Molecular targeted therapies in breast cancer: Where are we now?

Targeted therapies, in cancer treatment, represent a new generation of drugs that interfere with specific molecular targets (typically proteins) having critical roles to play in tumour growth or progression. The principle of targeted therapy is certainly not new: tamoxifen, a hormonal agent targeted at the estrogen receptor, has been in use for more than 30 years. However, this principle has re-gained significant emphasis with the recent development of new biological agents, such as trastuzumab, which was first approved for the treatment of advanced breast cancer (BC) in 1998. Presently, there are at least three different targeted therapies with well documented activity in advanced BC and all three are now being studied in the adjuvant setting; trastuzumab and bevacizumab are monoclonal antibodies, and lapatinib is a dual inhibitor of HER-1 and HER-2. This paper will review the increasing role of molecular targeted therapies in BC, with a particular focus on those drugs currently being tested in early BC, as well as, on future perspectives.     

The potential for gene-targeted radiation therapy of cancers

Targeted cancer therapy is the mantra now chanted by oncologists of all types. Everyone hopes that the rapid expansion in the knowledge of cancer cell genetics, signaling, regulatory factors and other changes that underlie malignant transformation and metastasis will lead to innovative approaches for the treatment of cancers. To date, successful targeted therapies have been derived from pharmaceutical chemistry - designing chemical compounds intended to disrupt a crucial pathway for malignant cells to survive, grow and metastasize. Radiotherapy also has a goal of more-selective targeting of therapeutic radiation effects to only tumor cells. In this review, we describe our efforts to create a form of gene-targeted radiation therapy by using the unique radiation effects of radionuclides that decay by the Auger process attached to oligonucleotide carrier-molecules that are capable of forming triplex DNA structures with target sequences in the genome of the human cancer cell.     

Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke

It has been a major challenge to develop effective therapeutics for stroke, a leading cause of death and serious debilitation. Intensive research in the past 15 years have implicated many regulators and the related mechanisms by which neuronal cell death is regulated. It is now clear that even a brief ischemic stroke may trigger complex cellular events that lead to both apoptotic and necrotic neuronal cell death in a progressive manner. Although efforts at developing specific chemical inhibitors for validated targets have been successful for in vitro enzymatic assays, the development of some of such inhibitors into human therapy has been often hindered by their in vivo bioavailability profile. Considerations for the ability to chemically target a cellular mechanism in manner compatible with disease targets in vivo might be emphasized early in the development process by putting a priority on identifying key targets that can be effectively targeted chemically. Thorough interrogation of cellular pathways by saturation chemical genetics may provide a novel strategy to identify multiple key molecular entities that can be targeted chemically in order to select a target suitable for the treatment of intended human diseases such as stroke.     

Metabolic targeted therapy of cancer: current tracer technologies and future drug design strategies in the old metabolic network

Targeted drugs tailored against genes and signaling proteins have formed the new era termed Targeted Therapies. Although the field is relatively young, since only about 5 years ago clinical trials started showing promise, there have are already been significant setbacks due to drug resistance caused by point mutations, alterations in gene expression or complete loss of target proteins with disease progression. Although new drugs are continuously designed and tried, it seems inevitable that genetic and signal protein targets pose too broad flexibility and variability, often changing target characteristics and thus escape treatments turning “magic bullets” into rather “wondering bullets”. This is especially true in cancer, where old and new targeted therapies continue to fail and the most recent ones do not offer much improvement on clinical outcome parameters. Metabolic targeted therapies are aimed at control points of the metabolic network by targeting particular enzymes of major macromolecule synthesis pathways in cancer. This review summarizes the potential benefits of targeted therapies in the metabolic network as applied with genetic and proteomic approaches. The metabolic target approach is most efficient if and when pathway flux information is available for drug target development using the stable isotope based dynamic metabolic profile (SIDMAP) of tumor cells, in vitro or in vivo.This revised version was published online in June 2005. The previous version did not contain colour images.     

Chemogenomics approaches to novel target discovery

Chemogenomics involves the combination of a compound’s effect on biological targets together with modern genomics technologies. The merger of these two methodologies is creating a new way to screen for compound–target interactions, as well as map chemical and biological space in a parallel fashion. The challenge associated with mining complex databases has initiated the development of many novel in silico tools to profile and analyze data in a systematic way. The ability to analyze the combinatorial effects of chemical libraries on biological systems will aid the discovery of new therapeutic entities. Chemogenomics provides a tool for the rapid validation of novel targeted therapeutics, where a specific molecular target is modulated by a small molecule. Along with targeted therapies comes the ability to discovery pathway nodes where a single molecular target might be an essential component of more than one disease. Several disease areas will benefit directly from the chemogenomics approach, the most advanced being cancer. A genetic loss-of-function screen can be modulated in the presence of a compound to search for genes or pathways involved in the compound’s activity. Several recent papers highlight how chemogenomics is changing with RNA interference-based screening and shaping the discovery of new targeted therapies. Together, chemical and RNA interference-based screens open the door for a new way to discovery disease-associated genes and novel targeted therapies.     

Targeting cell signaling pathways for drug discovery: an old lock needs a new key

In this age of targeted therapy, the failure of most current drug-discovery efforts to yield safe, effective, and inexpensive drugs has generated widespread concern. Successful drug development has been stymied by a general focus on target selection rather than clinical safety and efficacy. The very process of validating the targets themselves is inefficient and in many cases leads to drugs having poor efficacy and undesirable side effects. Indeed, some rationally designed drugs (e.g., inhibitors of receptor tyrosine kinases, tumor necrosis factor (TNF), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), bcr-abl, and proteasomes) are ineffective against cancers and other inflammatory conditions and produce serious side effects. Since any given cancer carries mutations in an estimated 300 genes, this raises an important question about how effective these targeted therapies can ever be against cancer. Thus, it has become necessary to rethink drug development strategies. This review analyzes the shortcomings of rationally designed target-specific drugs against cancer cell signaling pathways and evaluates the available options for future drug development.     

Chemogenomics approaches to novel target discovery

Chemogenomics involves the combination of a compound's effect on biological targets together with modern genomics technologies. The merger of these two methodologies is creating a new way to screen for compound-target interactions, as well as map chemical and biological space in a parallel fashion. The challenge associated with mining complex databases has initiated the development of many novel in silico tools to profile and analyze data in a systematic way. The ability to analyze the combinatorial effects of chemical libraries on biological systems will aid the discovery of new therapeutic entities. Chemogenomics provides a tool for the rapid validation of novel targeted therapeutics, where a specific molecular target is modulated by a small molecule. Along with targeted therapies comes the ability to discovery pathway nodes where a single molecular target might be an essential component of more than one disease. Several disease areas will benefit directly from the chemogenomics approach, the most advanced being cancer. A genetic loss-of-function screen can be modulated in the presence of a compound to search for genes or pathways involved in the compound's activity. Several recent papers highlight how chemogenomics is changing with RNA interference-based screening and shaping the discovery of new targeted therapies. Together, chemical and RNA interference-based screens open the door for a new way to discovery disease-associated genes and novel targeted therapies.     

放射性药物在肿瘤靶向治疗中的应用

放射性药物指供临床诊断或治疗用的放射性核素制剂或其标记化合物。放射性核素靶向治疗是利用对肿瘤细胞具有特异高亲和力的分子载体将核素定向导入特定的肿瘤组织,对肿瘤进行治疗。与传统的放疗和化疗相比,其具有选择性杀伤肿瘤细胞的特点。随着核医学的发展,SPECT/CT、PET/CT的普及,新靶点的发现和新型放射性药物的研发,利用放射性药物进行靶向治疗在肿瘤临床治疗中占据的地位越来越重要。本文简述了放射性药物的分类、组成及特点;综述了针对肿瘤相关抗原的放射免疫药物在非霍奇金淋巴瘤、结直肠癌和前列腺癌中的应用;受体介导的放射性核素药物在治疗神经内分泌肿瘤、前列腺癌和乳腺癌中的临床应用以及基于基因修饰的放射性药物在肿瘤靶向治疗中的实验研究进展。最后总结了放射性药物在肿瘤靶向治疗中的应用前景与面临的挑战,以期为靶向治疗肿瘤的放射性药物的开发和临床应用提供一些参考。     

New approaches to molecular cancer therapeutics

Cancer drug development is leading the way in exploiting molecular biological and genetic information to develop "personalized" medicine. The new paradigm is to develop agents that target the precise molecular pathology driving the progression of individual cancers. Drug developers have benefited from decades of academic cancer research and from investment in genomics, genetics and automation; their success is exemplified by high-profile drugs such as Herceptin (trastuzumab), Gleevec (imatinib), Tarceva (erlotinib) and Avastin (bevacizumab). However, only 5% of cancer drugs entering clinical trials reach marketing approval. Cancer remains a high unmet medical need, and many potential cancer targets remain undrugged. In this review we assess the status of the discovery and development of small-molecule cancer therapeutics. We show how chemical biology approaches offer techniques for interconnecting elements of the traditional linear progression from gene to drug, thereby providing a basis for increasing speed and success in cancer drug discovery.     

Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment

The cytochromes P450 (CYPs) are very efficient catalysts of foreign compound metabolism and are responsible for the major part of metabolism of clinically important drugs. The enzymes are important in cancer since they (a) activate dietary and environmental components to ultimate carcinogens, (b) activate or inactivate drugs used for cancer treatment, and (c) are potential targets for anticancer therapy. The genes encoding the CYP enzymes active in drug metabolism are highly polymorphic, whereas those encoding metabolism of precarcinogens are relatively conserved. A vast amount of literature is present where investigators have tried to link genetic polymorphism in CYPs to cancer susceptibility, although not much conclusive data have hitherto been obtained, with exception of CYP2A6 polymorphism and tobacco induced cancer, to a great extent because of lack of important functional polymorphisms in the genes studied. With respect to anticancer treatment, the genetic CYP polymorphism is of greater importance, where treatment with tamoxifen, but also with cyclophosphamide and maybe thalidomide is influenced by CYP genetic variants. In the present review we present updates on CYP genetics, cancer risk and treatment and also epigenetic aspects of interindividual variability in CYP expression and the use of these enzymes as targets for cancer therapy. We conclude that the CYP polymorphism does not predict cancer susceptibility to any large extent but that this polymorphism might be an important factor for optimal cancer therapy using selected anticancer agents.     

Amplified genes as therapeutic targets in cancer

The most effective targeted cancer therapies have arisen from research into genetically altered oncogenes, including BCR-ABL, HER2, RAS and EGFR. Recent advances in cancer genetics have identified many regions of the genome that undergo amplification (increase in copy number) but, in most cases, the key oncogenic targets driving the growth and survival of cancer cells remain unknown. In this review, we discuss high-throughput technologies for the discovery of putative oncogenes, and clinical and functional validation of these genes as targets for therapy. New technologies in translational genomics facilitate the identification, validation and prioritization of candidate molecular targets for anti-cancer therapy.     

原发性肝癌的表观遗传学及其治疗

肝癌是一种严重危害人类健康的恶性疾病,在全世界患癌人群中,肝癌的发生率排第五,死亡率排第二。原发性肝癌(Hepatocellular carcinoma, HCC)是最普遍的肝癌组织学亚型,属于异质性疾病,对其治疗涉及遗传学、基因组学、环境毒理学等多个领域。尽管许多分子靶向治疗药物如索拉菲尼等已经进入临床应用并证明有效,但细胞毒性等负效应不容忽视,目前迫切需要新的治疗靶点和药物高效并选择性的杀伤肝癌细胞。大量证据表明,肝脏肿瘤的发生和发展与表观遗传学密切相关,DNA甲基化、组蛋白修饰、miRNA表达的异常及表观遗传相关基因表达的异常都是HCC中显著的表观遗传异常现象。表观治疗药物可能会逆转异常基因的表达,从而使HCC的发生和发展得以控制。文章综述了HCC表观遗传学治疗方面的研究进展,展望了未来利用类似的疗法治疗肝癌的潜力。     

Using naturally occurring tumours in dogs and cats to study telomerase and cancer stem cell biology

The recently described cancer stem cell theory opens up many new challenges and opportunities to identify targets for therapeutic intervention. However, the majority of cancer related therapeutic studies rely upon rodent models of human cancer that rarely translate into clinical success in human patients. Naturally occurring cancers in dogs, cats and humans share biological features, including molecular targets, telomerase biology and tumour genetics. Studying cancer stem cell biology and telomere/telomerase dynamics in the cancer bearing pet population may offer the opportunity to develop a greater understanding of cancer biology in the natural setting and evaluate the development of novel therapies targeted at these systems.     

Focus: Personalized Medicine: Tailoring the Treatment of Melanoma: Implications for Personalized Medicine

Oncology has been revolutionized by the ability to selectively inhibit the growth of cancerous cells while ostensibly avoiding the disruption of proteins and pathways necessary for normal cellular function. This paradigm has triggered an explosion of targeted therapies for cancer, creating a burgeoning billion-dollar industry of small molecules and monoclonal antibodies [1]. Largely due to these new treatments, spending on cancer pharmaceuticals has surpassed $100 billion worldwide [2]. In particular, the treatment of melanoma, a deadly and fast-spreading form of skin cancer, has been transformed by these new targeted therapies. In this mini-review, we summarize the progress made in the field of personalized treatment of melanoma, with an emphasis on targeted therapies. We then outline future directions for treatment, including novel cell-mediated therapies and new potential targets.     

Tagged library approach facilitates forward chemical genetics

Forward chemical genetics has been highlighted as a new method for the study of various biological pathways using exogenous ligands. However, limited success in the field has demonstrated that, in many cases, it is not feasible to determine the protein targets of small-molecule probes. Identifying protein targets is an integral part of forward chemical genetics and is also the most challenging. Over the past decade, several biochemical and genetic methods have been developed to facilitate target identification processes. Even so, one of the major difficulties is that these methods require the chemical modification of active compounds, with a significant amount of structure-activity relationship (SAR) study to ensure that the small-molecule tags do not compromise bioactivity. In this article, we will highlight a new strategy for small molecule libraries that have built-in linkers in order to avoid this well-known problem and demonstrate their successful use in forward chemical genetics.     

Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways

Chemotherapy remains a commonly used therapeutic approach for many cancers. Indeed chemotherapy is relatively effective for treatment of certain cancers and it may be the only therapy (besides radiotherapy) that is appropriate for certain cancers. However, a common problem with chemotherapy is the development of drug resistance. Many studies on the mechanisms of drug resistance concentrated on the expression of membrane transporters and how they could be aberrantly regulated in drug resistant cells. Attempts were made to isolate specific inhibitors which could be used to treat drug resistant patients. Unfortunately most of these drug transporter inhibitors have not proven effective for therapy. Recently the possibilities of more specific, targeted therapies have sparked the interest of clinical and basic researchers as approaches to kill cancer cells. However, there are also problems associated with these targeted therapies. Two key signaling pathways involved in the regulation of cell growth are the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Dysregulated signaling through these pathways is often the result of genetic alterations in critical components in these pathways as well as mutations in upstream growth factor receptors. Furthermore, these pathways may be activated by chemotherapeutic drugs and ionizing radiation. This review documents how their abnormal expression can contribute to drug resistance as well as resistance to targeted therapy. This review will discuss in detail PTEN regulation as this is a critical tumor suppressor gene frequently dysregulated in human cancer which contributes to therapy resistance. Controlling the expression of these pathways could improve cancer therapy and ameliorate human health.     

Small and lethal: searching for new antibacterial compounds with novel modes of action.

The discovery of drugs used to combat infectious diseases is in the process of constant change to address the ever-worsening problem of antibiotic resistance in pathogens and a lack of recent success in discovering new antibacterial drugs. In the past 2 decades, research in both academia and industry has made use of molecular biology, genetics, and comparative genomics, which has led to the development of key technologies for the discovery of novel antibacterial agents. Genome-scale efforts have led to the identification of numerous molecular targets. Chemical diversity from synthetic combinatorial libraries and natural products is being used to screen for new molecules. A wide variety of approaches are being used in the search for novel antibiotics, and these can be categorized as being either biochemically focused or cell based. The over-riding goal of all methods in use today is to discover new chemical matter with novel mechanisms of action against drug-resistant pathogens.     

Molecular targets and signaling pathways regulated by interleukin (IL)-24 in mediating its antitumor activities

Cancer remains a major health issue in the world and the effectiveness of current therapies is limited resulting in disease recurrence and resistance to therapy. Therefore to overcome disease recurrence and have improved treatment efficacy there is a continued effort to develop and test new anticancer drugs that are natural or synthetic - (conventional chemotherapeutics, small molecule inhibitors) and biologic (antibody, tumor suppressor genes, oligonucleotide) product. In parallel, efforts for identifying molecular targets and signaling pathways to which cancer cells are “addicted” are underway. By inhibiting critical signaling pathways that is crucial for cancer cell survival, it is expected that the cancer cells will undergo a withdrawal symptom akin to “de-addiction” resulting in cell death. Thus, the key for having an improved and greater control on tumor growth and metastasis is to develop a therapeutic that is able to kill tumor cells efficiently by modulating critical signaling pathways on which cancer cells rely for their survival.Currently several small molecule inhibitors targeted towards unique molecular signaling pathways have been developed and tested in the clinic. Few of these inhibitors have shown efficacy while others have failed. Thus, targeting a single molecule or pathway may be insufficient to completely block cancer cell proliferation and survival. It is therefore important to identify and test an anticancer drug that can inhibit multiple signaling pathways in a cancer cell, control growth of both primary and metastatic tumors and is safe.One biologic agent that has the characteristics of serving as a potent anticancer drug is interleukin (IL)-24. IL-24 suppresses multiple signaling pathways in a broad-spectrum of human cancer cells leading to tumor cell death, inhibition of tumor angiogenesis and metastasis. Additionally, combining IL-24 with other therapies demonstrated additive to synergistic antitumor activity. Clinical testing of IL-24 as a gene-based therapeutic for the treatment of solid tumors demonstrated that IL-24 is efficacious and is safe. The unique features of IL-24 support its further development as an anticancer drug for cancer treatment.In this review we summarize the current understanding on the molecular targets and signaling pathways regulated by IL-24 in mediating its anticancer activity.     

Cancer-linked targets modulated by curcumin

In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting.     

Tubulin targets in the pathobiology and therapy of glioblastoma multiforme. I. class III β‐tubulin

Glioblastoma multiforme (GBM) is the most common and deadliest form of primary brain cancer in adults. Despite advances in molecular biology and genetics of gliomas currently there is no effective treatment or promising molecularly targeted experimental therapeutic strategies for these tumors. In previous studies we have shown aberrant overexpression of the class III β‐tubulin isotype (βIII‐tubulin) in GBM and have proposed that this change may reflect perturbations in microtubule dynamics associated with glioma tumorigenesis, tumor progression and malignant transformation into GBM. This minireview focuses on microtubules and tubulin as emerging targets in potential therapy of GBM using a new class of βIII‐tubulin‐targeted drugs in the light of recent developments concerning the function and potential role of this isotype in clinically aggressive tumor behavior, cancer stem cells, tumor hypoxia and chemoresistance to tubulin binding agents, principally taxanes. J. Cell. Physiol. 221: 505–513, 2009. © 2009 Wiley‐Liss, Inc.