improving outcomes for all with this deadly disease.     

Role of neoadjuvant therapy for nonmetastatic pancreatic cancer: Current evidence and future perspectives

Pancreatic adenocarcinoma (PDAC) is one of the most common and lethal human cancers worldwide. Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC, although only approximately 20% of the patients have resectable tumors when diagnosed. Neoadjuvant chemotherapy (NACT) is recommended for borderline resectable pancreatic cancer. Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology, as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC. In such challenging cases, new potential tools, such as ct-DNA and molecular targeted therapy, are emerging as novel therapeutic options that may improve old paradigms. This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.     

Neoadjuvant and Intrapleural Therapies for Malignant Pleural Mesothelioma

Historically, malignant pleural mesothelioma patients with potentially resectable disease have been treated with surgery and radiation alone. With improvements in systemic and intrapleural treatment options, a movement toward multi-modality therapy has become more common. Systemic treatment options largely consist of neoadjuvant chemotherapy with platinum doublets and most recently novel targeted agents, such as dasatinib. Intrapleural strategies have included injecting chemotherapy, chemotherapy with hyper thermic per fusion, gene therapy, and immunotherapy. The following review discusses the latest results in neoadjuvant and intrapleural therapies in malignant pleural mesothelioma.     

晚期胰腺癌的分子治疗研究现状

胰腺癌是全球第七大致命的恶性肿瘤，分别是美国胃肠道恶性肿瘤和癌症相关死亡的第二大和第三大原因。与其他恶性肿瘤相比，晚期胰腺癌患者的生存率最低，中位总体生存率为2~8个月，5年生存率为8.5%。治疗十分困难，给临床医生带来极大挑战。目前晚期胰腺癌的治疗药物匮乏，化疗仍然是其主要治疗方法。虽然化疗能短暂的控制疾病的进展，但是在生存期的延长方面却差强人意。分子靶向治疗已在其他的瘤种中取得了里程碑般的成就，譬如肺癌、结直肠癌等，但晚期胰腺癌患者的分子靶向治疗效果并不显著。这需要我们去寻找新的治疗靶点和药物。本文基于胰腺癌信号传导通路及肿瘤微环境，总结和分析晚期胰腺癌分子治疗的研究现状，探索未来胰腺癌治疗的发展方向。     

Recurrent glioblastoma multiforme: advances in treatment and promising drug candidates

Recurrent glioblastoma multiforme is a lethal disease with currently available treatment options having a limited impact on outcome. In this article, current and novel therapeutic approaches in the treatment of recurrent glioblastoma multiforme, including chemotherapy, targeted molecular agents, virotherapy/gene therapy and immunotherapy and challenges in developing novel therapeutic agents for glioblastoma multiforme will be discussed.     

Recurrent glioblastoma multiforme: advances in treatment and promising drug candidates

Recurrent glioblastoma multiforme is a lethal disease with currently available treatment options having a limited impact on outcome. In this article, current and novel therapeutic approaches in the treatment of recurrent glioblastoma multiforme, including chemotherapy, targeted molecular agents, virotherapy/gene therapy and immunotherapy and challenges in developing novel therapeutic agents for glioblastoma multiforme will be discussed.     

多发性骨髓瘤的免疫治疗研究进展

多发性骨髓瘤是血液系统恶性肿瘤,该病的复发及难治一直是一项难题。越来越多的研究发现免疫失调是骨髓瘤细胞逃避免疫监视、导致疾病发生发展的关键因素,因此免疫治疗为多发性骨髓瘤的治疗带来了很大的前景。其中一些免疫疗法已在临床应用中取得较好的治疗效果,一些仍在试验研究中的疗法也显示出巨大的治疗潜力。本文结合相关文献对免疫治疗中的免疫调节剂、靶向B细胞成熟抗原疗法的研究进展进行综述。     

Neoadjuvant Treatment for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options and exceedingly high mortality rates. Currently, cure can only be achieved through resection, however the vast majority of patients present with advanced disease for which upfront surgery is not an option. In an effort to improve surgical candidacy, neoadjuvant chemotherapy, with or without radiation therapy, is often used in an effort to downstage borderline resectable and locally advanced tumors, and some argue for its use even in patients with resectable tumors. Underlying this thinking is the recognition that pancreatic cancer is simultaneously both a locally invasive and systemic disease, even in patients without evidence of metastasis on imaging. Current evidence to date is largely retrospective, but suggests that neoadjuvant therapy can increase R0 (pathologically negative margin) resection rates and improve overall survival. The standard approach to neoadjuvant treatment involves choosing between the two most active combination regimens for metastatic disease, namely modified FOLFIRNOX and gemcitabine/nab-paclitaxel. Nonrandomized data indicate that these regimens can yield resection rates up to 68% and 36%, in borderline resectable and locally advanced PDAC, respectively. Furthermore, randomized data in patients with resectable PDAC treated with gemcitabine-based neoadjuvant therapy suggests that despite an approximate 10% drop in resection rates, there is a significant improvement in median overall survival. Herein, we will discuss the rationale for neoadjuvant therapy, current and former treatment regimens, common issues faced by clinicians when using these combinations, and several ongoing clinical trials.     

New developments in therapy for metastatic colorectal cancer

Considerable advances have recently been achieved in the medical treatment of metastatic colorectal cancer with the introduction of novel cytotoxic chemotherapies such as irinotecan, oxaliplatin, and capecitabine, and the integration of targeted therapies including bevacizumab and cetuximab. Multiple therapeutic options are now available in the first-and second-line settings. This review focuses on new significant developments in systemic therapy for patients with metastatic colorectal cancer.     

Systemische Therapie von Hirnmetastasen

Background

Local therapy of brain metastases is frequently effective but not applicable in multiple cerebral metastases and not able to target systemic metastases or the primary tumor. Systemic therapies are advantageous in this respect as they simultaneously treat the systemic disease which is frequently decisive for the prognosis.

Objective

The current role of systemic therapy in the management of brain metastases is presented.

Material and methods

Representative publications, particularly those more recent, on the systemic therapy of brain metastases of solid tumors were assessed and the results critically analyzed.

Results

In general, a substantial improvement in the overall prognosis of patients with brain metastases by treatment with systemic therapy has not yet been achieved; however, in certain entities, as in brain metastases of small-cell lung cancer and germ cell tumors, systemic chemotherapy should be used as first line treatment whenever possible and can be amended during the course of the disease by whole-brain radiotherapy (WBRT) and/or resection. With this treatment long-term survival can be achieved in many patients with germ cell tumors. In other solid tumors systemic chemotherapy should be considered for patients in a good general physical condition with clinically asymptomatic multiple brain metastases, particularly with active systemic disease and when pretreatment with WBRT has already been carried out. For some tumors the spectrum of therapeutic options has been extended by targeted therapy and immunotherapy.

Conclusion

Systemic therapy should often be regarded as a meaningful therapeutic supplement to neurosurgical and radiation therapeutic measures for therapy of brain metastases as a part of a multimodal treatment approach.     

Biomarker-driven and molecularly targeted therapies for pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan with PEGPH20 in patients with high expressing (hyaluronan-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease.     

鼻咽癌靶向治疗及免疫治疗的研究进展

鼻咽癌治疗方式主要包括放疗和化疗。近几年,尽管治疗方案有较多进展,但是局部复发或远处转移常常导致治疗失败。鼻咽癌与爱泼斯坦-巴尔病毒(EBV)感染、肿瘤淋巴细胞浸润(TIL)和程序性死亡受体1(PD-1)或其配体(PD-L1)表达增加有关,这些都可能成为治疗靶点,因此靶向及免疫治疗可能是未来的发展方向。目前有多项临床研究正在进行,验证了靶向及免疫治疗在鼻咽癌治疗中具有潜力,特别是在治疗复发或转移性鼻咽癌方面取得了突破进展。全文就靶向及免疫治疗在鼻咽癌中的研究进行综述。     

脑胶质瘤新型治疗方案研究进展

脑胶质瘤是最常见的原发性恶性脑肿瘤,具有较高的复发率和死亡率,单纯依赖手术切除难以根治,必须采用综合治疗方法。随着分子和免疫学研究的发展,以脑肿瘤电场治疗、靶向治疗和免疫治疗为代表的新型治疗方法逐渐增多,并且取得了一些新的进展,本综述旨在介绍近年来脑胶质瘤治疗领域的重要成果及对未来发展方向的展望。     

Metabolic reprogramming by driver mutation-tumor microenvironment interplay in pancreatic cancer: new therapeutic targets

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers globally with a mortality rate exceeding 95% and very limited therapeutic options. A hallmark of PDAC is its acidic tumor microenvironment, further characterized by excessive fibrosis and depletion of oxygen and nutrients due to poor vascularity. The combination of PDAC driver mutations and adaptation to this hostile environment drives extensive metabolic reprogramming of the cancer cells toward non-canonical metabolic pathways and increases reliance on scavenging mechanisms such as autophagy and macropinocytosis. In addition, the cancer cells benefit from metabolic crosstalk with nonmalignant cells within the tumor microenvironment, including pancreatic stellate cells, fibroblasts, and endothelial and immune cells. Increasing evidence shows that this metabolic rewiring is closely related to chemo- and radioresistance and immunosuppression, causing extensive treatment failure. Indeed, stratification of human PDAC tumors into subtypes based on their metabolic profiles was shown to predict disease outcome. Accordingly, an increasing number of clinical trials target pro-tumorigenic metabolic pathways, either as stand-alone treatment or in conjunction with chemotherapy. In this review, we highlight key findings and potential future directions of pancreatic cancer metabolism research, specifically focusing on novel therapeutic opportunities.

     

Promises and challenges of adoptive T-cell therapies for solid tumours

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.Subject terms: Immunotherapy, Cancer genomics, Cancer immunotherapy, Tumour immunology     

New therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is often diagnosed at an advanced stage when most potentially curative therapies such as resection, transplantation or percutaneous and transarterial interventions are of limited efficacy. The fact that HCC is resistant to conventional chemotherapy, and is rarely amenable to radiotherapy, leaves this disease with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools and strategies is much needed. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of chronic liver disease. However, in spite of this heterogeneity recent insights into the biology of HCC suggest that certain signaling pathways and molecular alterations are likely to play essential roles in HCC development by promoting cell growth and survival. The identification of such mechanisms may open new avenues for the prevention and treatment of HCC through the development of targeted therapies. In this review we will describe the new potential therapeutic targets and clinical developments that have emerged from progress in the knowledge of HCC biology, In addition, recent advances in gene therapy and combined cell and gene therapy, together with new radiotherapy techniques and immunotherapy in patients with HCC will be discussed.     

Systemic Therapy for Pancreatic Neuroendocrine Tumors

Patients with metastatic or advanced pancreatic neuroendocrine tumors (NETs) carry poorer prognoses relative to patients with other NETs due to bulkier and often, more proliferative baseline disease. Patients with these tumors also possess more approved treatment options relative to patients with other NETs, making therapeutic sequencing nuanced. As such, defining optimal therapeutic sequencing and developing more potent cytoreductive treatments for patients are significant areas of research need in the field. Herein this review, we discuss the current systemic therapy landscape, our approach to therapeutic sequencing in the clinic and ongoing studies seeking to define optimal sequencing of systemic therapies, and novel therapeutics in development, for patients with pancreatic NETs. We limit the scope of this latter topic to agents with preclinical or clinical rationale over the last 8 years to provide a contemporary view of the drug development landscape and focus primarily on new types of peptide receptor radionuclide therapy, anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors and anti-vascular endothelial growth receptor tyrosine kinase inhibitor plus immunotherapy combinations.     

免疫治疗研究进展及其在三阴性乳腺癌中的应用CSCD

针对侵袭性强的恶性肿瘤,目前在免疫治疗领域产生了很多潜在的新治疗策略。三阴性乳腺癌研究领域最重要的突破是明确其免疫表型和特征,设计出新的、有针对性的免疫调节靶点来进行治疗。研究最多的是免疫检查点抑制剂的应用,在晚期三阴性乳腺癌解救治疗和早期三阴性乳腺癌新辅助治疗中取得良好疗效。本研究对癌症免疫治疗研究进展及其在三阴性乳腺癌中的应用,尤其是免疫检查点抑制剂与化疗、放疗和靶向治疗联合使用的疗效等进行综述。