Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer

The estrogen receptor(ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, posttranslational modification of ER, deregulation of ER coactivators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin(m TOR), Mitogen activated kinase(MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modificationincluding dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific micro RNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the m TOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in Pub Med, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at Clinical Trials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.

Cyclooxygenase-2 and the inflammogenesis of breast cancer

Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2(COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following:(1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis;(2) essential features of mammary carcinogenesis(mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2(PGE-2) biosynthesis;(3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis;(4) extrahe-patic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and(5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive overexpression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer".

Stem cells in gastrointestinal cancers: The road less travelled

Cancer stem cells(CSC) are thought to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. Studies have described CSC in various gastrointestinal neoplasms such as colon, pancreas and liver and gastroesophageal tumors. The mechanism by which CSC develop remains unclear. Several studies have explored the role of dysregulation of the Wnt/β-catenin, transformation growth factor-beta and hedhog pathways in generation of CSC. In this review, we discuss the various molecular abnormalities that may be related to formation of CSC in gastrointestinal malignancies, strategies to identify CSC and therapeutic strategies that are based on these concepts. Identification and targeting CSC is an intriguing area and may provide a new therapeutic option for patients with cancer including gastrointestinal malignancies. Although great progress has been made, many issues need to be addressed. Precise targeting of CSC will require precise isolation and characterization of those cells. This field is also evolving but further research is needed to identify markers that are specific for CSC.Although the application of this field has not entered the clinic yet, there continues to be significant optimism about its potential utility in overcoming cancer resistance and curing patients with cancer.

Yttrium-90 microsphere selective internal radiation therapy for liver metastases following systemic chemotherapy and surgical resection for metastatic adrenocortical carcinoma

Adrenocortical carcinoma(ACC)is a rare malignancy with generally poor outcomes and limited treatment options.While surgical resection can be curative for early local disease,most patients present with advanced ACC owing to nonspecific symptoms.For those patients,treatment options include systemic chemotherapy and locoregional therapies including radiofrequency ablation and transarterial chemoembolization.We present the first reported case of utilizing yttrium-90 microsphere selective internal radiation therapy(SIRT)in combination with first line EDP-M(Etoposide,Doxorubicin,Cisplatin,Mitotane)chemotherapy and debulking surgical primary tumor resection for treatment of metastatic ACC.Stable complete radiologic response has been maintained after twelve months with resolution of clinical symptoms.These findings prompt the need for further consideration and studies to elucidate the role of SIRT in combination with systemic and surgical treatment for metastatic ACC.

A Single Institutional Experience with Panitumumab in Metastatic Colorectal Cancer

Introduction: Panitumumab is an EGFR inhibitor approved for use in metastatic refractory colorectal cancer. It is unclear whether patients who have progressed on cetuximab may benefit from subsequent panitumumab therapy. This retrospective analysis was conducted to describe the experience at The Ohio State University with panitumumab including in patients who have progressed on cetuximab. Methods: Patients who received at least 1 dose of panitumumab between September 2006 and December 2011 were identified using the hospital’s pharmacy database. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 was used to assess responses and Kaplan-Meier curves were used to estimate progression-free survival (PFS) and overall survival (OS). Results: Eighty-seven patients (median age 61 years) were identified. Sixty-seven percent of patients had tumors with wild-type KRAS, 3.4% had tumors with mutated KRAS and the KRAS status was unknown in 29.9%. Twenty-four percent of the patients had an ECOG performance status of 2 or above and 59.8% of patients had received ≥ 2 prior lines of chemotherapy. Thirty-two percent of patients received single-agent panitumumab while 68% received it in combination with chemotherapy. Of the patients with KRAS wild-type tumors, 10 (17.2%) had objective responses (3 complete, 7 partial) and 26 (44.8%) had stable disease. Median PFS and OS were 5.0 and 9.0 months. The presence of a rash, improved ECOG performance status and coadministration with either irinotecan or FOLFIRI, led to a significantly better OS in univariate analysis. Among patients who had clinical benefit with cetuximab, 71% had subsequent clinical benefit with panitumumab therapy. Conclusions: In our single institution analysis of patients who received panitumumab, the number of prior lines of therapy did not significantly affect OS, suggesting that panitumumab retains its efficacy in the 2nd and 3rd line setting. Additionally, panitumumab can benefit patients who previously had clinical benefit with cetuximab.

老年癌症患者的免疫治疗

癌症常见于老年人。初诊为恶性肿瘤的患者的中位年龄为66岁,癌症相关死亡的中位年龄为72岁[1]。老年人是癌症患病率增长最快的人群之一[2]。免疫治疗的发展,尤其是免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的问世,彻底改变了所有年龄层包括老年人在内的肿瘤患者的常规治疗方案。细胞毒性T淋巴细胞相关抗原4、程序性死亡受体1(programmed death receptor-1,PD-1)及其配体(programmed death-ligand 1,PD-L1)的抑制剂可改善多种肿瘤患者的总生存期(overall survival,OS)[3],且部分患者可获得持续缓解[4]。

脂质代谢重编程及其在癌症中潜在靶点的研究

脂质代谢的重编程是恶性肿瘤的一个新特征。在多种癌症中,脂肪摄取、储存和脂肪生成均被上调,这也促进了肿瘤的快速生长。脂质是构成膜的基本结构,并且具有信号分子和能量来源的功能。固醇调节元件结合蛋白(Sterol regulatory element-binding proteins,SREBPs)是内质网中一类膜结合转录因子,在调节脂质代谢中起着核心作用。最近的研究表明,SREBPs在各种癌症中高度上调并促进肿瘤生长。SREBP切割激活蛋白(SREBP cleavage-activating protein,SCAP)是SREBPs转运和激活的关键转运蛋白,也是一种关键的葡萄糖传感器,因此它将葡萄糖代谢与脂类从头合成联系在一起。靶向变异的脂质代谢途径已成为一种很有前景的抗癌策略。本综述总结了近年来我们所知的对恶性肿瘤中脂质代谢调节的最新研究进展,并着重介绍了癌症治疗中潜在的分子靶点及其抑制剂。

A 10-miRNA risk score-based prediction model for pathological complete response to neoadjuvant chemotherapy in hormone receptor-positive breast cancer

Patients with hormone receptor(HR)-positive tumors breast cancer usually experience a relatively low pathological complete response(p CR)to neoadjuvant chemotherapy(NAC).Here,we derived a 10-micro RNA risk score(10-mi RNA RS)-based model with better performance in the prediction of p CR and validated its relation with the disease-free survival(DFS)in 755 HRpositive breast cancer patients(273,265,and 217 in the training,internal,and external validation sets,respectively).This model,presented as a nomogram,included four parameters:the 10-mi RNA RS found in our previous study,progesterone receptor(PR),human epidermal growth factor receptor 2(HER2)status,and volume transfer constant(K).Favorable calibration and discrimination of 10-mi RNA RS-based model with areas under the curve(AUC)of 0.865,0.811,and 0.804 were shown in the training,internal,and external validation sets,respectively.Patients who have higher nomogram score(>92.2)with NAC treatment would have longer DFS(hazard ratio=0.57;95%CI:0.39–0.83;P=0.004).In summary,our data showed the 10-mi RNA RS-based model could precisely identify more patients who can attain p CR to NAC,which may help clinicians formulate the personalized initial treatment strategy and consequently achieves better clinical prognosis for patients with HRpositive breast cancer.

The potential role of DEK over-expression in the radiation response of head and neck cancer

Objective:To determine if DEK over-expression is associated with radiation resistance in HPV positive head and neck cancer cells.Methods:Control and DEK over-expressing keratinocytes and an HPV positive head and neck cancer cell line respectively were irradiated with 2–10 Gy and the impact on cell survival,γ-H2AX(a marker of DNA damage)and RAD51(homologous recombination)were analyzed via clonogenic assays,and immunofluorescence measurements respectively.Results:Upon exposure to increasing doses of radiation,DEK over-expression in keratinocytes at 2,4(P<0.05,P<0.05),and 10 Gy(P<0.01)and an HPV positive head and neck cancer cell line at 2,4,8,and 10 Gy(P<0.01)led to improved clonogenic cell survival.In parallel,irradiation decreased the percent ofγ-H2AX foci at 6,24,and 48 h post-irradiation(P<0.05,P<0.05,and P<0.01 respectively)in NIKS,and at 0,6,24,48 h post-irradiation(P<0.05,P<0.05,P<0.01,P<0.01)in C-SCC1 cells but enhanced the percent of RAD51 foci in both DEK over-expressing cell lines relative to their respective control cells at all times points(P<0.01).Conclusion:These results suggest DEK over-expression contributes to radio-resistance in HPV positive head and neck cancer cells,potentially by improving repair of DNA double strand breaks through homologous recombination.The molecular mechanisms and relevance to in vivo responses needs further investigation.

Pancreatic cancer: genetics, disease progression, therapeutic resistance and treatment strategies

Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States.It has a very low five-year survival rate(<5%)in the United States as well as in the world(about 9%).The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit.Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms.The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape.All these factors render the current treatment incompetent and prompt an urgent need for new,improved therapy.In this review,we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance.We have also evaluated new treatment strategies for pancreatic cancer,like targeted therapy and immunotherapy.

Lipid metabolism reprogramming and its potential targets in cancer

Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy.Increased lipid uptake,storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth.Lipids constitute the basic struc-ture of membranes and also function as signaling molecules and energy sources.Sterol regulatory element-binding proteins(SREBPs),a family of membrane-bound transcription factors in the endoplasmic reticulum,play a central role in the regulation of lipid metabolism.Recent studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor growth.SREBP cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor,thus linking glucose metabolism and de novo lipid synthesis.Targeting altered lipid metabolic pathways has become a promising anti-cancer strategy.This review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy,and highlights potential molecu-lar targets and their inhibitors for cancer treatment.

Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma

Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.

Leukemia:研究鉴定出与34种AML白血病亚群相关联的基因突变

针对成年急性髓细胞白血病（acute myeloid leukemia，AML）患者的一项新的大型研究将80种癌症相关基因突变与5种AML亚型相关联。这5种AML亚型可通过特异性的染色体异常加以确定。在未来，这些发现可能有助指导基因突变测试和治疗决策。

Higher-order assemblies in immune signaling:supramolecular complexes and phase separation

Signaling pathways in innate and adaptive immunity play vital roles in pathogen recognition and the functions of immune cells.Higher-order assemblies have recently emerged as a central principle that governs immune signaling and,by extension,cellular communication in general.There are mainly two types of higher-order assemblies:1)ordered,solid-like large supramolecular complexes formed by stable and rigid protein-protein interactions,and 2)liquid-like phase-separated condensates formed by weaker and more dynamic intermolecular interactions.This review covers key examples of both types of higher-order assemblies in major immune pathways.By placing emphasis on the molecular structures of the examples provided,we discuss how their structural organization enables elegant mechanisms of signaling regulation.

Review of cost and surgical time implications using virtual patient specific planning and patient specific implants in midface reconstruction

Aim:Summarize the available data on midfacial virtual patient specific planning and patient specific implants,highlighting the financial costs and savings,and additionally emphasize the potential cost implications of transitioning to“in-house”virtual 3D modeling and printing.Methods:Review of current literature.Results:Current literature suggests cost benefits of virtual patient specific planning and patient specific implants in the form of improved ischemia time,better boney apposition between flaps,and reduced patient complications.This reduction of complications includes a reduction in blood loss and time spent in the intensive care unit from flap failure.Improved boney apposition results in a higher likelihood of boney union and a further reduction in failure and complications.Subjective benefits of virtual patient specific planning and patient specific implants are shown in the form of improved reconstructive surgeon mental energy.In-house production of 3D models and presurgical planning provides additional cost benefits for providers as they can produce viable models at a fraction of the price of that which is produced by industrial companies.Providers can also construct and use models in an expedient manner compared to industrial models,allowing for the opportunity to be utilized in more acute settings.The foundation of developing an in-house workflow is adequate funding,resources,and clinical volume.Facilities also must focus on appropriate quality and safety measures,as well as appropriate workflow development for adequate production of models.Conclusion:Virtual patient specific planning and patient specific implants show benefits in midfacial reconstructive outcomes,resulting in realized financial and temporal gains for both patient and provider.These gains may be enhanced by moving to in-house planning and printing.