Anti-Cancer Agents in Medicinal Chemistry

(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')

ISSN: 1871-5206

Anti-Cancer Agents in Medicinal Chemistry
Volume 8, Number 5, June 2008

Contents

Tyrosine Kinase Inhibitors in Cancer Therapy
Guest Editor: S. Eckhardt


Editorial Pp. 461


Antiangiogenic Drugs and Tyrosine Kinases Pp. 462-469
J. Tímár and B. Döme
[Abstract]


Novel Molecular-Targeted Therapeutics for the Treatment of Cancer Pp. 470-480
H. Yasui and K. Imai
[Abstract]


Inhibition of Receptor Tyrosine Kinases in Combination with Chemotherapy for the Treatment of Breast Cancer Pp. 481-487
S.L. Moulder, B.S. Craft and G.N. Hortobagyi
[Abstract]


HER-2 Positive Breast Cancer: What Else Beyond Trastuzumab Based Therapy? Pp. 488-496
C. Widakowich, P. Dinh, E. de Azambuja, A. Awada and M. Piccart Gebhart
[Abstract]


General Articles


New Trends in Molecular Imaging of Tumor Angiogenesis Pp. 497-522
T. Berthelot, M.-C. Lasne and G. Déléris
[Abstract]


Monoclonal Antibodies in Clinical Oncology Pp. 523-532
S. Dalle, C. Thieblemont, L. Thomas and C. Dumontet
[Abstract]


Targeting Inhibitor of Apoptosis Proteins (IAPs) for Cancer Therapy Pp. 533-539
S. Fulda
[Abstract]


Bile Acids and Derivatives, Their Nuclear Receptors FXR, PXR and Ligands: Role in Health and Disease and Their Therapeutic Potential Pp. 540-563
A. Zimber and C. Gespach
[Abstract]


p53 Targeting Can Enhance Cancer Therapy via Radiation, Heat and Anti-Cancer Agents Pp. 564-570
T. Ohnishi, A. Takahashi, E. Mori and K. Ohnishi
[Abstract]


Hyperthermia Associated Osteonecrosis in Young Patients with Pelvic Malignancies Pp. 571-575
M. Jäger, S. Balzer, R. Wessalowski, J. Schaper, U. Göbel, X. Li and R. Krauspe
[Abstract]




Abstracts


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Editorial

The revolutionary discovery of the human genom opened novel approaches for understanding the malignant process. It is now generally accepted, that the neoplastic tissue is the result of a multistep genetic event induced by inherited and environmental factors. Each tumor cell is characterized by specific mutations. These genetic alterations are promising targets for inhibitory substances. Thus, such agents may be useful in cancer therapy.

The primary task of this scientific journal is to inform the scientific community involved in cancer research on the most recent developments in the synthesis and availability of these targeted compounds, including preclinical findings. It is hard to follow the myriads of these agents derived from chemical libraries by robotical means. Day by day, new target mutations are published which might be candidate molecules for therapy. However, the additional task of our journal is also to choose “hot topics” discussing agents which are in the focus of research interest due to their exceptional antitumor potency.

One such example is the group of tyrosine kinase inhibitors (TKI-s). In the last decade these agents were gradually introduced into the treatment strategy of malignancies. By now, for some of these compounds (e.g. trastuzumab, imatinib, rituximab) sufficient amount of data were compiled to learn that after a drug sensitive period tumor cells are capable to produce resistance by various genetic mechanisms. In the same time new molecular techniques were introduced into the clinical practice, the aid of which one might predict the favourable effect of a potential drug. Some new questions also emerged like the possible interactions between TKI-s and other targeted agents or standard chemotherapy. A special adverse reaction profile of these enzyme inhibitors necessitated also intensive research. Furthermore, the rationale to use multitargeted vs. single agents needs detailed explanation as well.

Consequently, a new generation of TKI-s arose in order to overcome the major difficulties listed above. Therefore this “hot topic issue” wants to inform the reader not only on the “old” but also on the “novel” compounds and to offer an overview of their actual state of development in the clinic. No doubt, that in the age of “translational research” such a survey is urgently needed especially for those, who are designing and producing effective anticancer drugs.

In this issue four internationally recognized research groups are contributing to the present day TKI research.

The authors of the first paper are J.Timár with B.Döme. Both are pathologists working at the National Institute of Oncology (NIO), Hungary, and the National Korányi Lung Institute , Budapest. Professor Timár is Head of the Tumor Progression Unit at the NIO and Editor of the prestigious “Pathology, Oncology , Research” journal. B .Döme is Assistant Professor working in the field of molecular genetics. Their views are focusing on the complex mechanisms existing between the metastasis formation and the TKI-s.The title of their paper is “Angiogenetic Drugs and Tyrosine Kinases”.

The second paper was written by H. Yasui and K. Imai, who are working at the Sapporo Medical University (Japan). They are active both experimentally as well as clinically. Moreover, Professor Imai is author of an excellent overview on molecular targeted cancer therapy which was published 2006 in a very respected medical journal. Both authors took the responsibility to prepare an enlarged survey for this journal. Accordingly, they classified the most recent agents into three categories: molecules active on the cell surface, those inhibiting signaling pathways and compounds targeting cell survival. The title of their paper is “Novel Molecular Targeted Therapeutics for the Treatment of Cancer”.

The third paper is the product of S.I.Moulder, B.S.Craft and G.N.Hortobagyi from the M.D.Anderson Cancer Center, University of Texas. It reflects also the view of the Phase I Program of the Department of Breast Medical Oncology. Since breast cancer is one of the major killers throughout the world, its therapy deserves special attention. The group of authors consists of worldwide wellknown research leaders whose findings are pioneering in breast cancer drug research. In their article – after a short discussion of the results so far achieved – they are presenting here the new molecular targeted agents which may improve breast cancer prognosis. Besides, special emphasis was put for the use of a combination of “old” and “novel” therapeutic regimens. The title of their paper is “Inhibition of Receptor Tyrosine Kinases in Combination with Chemotherapy for the Treatment of Breast Cancer”.

The fourth paper originated from the Institut Jules Bordet and the Université Libre de Bruxelles by C.Widakowich, P.Dinh, E.Azambuja, A.Awada, M.Piccart-Gebhart. While the previous article represents a survey including data recognized by the ASCO (American Society of Cliinical Oncology), this publication presents current strategies for the treatment of HER 2 positive patients “with particular focus on new TKI-s”. These findings and views are supported by the ESMO (European Society of Clinical Oncology), since breast cancer research is also in the forefront of this continent. As a result of this common US-EUROPE effort a major breakthrough might be expected in the therapy of breast cancer. The title of the paper is “What else beyond trastuzumab –based therapy?”

The author of these introductory remarks strongly hopes that all four articles will enlarge the horizon of the readers of this journal.


S. Eckhardt
Director Emeritus of the National Institute of Oncology
1122 Budapest, Ráth Gy. u. 7/9
Hungary
Tel: (36-1) 224-8751
Fax: (36-1) 224-8741
E-mail: eckhardt@oncol.hu


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Antiangiogenic Drugs and Tyrosine Kinases
J. Tímár and B. Döme

Various cancer types have different molecular and biological strategies for vascularization: neoangiogenesis, postnatal vasculogenesis, glomeruloid angiogenesis, intussusceptive microvascular growth, vessel cooption and vascular mimicry. The majority is still relatively obscure, which limits the development of more successful antivascular agents. It is not a surprise that, as our knowledge is deepest in case of tumor-induced neoangiogenesis, the first successful antiangiogenic drugs have been developed in this area. As neoangiogenesis involves growth factor receptors, most of them tyrosine kinases (KIT, Flt-3, VEGFRs, PDGFR, TIE2, FGFR1, EGFR and MET), several of these novel agents are tyrosine kinase inhibitors. This review summarizes our recent knowledge on various forms of cancer vascularization, the molecular mechanisms behind, depicting the “drugable” targets. In a short overview, we demonstrate the array of antiangiogenic approaches focusing on the tyrosine kinase inhibitors and summarize their preclinical activities. Finally we review the clinically available antiangiogenic tyrosine kinase inhibitors and demonstrate their current application and future perspectives. Further development in this field may depend on the identification of novel inhibitors targeting kinases that cannot be modulated yet by the available agents and on the development of vascularization strategy-specific design of these antivascular therapies.


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Novel Molecular-Targeted Therapeutics for the Treatment of Cancer
H. Yasui and K. Imai

Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in cancer, particularly the receptor tyrosine kinases, the intracellular pathways, and the genetic and epigenetic alterations, resulting in an unprecedented surge of novel, targeted therapies and therapeutic regimens. There are currently over 30 new agents being tested in the treatment of solid tumors as well as hematologic malignancies. Many of these are novel, targeted agents that have demonstrated significant efficacy and prolonged survival. Here, we discuss the current understanding of the mechanisms of action of novel molecular targeted cancer therapies being tested in the preclinical and clinical settings, including agents that act directly on the cell surface receptors, intracellular signaling pathways, and cell maintenance processes.


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Inhibition of Receptor Tyrosine Kinases in Combination with Chemotherapy for the Treatment of Breast Cancer
S.L. Moulder, B.S. Craft and G.N. Hortobagyi

Although significant advances have been made in the treatment of breast cancer using chemotherapy, less than half of the patients treated for localized breast cancer benefit from adjuvant chemotherapy and most patients with metastatic cancer eventually develop disease that is chemotherapy resistant. Targeted agents, such as inhibitors of tyrosine kinases, offer the opportunity to reverse chemotherapy resistance and enhance response in patients with localized and advanced breast cancer. Such combined approaches have been established for the treatment of advanced breast cancer and are now demonstrating benefit in the adjuvant arena. This review summarizes the results of several trials involving the use of tyrosine kinase inhibition in combination with chemotherapy for the treatment of breast cancer and discusses future directions for breast cancer biotherapy.


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HER-2 Positive Breast Cancer: What Else Beyond Trastuzumab-Based Therapy?
C. Widakowich, P. Dinh, E. de Azambuja, A. Awada and M. Piccart-Gebhart

HER-2 is a tyrosine kinase receptor which is overexpressed in 20-25% of breast cancer patients and is associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody directed against the HER-2 receptor, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in metastatic patients, as well as halving the recurrence rate and improving survival in early breast cancer.

Even with these impressive results, the reality is that not all patients will benefit form this therapy, and in those who do, resistance to trastuzumab can often develop within 1 year of treatment initiation.

Beyond trastuzumab therapy, a “second wave” of monoclonal antibodies and tyrosine kinase inhibitors has emerged. These drugs have variable properties including: 1) dual inhibition against EGFR and HER-2, such as lapatinib, HKI-272 and pertuzumab; 2) anti-angiogenesis such as bevacizumab and pazopanib; 3) anti-mTOR action such as Temsirolimus; and 4) anti-Hsp90 such as 17-AAG. When used in combination with trastuzumab, or with cytotoxic chemotherapy, or as single agents, these new anti-HER-2 strategies bear the potential of arresting the tumorigenesis process.

In this article, we present the current strategies in the treatment of breast cancer patients who overexpress HER-2, with particular focus on new tyrosine kinase inhibitors that can be used in combination with or after trastuzumab therapy.


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New Trends in Molecular Imaging of Tumor Angiogenesis
T. Berthelot, M.-C. Lasne and G. Déléris

Tumor development leading to cancer is a complex process involving several steps. Among them, angiogenesis, ie growth of new tumor induced blood vessels is one of the most important therapeutic targets in the search for anticancer agents. One point which remain to be addressed is the detection of tumor angiogenic areas, ie tumor angiogenesis imaging. After presenting the key points of tumor development which lead to neoangiogenesis, and providing an overview of the main therapeutic approaches in this field, this review focusses on the recent progress in angiogenesis imaging, namely the one dealing with matrix metalloproteases. These enzymes are indeed present to major phenomena of the tumor progression. The different imaging approaches are described, namely the ones using optical, radiochemical or magnetic resonance ones.


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Monoclonal Antibodies in Clinical Oncology
S. Dalle, C. Thieblemont, L. Thomas and C. Dumontet

Monoclonal antibodies have yet considerably modified the field of clinical oncology. The growing knowledge of key cellular pathways in tumor induction and progression, targeted therapies represent an increasing proportion of new drugs entering clinical trials. Some molecules such as trastuzumab, rituximab, alemtuzumab, cetuximab are now widely used in clinical practice. These antibodies are now tested in different indications alone or in combination with standard chemotherapy. They are also developed for the treatment of inflammatory diseases (rituximab). Numerous others antibodies are currently in pre-clinical and clinical development phases for several malignancies including renal carcinoma, melanoma, lymphomas, leukaemia, breast, ovarian and colorectal cancer. An alternative approach is to conjugate the monoclonal antibody to a toxin, a cytotoxic agent, or a radioisotope. In other cases these antibodies aim to modify the tumour microenvironnement through inhibition of angiogenesis or enhancing host immune response against cancer. If the molecule targeted by the antibodies is clearly identified, most often the precise mechanism of action of these immunoglobulins is not fully understood.They can have direct effects in inducing apoptosis or programmed cell death. They can block growth factor receptors, efficiently arresting proliferation of tumor cells. Indirect effects include recruiting cells that exert cytotoxicity, such as monocytes and macrophages (ADCC). Monoclonal antibodies also bind complement, leading to toxicity known as complement dependent cytotoxicity (CDC).The side effects associated with these new treatments were in part foreseeable depending on the affected cell or function. But new or surprising side effects emerged from clinical studies. We present an overview of the monoclonal antibodies used in clinical oncology or currently in development phases. We particularly focus on recent development including new indications, clinical trial results and specific side effects of monoclonal antibodies used in the treatment of cancer.


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Targeting Inhibitor of Apoptosis Proteins (IAPs) for Cancer Therapy
S. Fulda

Since cell death by apoptosis plays a key role in the regulation of tissue homeostasis, dysregulation of the cell’s intrinsic death program may foster tumor formation and progression. „Inhibitor of apoptosis proteins“ (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases. Aberrant expression and/or function of IAPs are found in many human cancers and have been implied in resistance to current treatment approaches. Recent insights into the role of IAPs have provided the basis for various exciting discoveries that aim at modulating expression or function of IAPs. Thus, targeting IAPs, e.g. by antisense approaches or small molecule inhibitors, presents a promising novel approach for future drug development and may proof to be a successful strategy to overcome apoptosis resistance of human cancers.


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Bile Acids and Derivatives, Their Nuclear Receptors FXR, PXR and Ligands: Role in Health and Disease and Their Therapeutic Potential
A. Zimber and C. Gespach

Bile acids, their physiology and metabolism, their role in carcinogenesis and other major human diseases are recently undergoing significant progress. Starting in 1999 when the orphan nuclear receptor FXR was shown to be specifically activated by bile acids, these compounds became part of the arsenal of ligands of the steriod hormone superfamily of nuclear receptors, including receptors of Vitamin D3, retinoids (RAR, RXR), and thyroid hormone. Another decisive discovery pointed later that the pregnane X-receptor (PXR) is activated by the endogenous toxic lithocholic acid, as well as several xenobiotics and drugs. Bile acids have recently emerged as key regulators of their own metabolism, and of lipid and carbohydrate metabolism. They have important role as promoters of esophageal and colon cancers, cholangiocarcinoma, as well as new implications in breast cancer development and metastasis. This Review will emphasize novel aspects of bile acids, FXR and PXR as regulators of interfaces at cell proliferation and differentiation, cell death, survival, invasion, and metastasis during normal development and cancer progression. Signaling pathways controlled by bile acids will be presented and discussed in relation to their impact on gene expression. The biological and pharmacological significance of bile acids and their recently developed synthetic derivatives and conjugates, as well as new development in the design of FXR agonists and antagonists for clinical applications in cancer prevention and therapy, will be evaluated. This part includes advances in the utilization of bile acid transporters in drug resistance, therapeutic targeting and delivery of anticancer drugs, as well as therapeutic combinations using new bile acid derivatives, sequestrating agents and reabsorption inhibitors, and their limitations.


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p53 Targeting Can Enhance Cancer Therapy via Radiation, Heat and Anti-Cancer Agents
T. Ohnishi, A. Takahashi, E. Mori and K. Ohnishi

In recent years, genes associated with cancer have been studied to assess their possible use as predictive indicators for cancer therapies. Among these, the gene product of the tumor suppressor gene p53 was found to play an important role in cancer therapy. The p53 molecule induces cell-cycle arrest, apoptosis and DNA repair after cells are subjected to cancer therapies involving radiation, heat and various anti-cancer agents. Mutations in p53 are observed at a high frequency in human tumors, and are present in about half of all malignant tumors in humans. Sensitization to radiation, heat and anti-cancer agents was observed in cells containing wild type p53, but not in cells containing mutated p53. This review discusses p53 activation of signaling pathways after exposure to cancer therapies which target p53; such therapies include chemical chaperones, the p53 gene, p53-C terminal peptides, and p53-targeting agents which enhance p53-central signal transduction pathways.


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Hyperthermia Associated Osteonecrosis in Young Patients with Pelvic Malignancies
M. Jäger, S. Balzer, R. Wessalowski, J. Schaper, U. Göbel, X. Li and R. Krauspe

Introduction: Progressive and non-juvenile avascular osteonecrosis (AVN) is a rare condition in children. During the last dec-ade, some data indicate that regional deep hyperthermia therapy (RHT) combined with either chemo- and / or radiotherapy in malignancies is associated with AVN in young patients. In this study, we present our data on AVN following RHT in children with intra-pelvic malignancies.

Material and Methods: Localization, extent of AVN, and associated joint effusions were evaluated via MRI and X-ray findings in 37 patients treated with RHT and chemotherapy ± additional radiotherapy for intra-pelvic malignancies in our study. AVN was classified in accordance to the Association Research Circulation Osseus (ARCO). In addition, the recurrence of sarcoma after RHT, the number of total joint replacements, and level of activity including sport activities were recorded in all patients. The mean follow-up was 6.2 years (SD: 4.1, range: 1-12 years).

Results: Eight out of 37 pediatric patients treated with RHT and chemotherapy ± additional radiotherapy showed AVN of the femoral head within our follow-up period. Five out of the eight children developed bone marrow edema within 6 months after RHT procedure and three additional patients within the first year. All patients except one showed a rapid progression of AVN from ARCO stage 0 to the post-collapse-stages III and IV in our study. Seven out of eight AVN patients survived without evidence of further malignancy. Although advanced stages of AVN were observed in our patient group, they were able to still maintain a high quality of life. No patients in our group have undergone total hip replacement thus far.

Conclusion: Based on our findings, we hypothesize a high risk of AVN in young children who receive RHT for pelvic sarcoma. However, further clinical investigation needs to be done to prove our hypothesis.