Current Cancer Drug Targets

ISSN: 1568-0096

Current Cancer Drug Targets
Volume 6, Number 4, June 2006

Contents


Targeted Therapies in Non-Small Cell Lung Cancer: Proven Concepts and Unfulfilled Promises Pp. 271-294
Jutta Auberger, Judith Loeffler-Ragg, Walter Wurzer and Wolfgang Hilbe
[Abstract]


Regulation of Multidrug Resistance by Pro- Inflammatory Cytokines Pp. 295-311
Emmanuel A. Ho and Micheline Piquette-Miller
[Abstract]


NOTCH Signaling as a Novel Cancer Therapeutic Target Pp. 313-323
L. Miele, H. Miao and B.J. Nickoloff
[Abstract]


The Use of Thalidomide in Myeloma Therapy as an Effective Anticancer Drug Pp. 325-331
Daniel M.-Y. Sze, Ross Brown, Shihong Yang, P. Joy Ho,John Gibson and Douglas Joshua
[Abstract]


Targeted Therapies in Gynecologic Cancers Pp. 333-363
Hye Sook Chon, Wei Hu and John J. Kavanagh
[Abstract]




Abstracts


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Targeted Therapies in Non-Small Cell Lung Cancer: Proven Concepts and Unfulfilled Promises
Jutta Auberger, Judith Loeffler-Ragg, Walter Wurzer and Wolfgang Hilbe

Targeted therapies focus on signaling pathways in cancer cells and other molecular processes involved in oncogenesis. Recent approaches affect the following major groups: the epidermal growth factor receptor (EGFR)-family, angiogenesis, the eicosanoid pathway, the PKC/ Ras/ MAPK pathway, the proteasome and inducers of apoptosis. Numerous phase I and II trials have provided promising results and recently, anti-EGFR and anti-VEGF treatments have proven their efficacy in phase III trials. However, others failed in phase III settings (e.g. PKC- and matrix metalloproteinase inhibitors) and it is a moot point, whether patients have been selected properly. The huge amount of new medications raises questions like when to use which strategy in which sequence. The successful implementation of targeted agents into clinical routine will depend on the verification of sufficient predictive markers, allowing their economically reasonable usage. In the current review the up-to-date knowledge concerning targeted therapies in NSCLC is summarized and their therapeutical potential is discussed.


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Regulation of Multidrug Resistance by Pro- Inflammatory Cytokines
Emmanuel A. Ho and Micheline Piquette-Miller

Various mechanisms have been implicated in the development of resistance of cancer cells to chemotherapy. Multidrug resistance (MDR) is a phenomenon in which cancer cells are resistant to the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents. One major mechanism by which this occurs is through the over-expression of ATP-dependent drug efflux transporters such as the P-glycoprotein (PGP) and multidrug resistance-associated protein (MRP). Regulation of MDR can occur at many levels including transcriptional, mRNA, protein and post-translational.

In recent years it has been demonstrated that alterations in the expression and activity of the MDR transporters are seen in numerous tissues during an inflammatory response. An acute inflammatory response is associated with many conditions including infection, injury, hypoxia and stress and is known to result in the induction of several pro-inflammatory cytokines. Whether the function of cytokines can be harnessed in overcoming drug resistance of tumors has yet to be examined and explored.

In this review, we will focus on the various studies investigating the regulation of MDR during an inflammatory response, in particular by cytokines. The mediators and pathways involved as well as the possible mechanisms of MDR regulation will be discussed. It is hoped that by understanding the clinical importance of inflammatory mediators in MDR, new doors will open and future insights will lead to the development of novel immunotherapeutics for the treatment of cancer.


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NOTCH Signaling as a Novel Cancer Therapeutic Target
L. Miele, H. Miao and B.J. Nickoloff

NOTCH-ligand interaction is a highly conserved mechanism that regulates specific cell fate decision during development. In addition to its functions in developmental and cell maturation processes, studies indicate that NOTCH activation plays a role in the onset and progression of many human malignancies.

The prevailing new strategy for rationally targeted cancer treatment is aimed at the development of target-selective “smart” drugs on the basis of characterized mechanisms of action. The connection between NOTCH signaling and tumorigenesis suggests that NOTCH may be such a target candidate.

Gamma-secretase is a large membrane-integral multisubunit protease complex, which is essential for NOTCH receptor activation. Inhibitors of this enzyme are being developed for Alzheimer’s disease, due to its role in cleaving beta-amyloid precursor in the brain. Recently, Gamma-secretase inhibitors (GSIs), as well as various biopharmaceutical or genetic NOTCH signaling inhibitors have been suggested as potential novel cancer therapeutic strategies.

This review summarizes the evidence linking NOTCH signaling to several types of cancer, as well as the possible therapeutic indications of NOTCH inhibitors and the challenges facing their clinical development.


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The Use of Thalidomide in Myeloma Therapy as an Effective Anticancer Drug
Daniel M.-Y. Sze, Ross Brown, Shihong Yang, P. Joy Ho,John Gibson and Douglas Joshua

Thalidomide and its immunomodulatory derivatives have provided the most significant advance in the therapy of myeloma since the introduction of high dose chemotherapy followed by stem cell transplantation nearly 20 years ago. The mechanism of action of thalidomide is complex and involves many aspects of malignant plasma cell growth and bone marrow stromal cell microenvironment interaction. Thalidomide was first used because of its anti-angiogenic properties, however it is the immunomodulatory actions that involve increasing host tumour-specific immunosurveillance by both T cell and natural killer cells which may be the most important mode of action.


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Targeted Therapies in Gynecologic Cancers
Hye Sook Chon, Wei Hu and John J. Kavanagh

With the rapid development of high-throughput techniques for identifying novel specific molecular targets in human cancer over the past few years, attention to targeted cancer therapy has dramatically increased. The term “targeted cancer therapy” refers to a new generation of drugs designed to interfere with a specific molecular target that is believed to play a critical role in tumor growth or progression, is not expressed significantly in normal cells, and is correlated with clinical outcome. There has been a rapid increase in the identification of targets that have potential therapeutic application. The clinical success of the small-molecule kinase inhibitor imatinib mesylate in chronic myeloid leukemia and gastrointestinal stromal tumors has accelerated the development of a new era of molecular targeted cancer therapy. The number of agents under preclinical and clinical investigation has grown accordingly. This emphasis on molecular biology and genetics has also resulted in significant changes in the treatment of gynecologic cancers. Several promising drugs targeting tyrosine kinases (EGFR and Her-2/Neu), mTOR, Raf kinase, proteasome, and histone deacetylases, as well as drugs affecting apoptosis and mitosis, are under development for clinical application. However, some clinical trials of p53 gene therapies and farnesyl transferase inhibitors have had limited success. In this review, we will focus on potential novel targets in gynecologic cancer and the development of targeted therapy and its clinical applications in gynecologic cancer.