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Chemotherapy and its evolving role in the management of advanced prostate cancer

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Asian Journal of Andrology 2014年第3期16卷 334-340页

作者： Michael T Schweizer Emmanuel S Antonarakis Prostate cancer Research Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore Maryland USA

Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.

关键词： cabazitaxel chemotherapy cyclophosphamide docetaxel mitoxantrone prostate cancer taxanes

Prostate cancer epigenetics and its clinicalmplications

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Asian Journal of Andrology 2016年第4期18卷 549-558页

作者： Srinivasan Yegnasubramanian sidney kimmel comprehensive cancer center Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland USA

Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

关键词： biomarkers DNA methylation epigenetics epigenomics prostatic neoplasms tumor

Use of androgen deprivation therapy in prostate cancer： indications and prevalence

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Asian Journal of Andrology 2012年第2期14卷 177-186页

作者： Roisin M Connolly Michael A Carducci Emmanuel S Antonarakis Prostate cancer Research Program Department of Medical Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231-1000 USA

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer, This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.

关键词： androgen deprivation therapy androgen synthesis anti-androgen prostate cancer

Genetic and epigenetic dependencies in colorectal cancer development

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Gastroenterology Report 2022年第1期10卷 115-131页

作者： Sehej Parmar Hariharan Easwaran cancer Genetics and Epigenetics OncologySidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMDUSA

Recent studies have mapped key genetic changes in colorectal cancer(CRC)that impact important pathways contributing to the multistep models for CRC initiation and *** parallel with genetic changes,normal and cancer tissues harbor epigenetic alterations impacting regulation of critical genes that have been shown to play profound roles in the tumor ***,these molecular changes are only loosely associated with heterogenous transcriptional programs,reflecting the heterogeneity in the various CRC molecular subtypes and the paths to CRC *** from mapping molecular alterations in early CRC lesions and use of experimental models suggest that the intricate dependencies of various genetic and epigenetic hits shape the early development of CRC via different pathways and its manifestation into various CRC *** highlight the dependency of epigenetic and genetic changes in driving CRC development and discuss factors affecting epigenetic alterations over time and,by extension,risk for cancer.

关键词： colorectal cancer epigenetics aging classification subtyping DNA methylation consensus molecular subtypes

Abiraterone acetate for prostate cancer： a new era ot hormonal therapies

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Asian Journal of Andrology 2011年第5期13卷 663-664页

作者： Emmanuel S Antonarakis johns hopkins sidney kimmel comprehensive cancercenter Baltimore MD 21231 USA

Therapies targeting the androgen receptor （AR） axis have constituted the HolyGraft in the management of advanced prostate cancer for seven decades） These hormonal therapies have traditionally taken two main forms： those that suppress gonadal androgen synthesis （e.g., the gonadotropin releasing hormone agonists/antagonists, such as leuprolide）, and those that inhibit the AR directly （e.g., the anti-androgens, such as bicalutamide）. However, although the vast majority of patients with prostate cancer initiaUy respond favorably to androgen-ablative therapies （manifested by tumor regressions and symptomatic improvements）, all patients will eventually develop further disease progression after a median of 18-24 months. This transformed disease state, known as castration-resistant prostate cancer （CRPC）, is invariably fatal.

关键词： Abiraterone hormonal therapies

The role of nuclear receptors in regulation of Th 17/Treg biology and its implications for diseases

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Cellular & Molecular Immunology 2015年第5期12卷 533-542页

作者： Benjamin V. Park Fan Pan Immunology and Hematopoiesis Division Department of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School ofMedicine Baltimore MD 21287 USA

Nuclear receptors in the cell play essential roles in environmental sensing, differentiation, development, homeostasis, and metabolism and are thus highly conserved across multiple species. The anti-inflammatory role of nuclear receptors in immune cells has recently gained recognition. Nuclear receptors play critical roles in both myeloid and lymphoid cells, particularly in helper CD4＋ T-cell type 17 （Th17） and regulatory T cells （Treg）. Th17 and Treg are closely related cell fates that are determined by orchestrated cytokine signaling. Recent studies have emphasized the interactions between nuclear receptors and the known cytokine signals and how such interaction affects Th 17/Treg development and function. This review will focus on the most recent discoveries concerning the roles of nuclear receptors in the context of therapeutic applications in autoimmune diseases.

关键词： nuclear receptors regulation

Functional implications of mitochondrial reactive oxygen species generated by oncogenic viruses

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Frontiers in Biology 2014年第6期9卷 423-436页

作者： Young Bong CHOI Edward William HARHAJ Department of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine Baltimore MD 21287 USA

Between 15% and 20% of human cancers are associated with infection by oncogenic viruses. Oncogenic viruses, including HPV, HBV, HCV and HTLV-1, target mitochondria to influence cell proliferation and survival. Oncogenic viral gene products also trigger the production of reactive oxygen species which can elicit oxidative DNA damage and potentiate oncogenic host signaling pathways. Viral oncogenes may also subvert mitochondria quality control mechanisms such as mitophagy and metabolic adaptation pathways to promote virus replication. Here, we will review recent progress on viral regulation of mitophagy and metabolic adaptation and their roles in viral oncogenesis.

关键词： mitochondria mitophagy virus ROS oncogenes

Albumin-linked prostate-specific antigen-activated thapsigargin- and niclosamide-based molecular grenades targeting the microenvironment in metastatic castration-resistant prostate cancer

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Asian Journal of Urology 2019年第1期6卷 99-108页

作者： Emmanuel S.Akinboye W.Nathaniel Brennen Samuel R.Denmeade John T.Isaacs Department of Oncology Prostate Cancer ProgramThe Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsThe Johns Hopkins University School of MedicineBaltimoreMDUSA

Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local ***,once metastatic,no available therapy is *** vast majority will die despite aggressive systemic combinational androgenablation ***,there is an urgent need for effective systemic therapeutics that sterilize the entire microenvironment in metastatic castration-resistant prostate cancer(mCRPC).To accomplish this goal,advantage can be taken of the unique biology of mCRPC *** their normal cell of origin,mCRPCs retain expression of the prostate-specific differentiation protein,prostate-specific antigen(PSA),which they abundantly secrete into their extracellular fluid(ECF).This unique,and essentially universal,secretion of enzymatically active PSA into the ECF by mCRPCs creates an exploitable therapeutic index for activation of systemically delivered highly lipophilic toxins as“molecular grenades”covalently linked to cysteine-34 of human serum albumin(HSA)via a stable maleimide containing PSA cleavable peptide such that PSA-dependent hydrolysis(i.e.,“detonation”)releases the grenades restrictively within the ECF of *** approach decreases dose-limiting host toxicity while enhancing plasma half-life from minutes to days(i.e.,pharmacokinetic effect)and increasing the tissue concentration of the maleimide coupled albumin delivery(MAD)in the ECF at sites of cancer due to the enhanced permeability of albumin at these sites(i.e.,enhanced permeability and retention effect).This allows the MAD-PSA detonated grenades to circulate throughout the body in a non-toxic *** within sites of mCRPC is there a sufficiently high level of enzymatically active PSA to efficiently“pull the pin”on the grenades releasing their lipophilic cellpenetrant toxins from ***,if a sufficient level of“detonation”occurs,this will kill mCRPC cells,and sterilize the entire PSA-rich metastatic sites via a bystander *** this review,two

关键词： Albumin-linked prodrug Maleimide coupled albumin delivery Thapsigargin Niclosamide

Exploiting novel molecular targets in gastrointestinal cancers

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World Journal of Gastroenterology 2007年第44期13卷 5845-5856页

作者： Wen W Ma Manuel Hidalgo sidney kimmel comprehensive cancer center The Johns Hopkins University School of Medicine 1650 Orleans Street CRB 1M88 Baltimore MD 21231 United States

Novel molecular targets are being discovered as we learn more about the aberrant processes underlying various cancers. Efforts to translate this knowledge are starting to impact on the care of patients with gastrointestinal cancers. The epidermal growth factor receptor (EGFR) pathway and angiogenesis have been targeted successfully in colorectal cancer with cetuximab, panitunumab and bevacizumab. Similarly, EGFR-targeting with erlotinib yielded significant survival benefit in pancreatic cancer when combined with gemcitabine. The multi-targeting approach with sorafenib has made it the first agent to achieve significant survival benefit in hepatocellular carcinoma. Efforts to exploit the dysregulated Akt/mTOR pathway in GI cancer therapy are ongoing. These molecular targets can be disrupted by various approaches, including the use of monoclonal antibody to intercept extracellular ligands and disrupt receptor-ligand binding, and small molecule inhibitors that interrupt the activation of intracellular kinases.

关键词： Colorectal Pancreatic Liver cancers Targeted therapy Epidermal growth factor receptor roTOR Angiogenesis