Reviews on Recent Clinical Trials

ISSN: 1574-8871

Reviews on Recent Clinical Trials
Volume 2, Number 2, May 2007

Contents

Novel Kinase Inhibitors in Cancer Therapy
Guest Editors: Ezra E.W. Cohen and Nikolai G. Rainov


Editorial Pp. 85-86


Receptor Tyrosine Kinases as Therapeutic Targets in Malignant Glioma Pp. 87-101
H. Ren, B.F. Yang and Nikolai G. Rainov
[Abstract]


Clinical Development of mTOR Inhibitors: A Focus on Lymphoma Pp. 103-110
Sonali M. Smith
[Abstract]


Targeting the Human Epidermal Growth Factor Receptor 2 (HER2) in the Treatment of Breast Cancer: Recent Advances and Future Directions Pp. 111-116
Rita Nanda
[Abstract]


Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: A Review of Recent Clinical Trials Pp. 117-120
Carrie B. Lee and Mark A. Socinski
[Abstract]


Therapeutic Strategies for Targeting BRAF in Human Cancer Pp. 121-134
Christine A. Pratilas and David B. Solit
[Abstract]


Implications of FLT3 Mutations in the Therapy of Acute Myeloid Leukemia Pp. 135-141
Ryan J. Mattison, Kelly R. Ostler, Frederick L. Locke and Lucy A. Godley
[Abstract]


Review of Clinic Trials: Agents Targeting c-Met Pp. 143-147
Oyewale Abidoye, Nadh Murukurthy and Ravi Salgia
[Abstract]


General Article


New Treatment Concepts In Diffuse Large B-Cell Lymphomas (DLBL): Chemotherapy and Biological Therapy Pp. 149-162
Jose Rodriguez and Antonio Gutierrez
[Abstract]




Abstracts


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Editorial

Tyrosine kinases (TK) were first described by Hunter and Cooper in the late 1970s as tyrosine-specific protein kinases encoded by transforming viruses and their normal cellular homologues [1]. Just a few years later it became already known that a number of oncogenes represented TKs [2]. It is now well known that TK are important mediators of the intracellular signaling cascade and play a key role in diverse biological processes such as growth, differentiation, metabolism, and apoptosis in response to external and internal stimuli. Although TK activity is tightly regulated in normal cells, they may acquire transforming functions due to mutations, overexpression, and autocrine or paracrine stimulation, thus leading to development and maintenance of malignancy [3]. The oncogenic activation of TK in cancer cells can be blocked by inhibitors with different molecular structure and specificity. Such inhibitors have been actively developed and tested particularly in the last decade as a promising approach to innovative genome-based cancer therapeutics [4].

The current hot topics issue of RRCT focuses on the biological role TK play in different human malignancies, as well as on different approaches for TK inhibition, such as small molecule inhibitors, monoclonal antibodies, heat shock proteins, and others. Small molecule inhibitors of TK (SMI-TK) are particularly exciting agents and have attracted much attention in the articles in this issue and in the biomedical community in general. Most SMI-TK compete with the ATP binding site of the catalytic domain of several oncogenic TK. They are usually orally bioavailable with a favorable safety profile that can be combined with standard chemotherapy or radiation therapy. Several SMI-TK have been found to have significant antitumor activity and have been approved for clinical use in some tumor entities or are currently in advanced clinical trials for others. Such drugs are imatinib mesylate, gefitinib, erlotinib, lapatinib, canertinib, semaxinib, vatalanib, sorafenib, sunitinib, and leflunomide.

SMI-TK are thus an important and large new class of targeted drugs that interfere with specific cell signaling pathways and allow relative target-specific therapy for TK-driven malignancies. The pharmacological properties and anticancer activities of the most important of these inhibitors are discussed in the present issue, mostly in the context of the particular tumor entities.

The use of TK-targeted therapies is naturally not without limitations. Such are the development of resistance or the lack of tumor response in some types of malignancies. The availability of new generations of molecularly designed SMI-TK and improved patient selection may help overcome some of these problems in the future. The application of modern proteomic techniques and increasing knowledge of the human kinome will aid in speeding up the TK drug discovery process and will allow faster introduction of experimental TK inhibitors to clinical applications.

In the first review article in this issue, Drs. Ren, Yang, and Rainov present the application of TK inhibitors to a specific disease, malignant glioma. With few effective therapeutic options for patients with glioma, this has been an area of active study with respect to novel agents. In fact, the biology of the disease would suggest that targeting specific proteins, such as EGFR, PDGFR, VEGFR, the Ras/Raf/MAP-kinase pathway and the PI3K/Akt/mTOR pathway would be efficacious. It is however evident that the development of these agents in glioma is in its early stages. Some agents have begun to show activity in select patient groups although the molecular heterogeneity of the disease may ultimately limit the universal application of any single agent.

In the second review article, Dr. Smith reviews the mammalian target of rapamycin (mTOR) and highlights its role in the genesis of malignant Non-Hodgkin lymphoma (NHL). MTOR is a central transducer of growth signals in normal and neoplastic cells via translational modulation. Under normal conditions, mTOR utilizes various companion proteins and upstream signals from PI3K/Akt to sense favorable environments for growth and cell cycle progression. Rapamycin is the prototype of all mTOR inhibitors, and works by binding to the 5’ end of the mTOR protein containing the FKBP12-rapamycin-binding domain component. Three mTOR inhibitors (MTI) have progressed through phase I and II clinical trials. These are the rapamycin analogues CCI-779/temsirolimus, RAD001/everolimus, and AP23573. These drugs appear to be well-tolerated and have shown promising activity in NHL. An important area of consideration for these drugs, as with many of the new targeted agents, is to identify patient subpopulations most likely to benefit from mTOR inhibition, and to predict sensitive or resistant phenotypes.

HER2 is not a new target in oncology with the availability of trastuzumab in breast cancer for several years. In the third article in this hot topics issue, Dr. Nanda reviews the data supporting the use of trastuzumab in advanced disease, highlights newer data regarding its use in the adjuvant setting, and discusses newer strategies to target the receptor tyrosine kinase especially in patients whose cancers become trastuzumab resistant.

Inhibition of angiogenesis has been hypothesized as an effective strategy for almost all cancer types. The treatment of non-small cell lung cancer is appreciably changing with recent randomized data demonstrating the efficacy of adding bevacizumab, a vascular endothelial growth factor monoclonal antibody, to cytotoxic chemotherapy. As a broader survey of receptors that influence angiogenesis in non-small cell lung cancer is defined, TK inhibitors have been developed and tested in clinical trials. In fact some have shown single agent activity and at least 4 are being evaluated in phase III clinical trials as discussed by Lee and Socinski.

In the fifth article of the issue, Drs. Pratilas and Solit describe activation of the MAPK pathway as a frequent event in many human cancer types. Activation of MAPK is often the result of mutations in RAS and BRAF. Activation of the MAPK signaling cascade, e.g. by mutated BRAF, eventually activates ERK signaling, induces proliferation and is capable of promoting malignant transformation of cells. The authors review the role of RAF and its paralogues (CRAF, BRAF, A-RAF) in activation of the MAPK/ERK pathway in different human malignancies (renal cell, ovarian, colon, melanoma) and summarize the results of therapeutic strategies targeted to different key TK in the pathway. Given the frequency of mutations in TK in the MAPK pathway in human malignancies, inhibitors of this pathway may find broad applicability in cancer patients, either alone or in combination with standard treatments.

Drs. Mattison, Ostler, Locke, and Godley discuss in their review FMS-like tyrosine kinase 3 (FLT3) in the context of acute myeloid leukemia (AML). FLT3 is a receptor TK that is expressed on the surface of hematopoietic stem cells and plays an important role in normal hematopoiesis. FLT3 is mutated in a significant percentage of AML with normal karyotype and correlates with poorer outcome in such cases. A number of FLT3 inhibitors capable of targeting additional RTKs (e.g. KIT, PDGFR, VEGF), such as PKC412, CEP-701/lestaurtinib, MLN518, SU5416, and SU11248/sunitinib are currently in the various stages of clinical testing. These drugs have been generally well tolerated and patients have achieved a clinical response when adequate levels of FLT3 inhibition have occurred in vivo. However, the clinical responses have usually been of limited durability and represented clearance of peripheral blasts only, while significant disease remained in the bone marrow. The authors compare the relatively low efficacy of the above FLT3 inhibitors in AML with the success of imatinib and other BCR-ABL inhibitors in CML and explain that AML is caused by several cumulative molecular abnormalities, only one of which includes FLT3 mutations, while in contrast chronic phase CML is caused solely by the BCR-ABL fusion gene.

In the final article of this hot topic issue, Drs. Abidoye, Murukurthy, and Salgia discuss c-Met biology and development of agents targeting this kinase. It is apparent that the protein is aberrantly expressed or mutated in several cancers forming the rationale for its inhibition. There are several agents in early stage clinical trials including small molecules, with variable specificity, and monoclonal antibodies. Thus far, preliminary data suggests that these agents are well tolerated at the doses administered and phase II trials should be initiated within the calendar year.

The current hot topic issue of RRCT contains an exciting wealth of information on the role of TK in the most clinically relevant types of human cancer. Preclinical and clinical developments of TK-targeted therapeutics are reviewed and discussed in the context of the cancers and patient subpopulations targeted by the respective drugs. These reviews represent a new era of oncology drug development with the hope of increased benefit to patients. This comes with several challenges as we move forward, including selecting appropriate patients for specific therapies, defining biologically effective doses, and managing toxicities that can be greatly disparate from current chemotherapy.

We would like to thank all the authors for their contributions and hope that the present hot topic issue of RRCT will stimulate new communications and collaborations between the scientific and clinical communities.

References
[1] Cooper JA, Hunter T. Changes in protein phosphorylation in Rous sarcoma virus-transformed chicken embryo cells. Mol Cell Biol 1981; 1(2): 165-78.
[2] Hunter T, Cooper JA. Protein-tyrosine kinases. Annu Rev Biochem 1985; 54: 897-930.
[3] Lengyel E, Sawada K, Salgia R. Tyrosine kinase mutations in human cancer. Curr Mol Med 2007; 7(1): 77-84.
[4] Fabbro D, Ruetz S, Buchdunger E, et al. Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther 2002; 93(2-3): 79-98.


Nikolai G. Rainov, MD DSc FRCSEd
Department of Neurosurgery
Klinikum Augsburg
D-86156 Augsburg
Germany
and
Department of Neurosurgery
Martin-Luther-University Halle-Wittenberg
D-06097 Halle, Germany
nikolai.rainov@medizin.uni-halle.de


Ezra E.W. Cohen
Department of Medicine Section of Hematology Oncology
The University of Chicago
IL 60637-1470 Chicago
USA
ecohen@medicine.bsd.uchicago.edu


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Receptor Tyrosine Kinases as Therapeutic Targets in Malignant Glioma
H. Ren, B.F. Yang and Nikolai G. Rainov

Malignant gliomas have retained their dismal prognosis despite aggressive multimodal conventional therapeutic approaches, illustrating the need for novel therapeutic strategies. Recent advances in the cellular and molecular biology of gliomas have enhanced our understanding of the role of receptor tyrosine kinases (RTK) and RTK-mediated signal transduction pathways in tumor initiation, maintenance, angiogenesis, and vascular proliferation. Special attention has been focused on targets such as epidermal growth factor receptors (EGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptors (VEGFR), and on pathways such as the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs known as small molecule inhibitors have been shown to modify the activity of these receptors and signaling pathways. Thus far, however, small molecule RTK inhibitor development has concentrated on a few RTK only, and drug activity has been comprehensively evaluated only in a limited number of different malignancies. One of the limiting factors for novel drug design and development is the incomplete knowledge of RTK functions in malignant glioma. This review summarizes current basic and clinical knowledge on the role of RTK in malignant glioma and on their importance as targets for new forms of therapy.


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Clinical Development of mTOR Inhibitors: A Focus on Lymphoma
Sonali M. Smith

The mammalian target of rapamycin (mTOR) kinase is positioned at the juncture of several pathways regulating cell growth and proliferation. It is the downstream effector of the oncogenic PI3K/Akt pathway and is a key regulator of translational initiation. Accumulating data support mTOR’s role in lymphomagenesis, and its inhibition in preclinical models leads to lymphoma regression. The rationale for testing mTOR inhibitors in patients with lymphoma is evident, and early clinical data is promising. Along with the prototype of mTOR inhibitors, rapamycin, there are three mTOR inhibitors furthest along in development: temsirolimus, everolimus, and AP23573. These agents are emerging as well-tolerated drugs with encouraging preliminary activity. Here we review the rationale for testing mTOR inhibitors in lymphoma, the phase 1 trials influencing dose and schedule of mTOR inhibitors, and summarize the clinical results in obtained to date in patients with lymphoma.


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Targeting the Human Epidermal Growth Factor Receptor 2 (HER2) in the Treatment of Breast Cancer: Recent Advances and Future Directions
Rita Nanda

The HER2/neu (HER2) gene is a member of a family of genes which has been implicated in cancer. These four genes, HER1/EGFR, HER2, HER3 and HER4 encode for transmembrane proteins that are involved in the regulation of cell proliferation, differentiation and survival. Amplification of HER2 occurs in 20%-25% of breast cancers and is associated with an aggressive tumor phenotype and poor prognosis. Results from five randomized, phase III clinical trials have recently demonstrated that trastuzumab (Herceptin^®) significantly improves disease free survival and overall survival when used in conjunction with chemotherapy for early stage HER2-positive breast cancer. Despite adjuvant trastuzumab, approximately 15% of patients with early stage disease recur, and those with metastatic disease eventually become resistant to therapy. Novel treatment approaches are needed for patients who have either intrinsic or acquired resistance to trastuzumab. This article reviews the role of trastuzumab in managing early and advanced stage HER2-positive disease, the role of lapatinib (Tykerb^®) in trastuzumab resistant disease, and the novel agents in development targeting mechanisms of trastuzumab resistance.


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Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: A Review of Recent Clinical Trials
Carrie B. Lee and Mark A. Socinski

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States. Therapeutic agents that target the underlying biology of this disease are necessary to improve outcomes. Angiogenesis plays a central role in NSCLC tumor growth and metastases. The vascular endothelial growth factor pathway (VEGF) as a therapeutic target was recently validated in NSCLC. Since then, a multitude of early phase clinical trials that incorporate the use of angiogenesis inhibitors, either as single agents or in combination with cytotoxic chemotherapy, have been conducted in advanced, refractory NSCLC. This article reviews these clinical trials with attention to toxicity, efficacy, and direction of further study. The data from these trials suggest that optimal use of anti-angiogenic agents in NSCLC is more likely in combination with standard cytotoxic agents, however the most effective combination with the least toxicity is yet to be determined.


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Therapeutic Strategies for Targeting BRAF in Human Cancer
Christine A. Pratilas and David B. Solit

Constitutive ERK activation is a common finding in human cancer and is often the result of activating mutations of BRAF and RAS. BRAF missense mutations occur in approximately 8% of human tumors, most frequently in melanoma, papillary thyroid cancer and colon cancer. Mutations in BRAF have been found predominantly in tumors in which RAS is commonly mutated but concurrent mutations of both BRAF and RAS are extremely rare. Though over 40 different kinase domain mutations in BRAF have been identified, a single base-pair substitution in exon 15 at codon 600 (V600E) is found in over 80% of cases. These mutations cluster in the glycine-rich loop and activation segments of the kinase and are predicted to induce kinase activation by disrupting the inhibitory glycine-rich loop/activation segment interaction which characterizes the inactive conformation. The majority of mutations identified cause constitutive kinase activation with the V600E mutation demonstrating approximately 500-fold greater kinase activity than wild-type BRAF. Supporting its classification as an oncogene, V600E BRAF stimulates ERK signaling, induces proliferation and is capable in model systems of promoting transformation. However, BRAF mutations are common in nevi and colon polyps suggesting that BRAF mutation alone is insufficient for tumorigenesis and additional mutations are required for cancer development. Though such data suggest that BRAF mutation is likely an early initiating event in tumors such as melanoma and colon cancer, preclinical studies suggest that tumors with V600E BRAF mutation remain dependent upon BRAF for proliferation and survival. Given its frequent occurrence in human cancer and the continued requirement for BRAF activity in tumors with BRAF mutation, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. The first generation of RAF inhibitors, including sorafenib, were notable for their lack of specificity and potency for RAF and these agents have shown limited efficacy in tumors with a high incidence of BRAF mutation such as melanoma. Novel inhibitors of the pathway with greater selectivity for BRAF and MEK are now in Phase 1 and 2 clinical trials with promising early results. To maximize the likelihood of success with these agents, clinical trials enriched with patients whose tumors possess BRAF and RAS mutations have been proposed.


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Implications of FLT3 Mutations in the Therapy of Acute Myeloid Leukemia
Ryan J. Mattison, Kelly R. Ostler, Frederick L. Locke and Lucy A. Godley

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that is expressed on the surface of hematopoietic stem cells and plays an important role in normal hematopoiesis. FLT3 is mutated in approximately one-third of cases of acute myeloid leukemia (AML) with normal karyotype. The mutations are most commonly internal tandem duplications found in the juxtamembrane domain of the FLT3 receptor. There are also cases of point mutations within the tyrosine kinase domain. The presence of a FLT3 mutation confers a poorer prognosis in disease-free survival and overall survival. Patients with an FLT3 mutation have poorer outcomes even with a concomitant nucleophosmin1 (NMP1) mutation, which is normally a good prognostic factor. These observations raise the question about how best to treat patients with AML who have FLT3 mutations. There are some retrospective data that allogeneic stem cell transplantation should be offered to patients with FLT3 mutations who have achieved a first remission, but prospective trials are lacking. There are a number of FLT3 inhibitors that are in various stages of clinical testing. It is hoped that this new class of drugs will be combined with traditional cytotoxic therapies to treat AML and improve outcomes in this difficult-to-treat patient population.


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Review of Clinic Trials: Agents Targeting c-Met
Oyewale Abidoye, Nadh Murukurthy and Ravi Salgia

Receptor tyrosine kinases are a group of molecules that can enhance cellular proliferation, cell motility and migration, and eventual metastasis. c-Met receptor tyrosine kinase has a significant biological and biochemical effect on cancer cells, and appears to be an important therapeutic target. In many cancers, c-Met (which can be activated by its ligand hepatocyte growth factor, HGF) can be overexpressed, activated, amplified, and/or mutated. The mutations of c-Met had initially been described in the tyrosine kinase domain, and we have described them in other “hot-spots” such as the juxtamembrane and semaphorin domains. Targeting c-Met has been very fruitful pre-clinically, and currently, there are several clinical trials for advanced cancers. Described in this review are some of the biological and biochemical aspects of c-Met, and detailed are a number of therapeutic strategies. With our understanding of c-Met biology and role in cancer, we should be able to arrive at a unique strategy to eradicate cancers in which c-Met plays a significant role.


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New Treatment Concepts In Diffuse Large B-Cell Lymphomas (DLBL): Chemotherapy and Biological Therapy
Jose Rodriguez and Antonio Gutierrez

While CHOP has been the standard treatment for DLBL, the low cure rate of approximately 40% implies that there is a need for improvement. Several hypotheses have been tested to optimize treatment. The Goldie and Coldman hypothesis sustains that drug resistance is a function of tumor burden and, accordingly, third generation regimens were designed. A randomized trial comparing CHOP with them showed no difference in the outcome. The myeloablative dose-intensity has become established as the best salvage therapy currently available for chemosensitive relapse of DLBL. However when tested as a frontline therapy clear results have not been obtained. The Norton and Simon hypothesis is based in Gompertzian kinetics whereby the growth rate of smaller tumors is higher. Thus, the dose-dense concept emerges, shortening the intervals between cycles and lowering tumor regrowth with CHOP-14 has recently been shown to improve the outcome in patients with DLBL. Addition of Rituximab-based immunotherapy is being tested in ongoing trials. Other approaches to optimize the treatment are based on a dynamic decision following early responses based on new imaging techniques. Finally, the analysis of tissue arrays and genomic profiling, which provide insights into the oncogenic pathways involved, is allowing the development of new targets.