Current Molecular Medicine - Volume 10, Issue 4, 2010

In November 2008, the Chulabhorn Research Institute (CRI), Bangkok, Thailand, hosted an international conference on “Recent Progress in Cancer Therapeutics”. The conference was graciously presided over by Her Royal Highness Princess Chulabhorn, President of the CRI. Prof. Dr. Chulabhorn Mahidol opened the conference by delivering a keynote lecture on “Genetic Alterations in Nasopharyngeal Carcinoma in the Thai Population”. The conference was under the joined sponsorship of the American Association for Cancer Research (USA), the Chulabhorn Research Institute (Thailand), the Fritz-Bender-Foundation (Germany), the Network Complement Related Diseases (Switzerland) and KPMG (Germany), (Mrs. S. Bartels-Hetzler). The meeting report of this conference has been published recently [1]. PROGRESS IN CANCER THERAPEUTICS Low productivity and the escalating costs of drug development have been well documented over the past years. A fraction of new pre-clinical compounds successfully pass experimental test batteries, and less than 10% of these compounds that enter clinical trials ulitmately make it to the market [2]. Among different cancer therapy strategies, the chemotherapy could appear to be conceptually outclassed because of its low cancer cell selectivity in comparison with novel molecular mechanism based agents. However, combined strategies, to use the chemotherapeutic high killing potential with new molecule targeted agents, may become an effective anti-tumor treatment approach. The concept of the “magic bullet”, initially ascribed to immunoglobulins by Paul Ehrlich at the beginning of the 20th century and strengthened by the hybridoma technology of Kohler and Milstein in the mid 70s, can nowadays be attributed to different target-specific molecules. The declared paradigm is the development of “personalized and tailored drugs” that precisely target the specific molecular defects of a patient's tumor, if the molecular signature of the inidividual cancer cells can be deciphered. This is the most promising way in the development of improved cancer care for the third millennium. Crystal ball gazing is not the correct way, scientists are trained to study and analyse problems of interest and report critically their findings. So-called “scientific prophets” and “self-nominated experts” can be entertaining but at worst look egocentric and possibly ridiculous. Advances of cancer therapy have occured over the last decade in many fields. Recent developments in nanotechnology offer researchers opportunities to significantly transform cancer therapeutics by facilitating more efficient drug targeting and delivery [3]. The gene-directed enzyme prodrug therapy (GDEPT) has been evaluated for many years and is now entering late-stage clinical trials [4]. Angiogenesis has emerged as a valid therapeutic target and anti-VEGF therapies have clearly demonstrated anti-tumor efficacy in various malignancies, especially when combined with conventional cytotoxic chemotherapy [5]. The progress made in understanding of thermal biology, physics, and bioenigneering, coupled with advances in conventional chemo- and radiotherapy modalities have all contributed to the next generation of clinical thermal therapy [6]. Advances in radiobiology research in normal tissues in the last 50 years have had a major impact on radiation oncology. This includes the linearquadratic model to adjust doses in altered fractionation protocols, and quantitation of repopulation processes to avoid toxicities in accelerated regimen [7]. Increased aerobic glycolysis in cancer, known as Warburg effect, has been observed in various tumor cells. The current understanding of the Warburg effect provides exciting opportunities for the development of new drugs to preferentially kill cancer cells by targeting the glycolytic pathway [8,9]. The recent discoveries of epidemiological and molecular links between diabetes/metabolic syndrome and cancer originated from interdisciplinary-oriented research will give us special attention to the ways in which food and nutrition, physical activity, and body composition may modify treatment modalities [10]. Understanding the complexity of cancer depends on an elucidation of the underlying regulatory networks, at the cellular and intercellular levels and in their temporal dimension. Combined targeting of the Notch and the p53 and p63 pathways could improve the efficacy and reduce the toxicity of cancer therapies [11]. Although currently available data indicate that elimination of malignant cells often depends on classical apoptotic pathways (mitochondrial and/or death receptor pathways), the evidence is mounting that alternative apoptotic and non-apoptotic pathways may effectively contribute to tumor cell death. Interestingly, a growing number of reports recognize novel therapeutic targets, including proteins in control of endoplasmic reticulum and Golgi homeostasis [12]....

Acquired deficiency of C1 inhibitor (C1-INH) with angioedema symptoms (acquired angioedema, AAE) is characterized by local increase in vascular permeability (agioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. The mediator of symptoms is bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein a serine protease controlled by C1-INH. Autoantibodies inactivating C1-INH are detected in the majority of patients and account for the deficiency. Irrespectively to the presence of anti-C1-INH autoantibodies lymphoproliferative diseases, ranging from benign monoclonal gammopathies to malignant lymphoma, are frequently associated with AAE. Demonstration that monoclonal components correspond to anti-C1-INH autoantibodies and correlation between course of lymphoma and course of AAE provide strong support to consider the two diseases expression of the same pathologic process.

RNA interference (RNAi), an evolutionarily conserved sequence-specific post-transcriptional gene silencing mechanism, is triggered by double-stranded RNA (dsRNA) that results in the degradation of homologous mRNA or in the inhibition of mRNA translation. The naturally occurring triggers for the RNAi pathway are small regulatory RNAs, including small interfering RNAs (siRNAs), processed from longer dsRNAs by the RNAse III enzyme Dicer, and microRNAs (miRNAs), generated in a regulated multistep process from endogenous primary transcripts (pri-miRNA). These primary transcripts are capped, polyadenylated and spliced, thus resembling conventional mRNAs. It is estimated that miRNAs regulate more than one third of all cellular mRNAs, and bioinformatic data indicate that each miRNA can control hundreds of gene targets. Thus, there are likely to be few biological processes not regulated by miRNAs. Although the biological functions of miRNAs are not completely revealed, there is growing evidence that miRNA pathways are a new mechanism of gene regulation in both normal and diseased conditions. Recent evidence has shown that miRNA mutations or aberrant expression patterns correlate with various diseases, such as cancer, viral infections, cardiovascular or neurodegenerative diseases and indicates that miRNAs can function as tumor suppressors and oncogenes. MiRNAs have not only emerged as a powerful tool for gene regulation studies but also for the development of novel drugs. Since they do not encode proteins, they are not traditional therapeutic targets of small-molecule inhibitors and thus comprise a novel class of therapeutics. This article will focus on the current progress in drug discovery using the miRNA strategy.

Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumours that are not epidemiologically related to inflammation. Compounds of the inflammatory tumour microenvironment include leukocytes, cytokines, complement components, and are orchestrated by transcription factors, such as NFkB and Stat3. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. An intrinsic (driven by genetic events that cause neoplasia) and an extrinsic (driven by inflammatory conditions which predispose to cancer) pathway link inflammation and cancer. Smouldering inflammation in the tumour microenvironment promotes proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, response to hormones and chemotherapeutic agents. Cancer-related inflammation represents a target for innovative diagnostic and therapeutic strategies.

Alterations in TGFß signaling are common in human cancers. TGFß has significant impact on tumor initiation and progression. Therapeutic strategies including neutralizing antibodies and small molecular inhibitors have been developed to target TGFß signaling. However, TGFß can work as both a tumor suppressor and a tumor promoter. A significant challenge to the development of successful TGFß antagonism treatment is understanding how and when TGFß switches its function from a tumor suppressor to a tumor promoter. Recent studies demonstrate that TGFß regulates the infiltration of inflammatory cells and cancer associated fibroblasts into the tumor microenvironment, resulting in changes in signaling cascade in tumor cells. Additionally, TGFß exerts systemic immune suppression and significantly inhibits host tumor immune surveillance. Neutralizing TGFß in preclinical mouse models enhances CD8+ T-cell and natural killer cell-mediated anti-tumor immune response. This new understanding of TGFß signaling in regulation of tumor microenvironment and immune response may provide useful information, particularly for patient selection and inflammation/immune biomarkers for TGFß antagonism therapy in clinical trials.

Fast growing solid tumours generally lack an inner organisation, which causes the problem of a sufficient nutrient of each part of the tumour that then happens only by diffusion. The low oxygen supply leads to the activation of hypoxia-inducible factors, which regulate a plethora of genes. The reaction of tumour cells to hypoxia can be divided into two parts: On the one hand, there are signal substances, predominantly growth factors and cytokines, which provoke the vascularisation (angiogenesis), lymph vessel development (lymphangiogenesis), and the innervation (neoneurogenesis) of tumours and thus connect the tumour to structures of the environment. On the other hand, genes for intracellular proteins and receptors are regulated, which lead to changes of the tumour cell functions. Best characterised is the metabolic shift, a high anaerobic glycolytic activity and simultaneously a reduction of respiration. Furthermore, proliferation, dedifferentiation, resistance to apoptosis, and the metastatic potential are affected. With regard to the latter, we herein show that the migratory activity and velocity of PC-3 human prostate carcinoma cells significantly increase under oxygendeprivation, which might be an explanation for the increasing number of experimental and clinical hints, that an anti-angiogenic therapy can promote the metastasis formation.

Wnt/β-catenin signaling plays a crucial role during embryogenesis. However, this signaling pathway also plays a role in normal adult tissues and in carcinogenesis, including cadmium (Cd2+) induced nephrocarcinogenesis, which is the topic of this review. Wnt/β-catenin signaling is tightly regulated in mature epithelia to balance cell proliferation, differentiation and death. This is accomplished by modulating phosphorylation of the multifunctional protein β-catenin which in turn determines its preference for a particular fate, i.e. cell-cell adhesion by binding to E-cadherin, proteasomal degradation, or co-activation of the transcription factor Tcf/Lef. The pivotal role of β-catenin is not limited to Wnt signaling, but can be challenged by other transcription factors under stress conditions (e.g. FOXO, HIF-1α, NF-κB, c-jun), where β-catenin acts as a molecular switch in response to the cellular redox status. Aberrant Wnt/β-catenin signaling can contribute to carcinogenesis of intestinal, lung or kidney epithelia, either by mutations of its signaling components and/or disruption of linked signaling networks. The nephrotoxic metal Cd2+ causes renal cancer in humans. Because it is not genotoxic, Cd2+ is thought to induce mutations and carcinomas indirectly: Possible mechanisms include oxidative stress, inhibition of DNA repair, aberrant gene expression, deregulation of cell proliferation, resistance to apoptosis, and/or disruption of cell adhesion. Wnt signaling may contribute to Cd2+ carcinogenesis because Cd2+ disrupts the junctional E-cadherin/β-catenin complex, resulting in excessive nuclear translocation of β-catenin and activation of Tcf4. Up-regulation of target genes of the β-catenin/Tcf4 complex, such as c-myc, cyclin D1 and the multidrug transporter P-glycoprotein (MDR1/ABCB1), leads to increased proliferation, evasion of apoptosis, adaptation to Cd2+ toxicity and thereby promotes the selection of mutated and pre-neoplastic cells.

The majority of melanoma cells do not express argininosuccinate synthetase (ASS), and hence cannot synthesize arginine from citrulline. Their growth and proliferation depend on exogenous supply of arginine. Arginine degradation using arginine deiminase (ADI) leads to growth inhibition and eventually cell death while normal cells which express ASS can survive. This notion has been translated into clinical trial. Pegylated ADI (ADI-PEG20) has shown antitumor activity in melanoma. However, the sensitivity to ADI is different among ASS(-) melanoma cells. We have investigated and reviewed the signaling pathways which are affected by arginine deprivation and their consequences which lead to cell death. We have found that arginine deprivation inhibits mTOR signaling but leads to activation of MEK and ERK with no changes in BRAF. These changes most likely lead to autophagy, a possible mechanism to survive by recycling intracellular arginine. However apoptosis does occur which can be both caspase-dependent or independent. In order to increase the therapeutic efficacy of this form of treatment, one should consider adding other agent(s) which can drive the cells toward apoptosis or inhibit the autophagic process.

Melanoma causes a considerable public health burden because of its dramatic rise in incidence worldwide since the mid-1960s and because the metastatic disease remains incurable, has a short median survival and is characterized by resistance to almost all classes of cytotoxic agents. DNA repair pathways are multiple and are able to repair, usually in an error-free manner, all kinds of DNA damage induced by exogenous and endogenous genotoxic agents. This review describes the role of DNA repair process in protecting us from cancer and particularly nucleotide excision deficiencies that are associated with melanoma development. Resistance of tumoral cells to antitumoral regimen can be caused by overexpression of DNA repair processes. We showed that melanoma metastasis was associated with higher expression of some DNA repair pathways leading to a better surveillance of replication fork fidelity. We showed a partially coordinated regulation of these repair genes. P53 and several transcription factors may regulate numerous of these repair genes. The repair pathways that are overexpressed in metastatic melanoma are those particularly efficient in repairing the major DNA damage produced by cytotoxic treatments. This implies that better analysis of DNA repair regulation is necessary to identify novel therapeutic targets and to allow clinicians to propose tailored therapies.

Chondroitin sulfate proteoglycan 4 (CSPG4), also known as High Molecular Weight- Melanoma Associated Antigen, is a cell surface proteoglycan which has been recently shown to be expressed not only by melanoma cells, but also by various types of human carcinoma and sarcoma. Furthermore, at least in squamous cell carcinoma of head and neck and in basal breast carcinoma, CSPG4 is expressed by cancer stem cells. CSPG4 plays an important role in tumor cell growth and survival. These CSPG4-associated functional properties of tumor cells are inhibited by CSPG4-specific monoclonal antibodies (mAb) in vitro. Moreover, CSPG4-specific mAb can also inhibit tumor growth and metastasis in vivo. The anti-tumor effects of CSPG4-specific mAb are likely to reflect the blocking of important migratory, mitogenic and survival signaling pathways in tumor cells. These results indicate that CSPG4 is a promising new target to implement mAb-based immunotherapy of various types of cancer.

Mistletoe is often used as complementary therapy in oncology. The anti-tumor effects of mistletoe (Iscador®) are well documented in-vitro in respect to inhibition of cell proliferation, induction of apoptosis, segmental activation of immune competent cells and trapping of chemotherapeutic drugs within cancer cells by modulating the inhibitory potential of P-glycoprotein (P-gp)-mediated transport of cell toxifying substances (cytotoxic drugs). However, the clinical activity of mistletoe treatment remains still controversial. Implementation of mistletoe therapy as supportive care into anti-cancer programs should be based on the best evidence and must continually be evaluated to ensure safety, efficacy, collection of new data, and cost-effectiveness. Useful domains that can be evaluated include symptom control, adherence to conventional treatment protocols, quality of life, individual outcome and potential advantages of a whole-system health approach. Here we report the results of a multicenter, controlled, retrospective and observational pharmacoepidemiological study in patients suffering from a pancreatic carcinoma. After surgery the patients were treated by adjuvant chemotherapy with gemcitabine supported by Iscador®, or with gemcitabine alone, or any other best of care, but not including Iscador®. Using a novel methodological pharmaco-epidemiological design and statistical approach it could be shown that Iscador® offers benefits - symptom control, overall survival - as supportive care within gemcitabine protocols of patients with surgically resected pancreatic carcinoma.