Current Cancer Therapy Reviews

ISSN: 1573-3947

Current Cancer Therapy Reviews
Volume 2, Number 1, February 2006

Contents


Editorial Pp. 1


Environmental Exposure, and Other Behavioral Risk Factors in Breast Cancer Pp. 3-21
Joanna Kruk and Hassan Y. Aboul-Enein
[Abstract]


New Targets, New Agents, and the Evolving Phenomena of Drug Resistance in Cancer Pp. 23-30
Shi-Ping Luh and Moulay A. Alaoui-Jamali
[Abstract]


YB-1 Activities in Oncogenesis: Transcription and Translation Pp. 31-39
Andreas G. Bader
[Abstract]


HCV-Related Transformation and New Therapeutic Strategies: An Update Pp. 41-56
Clara Balsano and Anna Alisi
[Abstract]


STAT Inhibition in the Treatment of Cancer: Transcription Factors as Targets for Molecular Therapy Pp. 57-65
David A. Frank
[Abstract]


Free Flap Head and Neck Reconstruction After Cancer Therapy: Current State of the Art Pp. 67-72
Efstathios G. Lykoudis, Marios G. Salmas and Dimitrios A. Assimakopoulos
[Abstract]


Tumor Control by Manipulation of the Human Anti-Apoptotic Survivin Gene Pp. 73-79
Zakir Khan, Pratiksha Bhadouria, Radha Gupta and Prakash S. Bisen
[Abstract]


Recent Clinical Trials in Non-Small Cell Lung Cancer Pp. 81-99
Suresh Ramalingam and Chandra P. Belani
[Abstract]




Abstracts

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Editorial

Although cytotoxic chemotherapy is still the cornerstone of systemic therapy for cancer, these treatments have marginal effectiveness in many malignancies and cause significant toxicity. It is now almost 20 years ago that the epidermal growth factor receptor (EGFR) was first proposed as a potential target for cancer. The EGFR TKI’s gefitinib and erlotinib have shown activity in NSCLC while cetuximab is an active agent in metastatic colorectal cancer. However, several pivotal trials of these new agents have failed to give the expected improved results.

One possible reason given for the failure of the phase 3 trials combining EGFR inhibitors with doublet chemotherapy for first-line treatment of advanced NSCLC was the lack of patient selection with regard to tumor sensitivity to EGFR inhibition. The most obvious marker of sensitivity to these agents is the EGFR expression level in a tumor. However, it has been demonstrated that the presence of this receptor alone does not predict response to either gefitinib or erlotinib in NSCLC. Other factors such as activation of EGFR in a particular patient may be critical determinants of response. The knowledge that some tumors have driving target aberrations coupled with gene-sequencing data provides the means to establish proof of principle about the validity of targets and/or targeted therapeutics.

A second lesson was learned in the failure of therapeutic efforts directed at Ras. Ras is situated at the apex of the MAPK pathway and belongs to a superfamily of guanine nucleotide triphosphates (GTPases) that transmit proliferative and survival signals. Ras plays a central role in an intricate array of signal transduction pathways characterized by crosstalk, feedback loops, and multicomponent signaling complexes. One strategy to overcome the challenges inherent in developing therapeutics against signaling elements situated in redundant pathways is to target elements downstream of convergence points of critical signaling modules. This reasoning has led to interest in Raf kinase, which is one of several downstream effectors of Ras, as target for therapeutic development against cancer. Promising small molecule inhibitors of Raf kinase include sorafenib (BAY43-9006) and sutent (Pfizer SU) in renal cell cancer.

Given that multiple pathways are often implicated in tumor cell growth, and the high likelihood for crosstalk between the components of these pathways, single targeted agent inhibitior therapy may be insufficient to induce durable antitumor effects. Targeted agents may be combined to allow vertical or horizontal inhibition of relevant pathways. Vertical inhibition targets multiple points within the same molecular pathway, whereas horizontal inhibition acts at points across multiple pathways. The efficacy of horizontal inhibition in advanced renal cell cancer is suggested by promising initial results combining the anti-EGFR agent erlotinib, with the anti-VEGF antibody bevacizumab.

Finally, assessing antitumor activity with the new targeted drugs has also been challenging. In preclinical models, many targeted agents induce growth arrest or inhibition rather than tumor shrinkage. The 30% unidimensional shrinkage by standard Response Evaluation Criteria (RECIST) is an arbitrary standard that does not necessarily have biological or clinical significance. Indeed, both sorafenib and sutent are very active single agents in metastatic renal cell cancer when assessed by time to disease progression and not by RECIST criteria.

The oncology literature is increasingly dominated by new biological targets and trials of targeted agents. In this issue of Current Cancer Therapy Reviews, the article by Luh and Alaui-Jamali reviews new targets, agents and drug resistance. The papers by Bader, Frank and Khan et al. discuss new potential targets such as YB-1, STAT-1 and survivin. The challenge to the medical oncologist is to assimilate this rapid growth of basic science information into successful clinical trials.

Allan Lipton
(Editor-in-Chief)
Pennsylvania State University
Hershey, PA
USA
E-mail: alipton@psu.edu


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Environmental Exposure, and Other Behavioral Risk Factors in Breast Cancer
Joanna Kruk and Hassan Y. Aboul-Enein

Breast cancer continues to be worldwide public health concern in America and Western Europe as the commonest cancer among women and the second highest reason of cancer death. Epidemiological evidences implicating environmental and lifestyle risk factors in breast cancer etiology are accumulating. In this review, the current state of knowledge is reviewed, pertaining to relationship between environmental exposures (persistent chemicals, radiation, electromagnetic fields), lifestyle (physical activity, diet, obesity, smoking, alcohol use, oral contraceptive, hormone replacement therapy) and breast cancer risk. This paper also summarises the epidemiological literature on the cellular mechanisms of steroidal estrogens metabolism to carcinogenic products.

The epidemiological data have shown that investigation of breast cancer risk among women is difficult to study because of confounding or modification from reproductive female characteristics. Moreover, multiple factors, known as well as unknown, may contribute to the breast cancer development. Through the inconsistencies and contradictions that appear to exist in the literature with respect to the role of environmental and lifestyle factors in genesis of breast cancer, several factors have been identified that are likely to have a major effect on breast cancer risk. Radiation exposure has been a well-defined environmental factor for breast cancer, especially at young ages. The environmental hazard chemicals and electromagnetic fields exposition are discussed as potential mammary carcinogens, but association between those environmental causes and breast cancer risk was not confirmed.

Obesity in postmenopausal women and sedentary lifestyle increase the risk of breast cancer. Moderate to high levels of the alcohol consumption, current oral contraceptive use, especially by young women, and prolonged use of hormone replacement therapy causes a moderate increase in the risk of breast cancer.


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New Targets, New Agents, and the Evolving Phenomena of Drug Resistance in Cancer
Shi-Ping Luh and Moulay A. Alaoui-Jamali

Drug resistance is the most common cause of relapses and represents a major limitation for successful management of advanced cancers. Patients with relapse often experience an aggressive progression of the disease. The use of conventional chemotherapy drug combinations remains of limited success given the common occurrence of a broad cross-resistance toward structurally and functionally unrelated drugs. Initial optimism surrounding modulation of single cellular drug resistance markers identified in preclinical models has resulted in very limited predictive and clinical benefit primarily because of alternative mechanisms that operate in drug resistant cancer cells. Even modulators can become entangled in the same problems that they were intended to solve, namely cell resistance to the modulator itself.

The recent shift in the use of targeted agents, particularly those targeting tyrosine kinase receptors and signaling components, has provided exciting clinical results. In particular, recent clinical trials have demonstrated the utility of these targets as surrogate markers to guide the selection of patient populations susceptible to respond to treatment. Yet, these optimisms are tempered in part because resistance to targeted therapies is now documented to occur in experimental models and in the clinic. This review interface mechanisms of drug resistance to targeted therapies versus non-specific chemotherapy, with emphasis on fundamental challenges to be resolved to improve the therapeutic management of refractory cancers.


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YB-1 Activities in Oncogenesis: Transcription and Translation
Andreas G. Bader

The Y box-binding protein 1 (YB-1) is a multifunctional DNA/RNA-binding protein regulating transcriptional and translational processes. Emerging evidence suggests a role for YB-1 in malignant human disease. Protein expression levels of YB-1 are increased in numerous human cancers, and nuclear YB-1 correlates with poor prognosis of tumor patients. However, YB-1 has also anti-oncogenic activities and interferes with phosphoinositide 3-kinase dependent cellular transformation. The anti-oncogenic activity correlates with cytoplasmic localization and with inhibition of protein synthesis. This review seeks to highlight the transcriptional and translational functions of YB-1 and its role in oncogenesis.


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HCV-Related Transformation and New Therapeutic Strategies: An Update
Clara Balsano and Anna Alisi

The hepatitis C virus (HCV) is a single-stranded enveloped RNA virus, belonging to the Hepacivirus genus within the Flaviviridae family. HCV infection has become a major worldwide health problem because it causes a chronic hepatitis leading to hepatocarcinoma (HCC) and to non-Hodgkin’s B-cell lymphoma (NHL). The absence of a reliable experimental model, which mimics the physiological effect of HCV infection in human subjects, hampered the analysis of the mechanisms by which HCV leads to cancer. Nevertheless, both in vitro expression systems and in vivo transgenic mice studies suggest that HCV persistent infection in the host is able to induce neoplastic transformation. The oncogenic properties of HCV are often related to the ability of HCV-encoded proteins to interfere with cell signaling through the interaction with different molecules involved in the control of cell proliferation, apoptosis and interferon (IFN)-signaling pathways. The present systematic review will mainly focus on the HCV proteins dependent pathogenetic effects on the most important regulatory proteins of cell homeostasis. Since poor efficacy of the current therapy, studying the mechanisms underlying HCV-induced cell transformation and immune evasion will help researchers to identify new therapeutic targets, which may be useful in the near future to develop more effective and better-tolerated therapies, capable of impairing or reversing the progression of HCV-related tumors.


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STAT Inhibition in the Treatment of Cancer: Transcription Factors as Targets for Molecular Therapy
David A. Frank

The ability to inhibit kinases such as Bcr-Abl, Her2, Flt3, and the epidermal growth factor receptor has ushered in a new generation of targeted therapies, based on the unique molecular abnormalities present in tumor cells. However, activation of most of these kinases is found in only a small fraction of tumors. In most cancers, a variety of kinases may become activated, but the malignant phenotype of a cell is driven through the downstream activation of a relatively small number of transcription factors. One family of transcription factors found to be activated in a wide spectrum of human cancers is the signal transducers and activators of transcription, or STATs. In tumor systems, STAT inhibition has been shown to decrease cellular proliferation and lower the threshold for apoptosis. By contrast, inhibition of STATs in normal tissue is generally well tolerated, presumably due to the presence of complementary or redundant signaling pathways. With increased knowledge regarding the molecular steps in the activation of STATs and other transcription factors, very specific inhibitors can be designed and synthesized. Hence, either alone or in combination with targeted or cytotoxic therapies, inhibition of STATs and other transcription factors may be a powerful new approach towards cancer therapy.


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Free Flap Head and Neck Reconstruction After Cancer Therapy: Current State of the Art
Efstathios G. Lykoudis, Marios G. Salmas and Dimitrios A. Assimakopoulos

Surgical treatment of head and neck cancer, in certain cases, inflicts large tissue defects. Some of these defects are associated with devastating functional deficits and disfiguring deformities. In addition, radiation therapy, whenever necessary, often leads to wound breakdown, dehiscence and fistula formation, due to healing mechanism impairment.

The advent, development, and nowadays routine use of microsurgical techniques has revolutionized the reconstructive approach in this patient population and changed the outcomes dramatically. Free flap use has both ensured the best possible function and aesthetics and become the “gold standard” in complex head and neck reconstruction.

Defects of the head and neck can be anatomically grouped into the following categories: a. Skull base, b. Midface, c. Tongue, d. Oral cavity, e. Mandible and f. Hypopharynx, larynx and cervical esophagus. Certain reconstructive goals should be met for each of these categories.

Objectives of this article are threefold. First, to report the reconstructive goals in patients with head and neck cancer, second, to outline the indications of free flap use for each category of head and neck defects due to cancer therapy, and third to review in detail the free flap reconstructive options with respect to functional and aesthetic restoration for each kind of defect, according to the recent international literature.


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Tumor Control by Manipulation of the Human Anti-Apoptotic Survivin Gene
Zakir Khan, Pratiksha Bhadouria, Radha Gupta and Prakash S. Bisen

Survivin is a relatively unique member of the inhibitor of apoptosis protein (IAP) family. It contains a single baculovirus IAP repeat (BIR) domain. It is involved in the control of cell cycle and inhibition of apoptosis. Survivin is of interest because it is specifically up-regulated in cancer cells and completely down-regulated and undetectable in normal adult tissues. Thus, survivin has proved to be a promising therapeutic target for normal anti-cancer therapy. Survivin protects the fast dividing tumor cells against default apoptosis to facilitate aberrant mitosis. Down-regulation of survivin with multiple approaches, suppress tumor progression and induce apoptosis on its own or in combination with chemotherapy and radiotherapy.


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Recent Clinical Trials in Non-Small Cell Lung Cancer
Suresh Ramalingam and Chandra P. Belani

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related mortality worldwide. Considerable progress has been made in recent times that have led to improved outcome for patients with all stages of NSCLC. There is increasing evidence that systemic therapy is integral for the treatment of all stages of NSCLC. Adjuvant chemotherapy has been proven in multiple recent trials to improve survival for patients with surgically resected early stage NSCLC. A combined modality approach consisting of external beam radiation and systemic chemotherapy is regarded as the standard of care for patients with locally advanced, unresectable NSCLC (LA-NSCLC), where it has curative potential. However, for patients with advanced stage or metastatic disease, treatment continues to be palliative, though benefits in survival and quality of life have been established with systemic therapy. While platinum combinations continue to be central to therapy of NSCLC, non-platinum two-drug regimens utilizing novel agents such as the taxanes, gemcitabine, pemetrexed and irinotecan are also in clinical use. The emergence of molecularly targeted agents has also widened the therapeutic arena for NSCLC. Survival benefit has been noted with erlotinib, an inhibitor of the epidermal growth factor receptor, for patients who progressed following 1 or 2 prior chemotherapy regimens. Another targeted approach that has recently emerged as a front-runner is anti-angiogenic therapy. Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), improved survival when combined with chemotherapy for patients with advanced stage non-squamous NSCLC. These exciting developments have contributed to optimism for NSCLC patients and also fuelled enthusiasm among researchers. This article reviews the pivotal clinical trials that have led to important changes in the treatment paradigms for NSCLC in recent years.