Current Cancer Drug Targets - Volume 10, Issue 1, 2010

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Background: The development of resistance to endocrine agents is a major issue in the treatment of ER-positive breast cancer patients. Evidence of cross-talk among signaling pathways and recent advances in understanding biology of this neoplasm have led to the new concept of hormone-biological therapy. Aims: The main aim of this review was to comprehensively examine ongoing and concluded clinical trials about endocrine agents used in combination with biological drugs. The second aim was to provide up-to-date knowledge of preclinical studies in this flourishing field, considering several in vitro and in vivo models, by focusing on the main signaling pathways involved in breast tumorigenesis. Materials and Methods: We performed a literature search for papers published in MEDLINE database until January 2009. We selected the most significant data presented as abstract or poster during the relevant international meetings for breast cancer (ASCO, ESMO and San Antonio Breast Cancer Symposium). Moreover, we systematically reviewed a publicly available registry of federally and privately supported clinical trials conducted in the United States and around the world to provide updated information about concluded trials and ongoing trials not yet published. Results/Conclusion: Hormone-biological therapy is a relatively new option in the treatment of breast cancer with and some combinations seemingly effective in certain settings. Numerous trials are ongoing and they will help to better clarify the role of different combined therapies. In parallel, cancer biology has a central role in providing a deeper understanding of this heterogeneous disease where preclinical studies will be necessary to test new compounds and strategies.

Malignant mesothelioma (MM) is a rare, highly aggressive tumor that arises from the surface serosal cells (pleural, peritoneal and pericardial cavities). Epidemiological and clinical data show that there is an association between asbestos exposure and MM development, even if the exact mechanism whereby asbestos induces MM is unknown. The continuing identification and elucidation of the molecular defects involved in mesothelioma pathogenesis and progression should lead to better disease control and greater therapeutic options in the near future. Goal of this article is to summarize the most recent advances in molecular pathogenesis of mesothelioma with particular emphasis on genes that could be considered as biomarkers or therapeutic targets and discuss possible clinical implications of these findings.

The broad antimicrobial and antitumoral reactivity of Vγ9Vδ2 T cells, their ability to produce inflammatory cytokines involved in protective immunity against intracellular pathogens and tumors and their strong cytolytic and bactericidal activities suggest their direct involvement in immune control of cancers and infections. γδ T cells can be selectively activated by naturally occurring or synthetic phosphoantigens, and drugs that enhance their accumulation into stressed cells, offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate endogenous phosphoantigens, has enabled investigators to design experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances of the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with different types of cancer.

Targeting vascular endothelial growth factor (VEGF) pathway represents a successful strategy in the treatment of metastatic colorectal cancer (mCRC). Since the approval of the first antiangiogenic drug, the anti-VEGF monoclonal antibody bevacizumab, a number of other molecules have been tested in preliminary trials and are currently under investigation in phase III randomized studies. At present, no clinical tools are available to select patients more likely to benefit from VEGF pathway inhibitors nor to exclude those who are proner to suffer from specific adverse events, so that almost all mCRC patients are potentially candidate to receive an antiangiogenic-containing regimen. To overcome this substantial limit, a consistent aid is awaited by the identification of molecular tools of selection. Retrospective analyses and translational studies have been conducted and are currently ongoing to address this major question, investigating molecular, biological and genetic markers. This review aims at resuming the state-of-the-art about the role of VEGF pathway inhibitors in the treatment of mCRC and at focusing on the present knowledge about candidate biomarkers as predictors of activity and toxicity.

New emerging data suggest that bisphosphonates may exert antitumor properties. Preclinical studies have demonstrated that zoledronic acid (ZA) can induce direct and indirect antitumor activities such as inhibition of angiogenesis, invasion and adhesion of tumor cells, and overall tumor progression, stimulation of adoptive and innate immunity and emerging evidence suggests that the use of these agents may prevent the development of skeletal and extra skeletal metastases. This review will critically describe the new growing evidence of antitumor activity exerted by bisphosphonates in cancer patients, both in metastatic disease and in the adjuvant setting. The effects of bisphosphonates on survival in metastatic cancer patients will be described and evidence from retrospective analyses and prospective studies will be critically reported. The early evidence from prospective analyses of survival impact by ZA in the adjuvant setting in breast cancer will be discussed together with the recently published results of the ABCSG-12 study. A new “era” for bisphosphonates in the oncological setting is opening. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of adjuvant and metastatic cancer therapies.

Bortezomib is a proteasome inhibitor. It targets the ubiquitin-proteasome pathway with subsequent inhibition of the degradation of proteins involved in cell cycle regulation and cancer cell survival. The best known molecular mechanism concerns the inhibition of IκB breakdown and the related stabilization of NFκB, thus preventing its translocation to the nucleus for the activation of downstream pathways. Bortezomib is the only drug in this class which has been approved for clinical use. It has shown an efficient antitumor effect in a phase III clinical trial (APEX) involving relapsed multiple myeloma patients. Response rate, time to progression and overall survival have been improved in patients treated with bortezomib and dexamethasone compared to dexamethasone alone. These results have induced several researchers to suggest preclinical and clinical studies for the application of bortezomib in solid tumors. Preclinical data have proved useful in the identification of several of the biological processes implicated, including cell cycle arrest at the G2/M phase, upregulation of p21, apoptosis regulation, microvessel density reduction, overcoming chemotherapy resistance. The clinical results obtained so far with the use of bortezomib in patients with solid malignancies are still not sufficient for the introduction of the drug into clinical practice. Furthermore, the results obtained with the use of bortezomib combined with cytotoxic drugs have not proved any more satisfactory than those obtained with bortezomib used as a single agent. Other preclinical studies are required in order to reach a clearer understanding of the relevance of bortezomib in the therapy of solid tumors.

Recent insights into the molecular pathogenesis of colorectal cancer (CRC) have given rise to specific targetdirected therapies, including monoclonal antibodies (mAb) against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). These drugs have been approved as first, second and third line therapies for metastatic CRC (mCRC) and the advent of target-specific cancer therapeutics has remarkably improved the outcomes of patients with CRC. The molecular mechanisms underlying the clinical response to these drugs are not fully understood, although recent studies have elucidated the effect of intracellular signaling pathways involving in particular RAS/RAF/MAPK signaling on the safety and efficacy of target-specific drugs. Activating mutations of KRAS and BRAF genes are genetic events in tumorigenesis and these mutations are implicated as predictive factors in determining response, in particular to anti-EGFR drugs, and additional data suggest that other EGFR downstream pathways such as PI3K/PTEN/Akt or JAK/STAT are also important when considering mechanisms of EGFR antibody resistance. Recently the European Medical Agency (EMEA) approved the use of the mAb Panitumumab (December 2007) and approved a license extension for the use of the mAb Cetuximab in combination with chemotherapy as first-line treatment (October 2008) in mCRC patients with no mutations in the codon 12 and 13 of KRAS gene. The predictive value of KRAS mutations in the treatment of CRC has been very useful to clinicians and patients in terms of decision making, avoiding toxicities, and decreasing financial burden. This success also encourages researchers to find new markers with the same strong predictive value. Future studies also need to identify patterns of multiple mutations to further increase the power of patient selection for anti-EGFR therapy. These advances allow us to truly enter a new and exciting era of individualized therapy in oncology. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatments conferred by KRAS and other gene mutations as well as the laboratory methods used to detect all these genetic variations.

Cetuximab (IMC-C225, Erbitux ImClone Systems Inc, New York, NY) is a recombinant, human/mouse chimeric monoclonal antibody (MAb) that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) as well as other ligands. Cetuximab binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases and their associated downstream signalling (MAPK, PI3K/Akt, Jak/Stat pathways) resulting in inhibition of many cellular processes such as induction of apoptosis, cell growth, decreased Matrix Metallo-Proteinase (MMPs) and vascular endothelial growth factor (VEGF) production. Cetuximab is also able to display cytotoxic effect through antibody-dependent cellular cytotoxicity (ADCC). In vitro and in vivo experiments elucidated a wide range of biological properties attributed to cetuximab, these include: direct inhibition of EGFR tyrosine kinase activity, inhibition of cell cycle progression, inhibition of angiogenesis, invasion and metastatization processes, activation of pro-apoptotic molecules and synergic cytotoxicity effect with chemotherapy and radiotherapy. Several studies have shown cetuximab is able to inhibit growth of EGFR-expressing tumor cells in vitro as well as in nude mice bearing xenografts of human cancer cell lines. Moreover, numerous clinical trials demonstrated cetuximab efficacy in different tumor types and it is approved by Food and Drugs Administration (FDA) for use in the treatment of metastatic colorectal cancer (mCRC) as single agent or in combination with chemotherapy, for locally/regionally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy, and as monotherapy for recurrent/metastatic HNSCC after failing platinum-based chemotherapy. This review will illustrate pre-clinical and clinical data on biological properties of cetuximab focusing on the predictive markers of clinical response to this drug.

Although Bid is considered to be a cell apoptotic mediator, current studies suggest that it has a possible role in cell survival for mouse embryonic fibroblasts (MEFs) in response to low doses of anti-(±)-5- methylchrysene-1,2-diol- 3,4-epoxide (≤0.25μM) (5-MCDE). We found that the exposure of MEFs to 0.25 μM 5-MCDE resulted in a slight apoptotic induction, while this apoptotic response was substantially increased in the Bid knockout MEFs (Bid-/-), suggesting that there is a Bid-mediated anti-apoptotic function in this response. This notion was further supported by the findings that re-constitution expression of Bid into Bid-/- cells could inhibit the increased apoptosis. Further studies show that the antiapoptotic function of Bid was associated with its mediation of COX-2 expression. This conclusion was based the reduction of COX-2 expression in Bid-/- cells, the restoration of low sensitivity to 5-MCDE-induced apoptosis by the introduction of Bid into Bid-/- cells, and increased sensitivity of WT MEFs to 5-MCDE-induced apoptosis by the knockdown of COX-2 expression. Furthermore, we found that Bid mediated COX-2 expression through the IKKβ/NFκB pathway because the deficiency of Bid in Bid-/- MEFs resulted in the blockade of IKK/NFκB activation and knockout of IKKβ caused abrogation of COX-2 expression induced by 5-MCDE. Collectively, our results demonstrate that Bid is critical for COX-2 induction through the IKKβ/NFκB pathway, which mediates its anti-apoptotic function, in cell response to low doses of 5-MCDE exposure.

Tumors of the epithelial surface account for about 80% of all ovarian neoplasms and exhibit a heterogeneous histological classification affecting survival. Tumors of low malignant potential, defined as borderline ovarian tumors (BOTs), have a markedly better survival and low recurrence, even if surgery still represents the common management for this type of cancer. It is still debated in the literature if BOTs can be considered as intermediate precursors in the progression to high grade ovarian tumors. Evidences now propose that high-grade serous carcinomas are not associated with a defined precursor lesion. Together with histopathological studies, mutations of KRAS, BRAF and p53 genes, microsatellite instability (MSI) and under- or over-expression of many genes and proteins have been used to address this question. Despite the large body of data summarized, a limited number of molecules proved to be useful in elucidating BOTs pathogenesis and only a few of these showed possible application in the therapy. We believe that high-throughput technologies would help to overcome these limitations offering the promise of a better understanding of BOTs classification. The aim is to guide the diagnosis and prognosis of BOTs to develop new possible therapeutic molecular targets avoiding surgery.

Despite recent advancements in treatment modalities, the overall survival and quality of life of patients with head and neck squamous cell carcinoma (HNSCC) have not significantly improved over the past decade. With the increasing emergency of new biological agents, the development of novel treatment schemes based on cancer cell biology may be promising for this group of patients. We previously introduced the “oncogene addiction” concept as a rationale for molecular targeting in cancer therapy and prevention. In this context, an increasing number of preclinical studies have demonstrated that the Signal Transducers and Activators of transcription 3 (Stat3) transcription factor play critical roles in the development and progression of a variety of tumors including HNSCC, by regulating cell proliferation, cell cycle progression, apoptosis, angiogenesis, immune evasion, Epithelial-Mesenchymal Transition (EMT) and through effects in cancer stem cells. The purpose of this review is to summarize current experimental and clinical evidence that suggests that HNSCC might be addicted to Stat3 and describes the molecular mechanisms that may explain this phenomenon. In addition, we discuss whether this addiction is an exploitable target for developing approaches for the treatment and prevention of HNSCC.