Current Cancer Drug Targets - Volume 12, Issue 5, 2012

For the last twenty years, significant progress in molecular and cellular biology has resulted in a better characterization and understanding of the molecular abnormalities in leukemias. These achievements have provided new opportunities for the development of innovative, more effective drugs. Novel therapies are being evaluated both in preclinical studies and in early clinical trials. In this editorial, we demonstrate a brief review of the present insights into new therapeutic strategies for acute and chronic leukemias.

Chronic myeloid leukemia (CML) therapy has dramatically changed in the last decade due to the introduction of tyrosine kinase inhibitors (TKIs) - imatinib, nilotinib and dasatinib. Despite the significant prolongation of overall survival of CML patients there is still room for improvement. Approximately 20-25% of patients initially treated with imatinib will need alternative therapy, due to drug resistance which is often caused by the appearance of clones expressing mutant forms of BCR-ABL. Second generation TKIs dasatinib and nilotinib have shown promising results in imatinibresistant or intolerant CML patients, but are not active against CML clones with highly resistant T315I mutation. In recent years special attention is placed on small pool of leukemic stem cells which may contribute to the persistence of the leukemia. This article provides a review of preclinical and clinical data concerning the most promising new directions in CML treatment, with special emphasis on new drugs active in T315I mutation and compounds affecting leukemic stem cells.

During the last decades advanced treatment options for chronic lymphocytic leukemia have enabled the shift from rather ineffective palliative treatment to therapies that are aiming for long lasting complete remission and prolongation of survival. This remarkable progress was achieved by combining conventional chemotherapy with monoclonal antibodies such as rituximab and alemtuzumab. Despite this improvement, CLL remains an incurable disease and all patients will eventually relapse and become refractory to treatment. Allogeneic stem cell transplantation is the only curative option but is feasible only in a minority of patients due to the comorbidity and impaired physical fitness of many patients, since the mean age at first diagnosis lies between 70 and 75 years. Therefore, novel less-toxic therapeutic agents are needed, particularly for patients with comorbidities or high-risk cytogenetic abnormalities. Research in the field of CLL and growing understanding of the pathogenesis of B-cell lymphomas has produced a wide variety of new substances for different targets, e.g. different novel monoclonal antibodies, immunomodulatory agents and inhibitors targeting different kinases of B-cell receptor signalling cascade, such as Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K). This article reviews novel drugs that were recently developed for the use in CLL. The agents discussed in this article were selected for having already shown preliminary evidence of clinical activity.

Rarer chronic lymphoid leukaemias represent a challenge to the clinicians due to the limited information on their pathogenesis, difficulties on setting up prospective clinical trials and to their refractoriness to drugs used in the most common form of chronic lymphocytic leukaemia (CLL). In this review all these issues are addressed in three B-cell leukaemias: B-cell prolymphocytic leukaemia (B-PLL), hairy cell leukaemia (HCL) and HCL-variant and three T-cell leukaemias: T-cell prolymphocytic leukaemia (T-PLL), T-cell large granular lymphocytic leukaemia (T-cell LGLL) and adult T-cell leukaemia lymphoma (ATLL). Data will be presented on the natural history, current therapies and emerging drugs potentially useful in the treatment of patients with these leukaemias. Emphasis is made on: 1- the novel agents targeting a variety of B and T-cell antigens expressed on the surface of the leukaemic cells; these are either unconjugated monoclonal antibodies (McAb) such as Rituximab (anti-CD20), the second and third generation of anti-CD20 McAbs, Alemtuzumab (anti-CD52), Siplizumab (anti-CD2), Daclizumab (anti-CD25) and KW-0761, an anti-chemokine receptor 4 (CCR4) or McAbs conjugated to toxins such as CD22 linked to the pseudomonas exotoxin or radiolabelled McAb; 2- the use of new purine nucleosides such as nelarabine and 3- agents targeting deregulated genes in the leukaemic cells from these diseases such as the Poly (ADP-ribose) polymerase (PARP) Olarapib in T-PLL with deregulation of the ataxia telangiectasia mutated (ATM) gene. Data of phase I and II clinical studies with these agents as well as the potential and current use of other drugs are outlined.

Over the past several decades the important progress has been made in the management of acute lymphoblastic leukemia (ALL), especially among children. However, in adult patients reported cure rates seldom exceeded 40%, despite the use of hematopoietic stem-cell transplantation in many cases. Conventional chemotherapy is toxic and ineffective. Therefore, new treatment options and risk-adapted therapies are needed to improve the outcome of ALL patients. This review is focused on new systemic treatment modalities, such as nucleoside analogues, purine synthetase inhibitors, monoclonal antibodies, tyrosine kinase inhibitors and other agents targeting molecular pathways that are aimed to benefit patients and improve the outcome of their treatment.

Acute myeloid leukemia (AML) is a challenging disease to treat with the majority of patients dying from their illness. While overall survival has been markedly prolonged in acute promyelocytic leukemia (APL), survival in younger adults with other subtypes of AML has only modestly improved over the last twenty years. Physicians who treat AML eagerly await drugs like Imatinib for chronic myeloid leukemia, Cladribine for hairy cell leukemia, and Rituximab for non-Hodgkin Lymphoma which have had an important impact on improving outcome. Recent research efforts have focused on refining traditional chemotherapeutic agents to make them more active in AML, targeting specific genetic mutations in myeloid leukemia cells, and utilizing novel agents such as Lenalidomide that have shown activity in other hematologic malignancies. Here, we focus on reviewing the recent literature on agents that may assume a role in clinical practice for patients with AML over the next five years.

Although the action of estrogens has been traditionally explained by the binding to and transactivation of the nuclear estrogen receptor (ER)α and ERβ, recently the G protein-coupled receptor GPR30/GPER has been involved in the rapid estrogen signaling. We investigated the ability of two original molecules, which were named GPER-L1 and GPERL2, to bind to and activate the GPER transduction pathway in cancer cells. Competition assays, docking simulations, transfection experiments, real-time PCR, immunoblotting, gene silencing technology and growth assays were performed to ascertain the selective action of GPER-L1 and GPER-L2 in activating the GPER-mediated signaling. Both compounds, which did not show any ability to bind to and activate the classical ERs, were able to bind to GPER and to trigger the rapid activation of the GPER/EGFR/ERK transduction pathway which led to the up-regulation of GPER-target genes. Notably, GPER-L1 and GPER-L2 induced the proliferation of SkBr3 breast and Ishikawa endometrial cancer cells at nM concentrations through GPER, hence providing further evidence on their capability to elicit relevant biological responses mediated by GPER. The identification and characterization of these novel compounds as selective GPER agonists represent a valuable tool to further dissect the pharmacology of this novel estrogen receptor and to better differentiate the specific functions elicited by each estrogen receptor subtype in cancer cells.

The two members of the LIM domain kinase family (LIMK1 and LIMK2) represent crucial keys in the signaling pathways that modulate the structure and activity of actin cytoskeleton. They maintain the optimal balance between phosphorylated and unphosphorylated cofilin that in turn acts by severing filamentous actin into globular actin and ensures actin turnover and cytoskeleton regulation. Many macromolecular partners able to regulate LIMK activity (positive and negative regulators) do exist. Proteins that enhance or reduce the nucleocytoplasmic shuttling of LIMK by direct or indirect interaction are also known. Among many LIMK activators, members of the Rho family of small GTPases (i.e., Rho, Rac, and Cdc42) and their downstream effectors (i.e., ROCK, PAK, and MK2) are involved in the progression of various human cancers toward invasive and metastatic stages. As LIMK are centrally positioned in the pathways leading to cytoskeleton dynamics and regulation, they could be considered as valuable targets for actin regulation. Fine modulation of LIMK activity could be a major challenge to inhibit tumor cell invasion mediated by one or a combination of the upstream signaling factors. As LIMK play a critical role in tumor cell invasion, they may be candidate targets for developing novel therapeutic agents toward tumor invasion and metastasis.

Nasopharyngeal carcinoma (NPC) is a highly malignant and frequently metastasized tumor, and the prognosis is very poor when distant metastases occur. Recently, immunotherapy is becoming a promising therapeutic approach. Interferon-α (IFN-α) represents the cytokines exhibiting the longest record of use in clinical oncology. In this study, we examined the antitumor effects of IFN-α1b on NPC. The results showed that recombinant human IFN-α1b (hIFN-α1b) suppressed cell growth, induced a G1-phase cell cycle arrest in vitro, increased the expression of p16 and pRb, and decreased the expression of CCND1 and CDK6. In vivo analyses showed that either recombinant adeno-associated virus (rAAV)-IFN-α1b or hIFN-α1b treatment inhibited tumor growth and metastasis, reduced intratumoral microvessel density, increased cell apoptosis and necrosis, and induced prolonged survival. Notably, rAAV-IFN-α1b or hIFN-α1b treatment led to significantly higher serum levels of IL-12 and GM-CSF in mice compared to respective controls. Our findings suggest that IFN-α1b acts as a multifunctional antitumor agent in NPC, which may have important therapeutic implications.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the Philadelphia-positive chromosome deriving from a translocation between chromosomes 22 and 9. The oncogenic product of this aberrant chromosome is the constitutively active tyrosine kinase BCR-ABL that is responsible for leukemic cell growth, proliferation and survival driven by the dysregulation of a large array of signal transduction pathways. Inhibition of BCRABL with tyrosine kinase inhibitors proved to be an efficient therapy of CML in the chronic phase. Unfortunately, the impressive success of BCR-ABL inhibitors as front-line therapy in CML has been tempered by problems of disease persistence or relapse arising from different mechanisms, including mutations in the kinase domain of the enzyme BCRABL and mechanisms independent from BCR-ABL activity. Growing evidence has also suggested a pivotal role of persistent leukemic cancer stem cells, characterized by high self-renewal and pluripotency, in CML maintenance and/or relapse. The present review deals with the most recent advances in this challenging field and focuses on the development of new drugs and therapeutic approaches to eradicate the subtle and dangerous leukemic stem cells responsible for maintaining and sustaining tumor growth.