The role of BRCA 1 and BRCA2 in prostate cancer

One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 （BRCA2） are the genetic events known to date that confer the highest risk of prostate cancer （8.6-fold in men ≤ 65 years）. Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sooradic cases with similar characteristics.

Immuno-oncology combinations： raising the tail of the survival curve

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Identification of new genetic risk factors for prostate cancer

There is evidence that a substantial part of genetic predisposition to prostate cancer （PCa） may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes： MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Telomere Elongation in the Breast Cancer Cell Line 21NT after Treatment with an Epigenetic Modifying Drug

Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere lengths by causing a significant and stable increase in telomere lengths of the breast cancer cell line. The increase in telomere lengths was consistently observed when various telomere length methods were used. Conclusions: Further investigation is required to understand the underlying mechanism involved, and the significance of telomere length elongation in relation to clinical outcome when epigenetic modifying drugs are utilized.

Geriatric assessment for older people with cancer:policy recommendations

Most cancers occur in older people and the burden in this age group is increasing.Over the past two decades the evidence on how best to treat this population has increased rapidly.However,implementation of new best practices has been slow and needs involvement of policymakers.This perspective paper explains why older people with cancer have different needs than the wider population.An overview is given of the recommended approach for older people with cancer and its benefits on clinical outcomes and cost-effectiveness.In older patients,the geriatric assessment(GA)is the gold standard to measure level of fitness and to determine treatment tolerability.The GA,with multiple domains of physical health,functional status,psychological health and socio-environmental factors,prevents initiation of inappropriate oncologic treatment and recommends geriatric interventions to optimize the patient’s general health and thus resilience for receiving treatments.Multiple studies have proven its benefits such as reduced toxicity,better quality of life,better patient-centred communication and lower healthcare use.Although GA might require investment of time and resources,this is relatively small compared to the improved outcomes,possible cost-savings and compared to the large cost of oncologic treatments as a whole.

MRI定量肝灌注指数图:一种可能对抗肿瘤血管生成复合物BIBF1120(一种有效三联血管激酶抑制剂)治疗肿瘤效果可重复评估的方法

肝转移灶由肝动脉供血，造成肝灌注指数（HPI）增高。本研究的目的是用动态增强MRI定量分析肝转移灶在接受一种抗血管生成新药治疗前后的灌注指数。10例已知肝转移瘤的病人接受了动态增强MR成像检查。转移灶及全肝的HPI均由感兴趣区（ROI）获取，并以像素对像素的方式定量计算钆喷酸葡胺（Gd—DTPA）的浓度改变。治疗前HPI测量误差用Bland—Ahman法分析，在应用抗血管生成药物BIBF1120治疗前后中位HPI的比较应用Wilcoxon秩和检验。治疗前，

Targeting EZH2 for the treatment of soft tissue sarcomas

Soft tissue sarcomas(STS)are a heterogenous group of rare malignancies of mesenchymal origin,affecting both children and adults.The majority of STS have a poor prognosis and advanced stage at the time of diagnosis.Standard treatments for STS largely constitute tumour resection with chemotherapy and/or radiotherapy,and there has been little significant advancement in the application of novel therapies for treatment of these tumours.The current multimodal approach to therapy often leads to long-term side effects,and for some patients,resistance to cytotoxic agents is associated with local recurrence and/or metastasis.There is,therefore,a need for novel therapeutic strategies for the treatment of STS.Recent advances in epigenetics have implicated the histone methyltransferase,EZH2,in the development and progression of diseases such as breast cancer,lymphoma and more recently STS.Here we will review the current literature for EZH2 in STS,including high expression of EZH2 in STS and correlation of this with specific features of malignancy(metastasis,histological grade,and prognosis).The effects of targeting EZH2 using RNA interference and small molecule inhibitors will also be reviewed and the potential for the use of EZH2 inhibition in therapeutic strategies for STS patients will be discussed.

Sarcomas - the model for multidisciplinary care in cancer

Sarcomas were one of the first cancers for which multidisciplinary clinics and team meetings were set up,acknowledging the need for all the diagnostic and treatment disciplines to be involved in the clinical decision-making process.This is amply demonstrated by the papers chosen for this special issue of the Journal of Cancer Metastasis and Treatment,which includes articles on basic biology,translational research,pathology,surgery and survivorship.

Platinum drug sensitivity and resistance in testicular germ cell tumors:two sides of the same coin

Testicular germ cell tumors(TGCTs)represent the most common malignancies in young males but they also show the highest cure rate in solid tumors with more than 95%newly diagnosed TGCTs being ultimately cured[1].Singh et al.[2]recently provided precious insight into the genomic aberrations underpinning the molecular characteristics of these tumors and a clear presentation of the mechanisms underlying sensitivity/resistance to platinum.More importantly,the authors identified pre-target,on-target and post-target factors that can explain,the two sides of the same coin:the exquisite sensitivity of these cancers to platinum-based chemotherapy and at the same time,drug resistance when these factors are lacking.

Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes

Acute myeloid leukaemia(AML)patients harbouring certain chromosome abnormalities have particularly adverse prognosis.For these patients,targeted therapies have not yet made a significant clinical impact.To understand the molecular landscape of poor prognosis AML we profiled 74 patients from two different centres(in UK and Finland)at the proteomic,phosphoproteomic and drug response phenotypic levels.These data were complemented with transcriptomics analysis for 39 cases.Data integration highlighted a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia,which we term MLLGA and MLLGB.MLLGA presented increased DOT1L phosphorylation,HOXA gene expression,CDK1 activity and phosphorylation of proteins involved in RNA metabolism,replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples.MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and inosine-5-monosphosphate dehydrogenase(IMPDH)relative to other cases.Intermediate-risk KMT2A-MLLT3 cases were mainly represented in a third group closer to MLLGA than to MLLGB.The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia,suggesting a role of the nucleolar activity in sensitivity to treatment.In summary,our multilayer molecular profiling of AML with poor prognosis and KMT2A-MLLT3 karyotypes identified a phosphoproteomics signature that defines two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia.These data provide a rationale for the potential development of specific therapies for AML patients characterised by the MLLGA phosphoproteomics signature identified in this study.

Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer

Inframe insertions of three or more base pairs in exon 20 of the epidermal growth factor receptor(EGFR)gene were among the first EGFR mutations to be identified as oncogenic drivers in non-small cell lung cancer(NSCLC).However,unlike the classical EGFR L858R point mutation or exon 19 deletions,which represent the majority of EGFR mutations in NSCLC,low frequency EGFR exon 20 insertion mutations are associated with de novo resistance to targeted EGFR inhibitors and correlate with a poor patient prognosis.Here,we review the developments over the last 5 years in which pre-clinical studies,including elucidation of the crystal structure of an EGFR exon 20 insertion mutant kinase,have revealed a unique mechanism of kinase activation and steric conformation that define the lack of response of these EGFR mutations to clinically approved EGFR inhibitors.The recent development of several novel small molecule compounds that selectively inhibit EGFR exon 20 insertions holds promise for future therapeutic options that will be effective for patients with this molecular subtype of NSCLC.

Postoperative Regulatory T-Cells and Natural Killer Cells in Stage I Nonsmall Cell Lung Cancer Underwent Video-assisted Thoracoscopic Lobectomy or Thoracotomy

Background： Regulatory T-cells （Treg） play key roles in suppressing cell-mediated immunity in cancer patients. Little is known about perioperative Treg fluctuations in nonsmall cell lung cancer （NSCLC）. Video-assisted thoracoscopic （VATS） lobectomy, as a minimal invasive procedure for treating NSCLC, may have relatively less impact on the patient＇s immune system. This study aimed to observe perioperative dynamics of circulating Treg and natural killer （NK） cell levels in NSCLC patients who underwent major Iobectomy by VATS or thoracotomy. Methods： Totally, 98 consecutive patients with stage I NSCLC were recruited and assigned into VATS or thoracotomy groups. Peripheral blood samples were taken on 1-day prior to operation, postoperative days （PODs） I, 3, 7, 30, and 90. Circulating Treg and NK cell counts were assayed by flow cytometry, defined as CD4＋CD25＋CD127w cells in CD4＋ lymphocytes and CD56＋I6＋CD3 cells within CD45＋ leukocytes respectively. With SPSS software version 21.0 （SPSS Inc., USA）, differences between VATS and thoracotomy groups were determined by one-way analysis of variance （ANOVA）, and differences between preoperative baseline and PODs in each group were evaluated by one-way ANOVA Dunnett t-test. Results： In both groups, postoperative Treg percentages were lower than preoperative status. No statistical difference was found between VATS and thoracotomy groups on PODs 1, 3, 7, and 30. On POD 90, Treg percentage in VATS group was significantly lower than in thoracotomy group （5.26 ± 2.75 vs. 6.99 ±3.60, P = 0.012）. However, a higher level of NK was found on all PODs except on POD 90 in VATS group, comparing to thoracotomy group. Conclusions： Lower Treg level on POD 90 and higher NK levels on PODs 1, 3, 7, 30 in VATS group might imply better preserved cell-mediated immune function in NSCLC patients, than those in thoracotomy group.

Pazopanib in advanced soft tissue sarcomas

Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma(STS).Initially developed as a small molecule inhibitor of vascular endothelial growth factor receptors,preclinical work indicates that pazopanib exerts an anticancer effect through the inhibition of both angiogenic and oncogenic signaling pathways.Following the establishment of optimal dosing and safety profiles in early phase studies and approval for the treatment of advanced renal cell carcinoma,pazopanib was investigated in STS.A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes.The efficacy of pazopanib in specific STS subtypes has been further described in real-world-based case series in both mixed and subtype-specific STS cohorts.At present,there are no clinically validated predictive biomarkers for use in selecting patients with advanced STS for pazopanib therapy,limiting the clinical effectiveness and cost-effectiveness of the drug.In this review,we summarize the preclinical and clinical data for pazopanib,outline the evidence base for its effect in STS and explore reported studies that have investigated putative biomarkers.

TELS: A Novel Computational Framework for Identifying Motif Signatures of Transcribed Enhancers

In mammalian cells, transcribed enhancers(TrEns) play important roles in the initiation of gene expression and maintenance of gene expression levels in a spatiotemporal manner. One of the most challenging questions is how the genomic characteristics of enhancers relate to enhancer activities. To date, only a limited number of enhancer sequence characteristics have been investigated, leaving space for exploring the enhancers’ DNA code in a more systematic way. To address this problem, we developed a novel computational framework, Transcribed Enhancer Landscape Search(TELS), aimed at identifying predictive cell type/tissue-specific motif signatures of TrEns.As a case study, we used TELS to compile a comprehensive catalog of motif signatures for all known TrEns identified by the FANTOM5 consortium across 112 human primary cells and tissues.Our results confirm that combinations of different short motifs characterize in an optimized manner cell type/tissue-specific TrEns. Our study is the first to report combinations of motifs that maximize classification performance of TrEns exclusively transcribed in one cell type/tissue from TrEns exclusively transcribed in different cell types/tissues. Moreover, we also report 31 motif signatures predictive of enhancers’ broad activity. TELS codes and material are publicly available at http://www.cbrc.kaust.edu.sa/TELS.

Overcoming tumor antigen heterogeneity in CAR-T cell therapy for malignant mesothelioma(MM)

Malignant mesothelioma(MM)is a rare,aggressive solid tumor with limited therapeutic options and poor therapeutic response.The role of immunotherapy in MM is now well established and therapeutic options,such as checkpoint inhibitors,are increasingly being approved.Chimeric antigen receptor(CAR)-T cell therapy is successfully implemented in several hematologic cancers,but currently has inadequate effect in solid tumors,owing to several limitations,such as trafficking and infiltration,limited T cell persistence and exhaustion,the immunosuppressive TME and tumor antigen heterogeneity.The lack of uniform and universal expression of tumor-associated antigens(TAAs)on tumor cells,as well as TAA heterogeneity following tumor editing post-therapy,are issues of significant importance to CAR-T cell and associated antigen-targeting therapies.Our review discusses the concept of tumor antigen heterogeneity in MM,the consequences for CAR-T cell therapies and the strategies to overcome it.

Targeting MYCN and ALK in resistant and relapsing neuroblastoma

Neuroblastoma, a tumor of peripheral nerve, is the most common solid tumor of young children. In high-risk disease, which comprises approximately half of patients, death from chemotherapy-resistant, metastatic relapse is very frequent. Children who relapse exhibit clonal enrichment of two genomic alterations: high-level amplification of the MYCN oncogene, and kinase domain mutations of the anaplastic lymphoma kinase (ALK) gene. Overall survival in this patient cohort is less than 15% at 3 years, and there are few options for rationally targeted therapy. Neuroblastoma patients exhibit de novo resistance to many existing ALK inhibitors, and no clinical therapeutics to target MYCN have yet been developed. This review outlines the international efforts to uncover mechanisms of oncogenic action that are therapeutically targetable using small-molecule inhibitors. We describe a mechanistic interaction in which ALK upregulates MYCN transcription, and discuss clinical trials emerging to develop transcriptional inhibitors of MYCN, and to identify effective inhibitors of ALK in neuroblastoma patients.