Preclinical and clinical activity of the topoisomerase I inhibitor, karenitecin, in melanoma

INTRODUCTION: This review covers the preclinical and clinical activity of the novel camptothecin analog, karenitecin, in melanoma. AREAS COVERED: While the camptothecins are widely used antitumor agents that inhibit topoisomerase I, their utility is limited by instability, high interpatient variability and the development of drug resistance. Karenitecin was rationally designed to overcome these limitations. The authors review the data on karenitecin in preclinical models and in clinical trials in melanoma using studies published in Medline and reports presented at AACR and ASCO. EXPERT OPINION: Karenitecin shows activity in melanoma, both as a single agent and in combination. In adverse prognostic factor melanoma, karenitecin showed prolonged disease stabilization in 34% of patients. Because preclinical studies suggested a synergistic interaction between karenitecin and HDAC inhibitors, a schedule-specific combination Phase I-II trial of valproic acid and karenitecin was carried out in heavily pretreated melanoma patients which showed a benefit rate in 47% patients with acceptable toxicity. The treatment for melanoma is in rapid transition and genomic profiling is now an integral part, and hence the optimal use of karenitecin in melanoma should be re-evaluated with regard to specific mutational status.     

Lestaurtinib,a multitargeted tyrosinse kinase inhibitor: from bench to bedside

Importance of the field: Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population.

Areas covered in this review: An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade.

What the reader will gain: The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent.

Take home message: Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.     

PLX4032: does it keep its promise for metastatic melanoma treatment?

Importance of the field: Activating mutations in the BRAF kinase gene have been identified in 50% of all melanomas. PLX4032, a selective and potent inhibitor of BRAF V600E mutant tumor cells, has shown inhibition of tumor growth in cell lines harboring BRAF V600E mutations. Data from early clinical trials showed promising results in the treatment of patients with metastatic melanoma.

Areas covered in this review: An extensive literature search was conducted that included published articles and abstracts on PLX4032 to evaluate the existing data in both preclinical and Phase I–II studies.

What the reader will gain: The review comprises the rationale for choosing a selective BRAF inhibitor for certain types of melanoma, its mode of action, associated toxicities and potential pitfalls.

Take home message: Despite the convincing response rates in Phase I trials, duration of tumor response is limited in some patients, and a cure cannot be expected. Intrinsic and acquired PLX4032 resistance still has to be investigated; signaling pathway switching is probably the most important factor for development of resistance. Combination therapy with simultaneous inhibition of different pathways might be more effective and warrants further investigation. The toxicity profile of PLX4032 is considerably low, and special attention is needed to address the development of keratoacanthomas and cutaneous squamous cell carcinomas.     

Molecular targeted therapy for patients with melanoma: the promise of MAPK pathway inhibition and beyond

Importance of the field: Recent discoveries have expanded the understanding of the molecular signaling events critical to melanomagenesis and led to the development of targeted therapeutic agents that are revolutionizing the treatment of patients with advanced melanoma.

Areas covered in this review: This article reviews current therapy and its limitations, describes the key pathogenic mechanisms in melanoma for which inhibitors have been tested, and summarizes the results of clinical trials involving molecularly targeted agents in this disease.

What the reader will gain: There has been an explosion of preclinical and clinical research aimed at targeting the key molecular alterations in melanoma for therapeutic benefit. These findings will be presented and placed in the proper clinical context, affording information regarding the current molecular targets in the melanoma and the activity and limitations of therapeutic agents directed against them.

Take home message: Greater understanding of the pathogenic mechanisms underlying melanoma development has prompted the development of new therapeutic approaches aimed at counteracting these processes. While progress made over the past few years has generated considerable excitement, the benefits of these new therapies are still limited by incomplete and transient tumor regressions. It is hoped that with further investigation, particularly into mechanisms of treatment de novo and acquired treatment resistance, these limitations can be overcome.     

Talaporfin sodium

Importance of the field: Despite therapeutic advances, cancer remains the cause of an estimated 23% of deaths in the USA. New treatments for malignancy are greatly needed.

Areas covered in this review: Talaporfin sodium is a light-activated drug that causes tissue death through induction of apoptosis. Systemic antitumor effects mediated by CD8⁺ T cells have been demonstrated in preclinical studies, providing a mechanism for distant response of tumors noted in clinical trials. Talaporfin sodium is approved in Japan for early-stage endobronchial cancer. Phase I and II studies in solid tumors have shown tumor regression in patients refractory to other therapies. Phase III pivotal studies against hepatocellular carcinoma as monotherapy and liver-metastatic colorectal cancer in combination with chemotherapy are ongoing. Talaporfin sodium is also in studies in men with symptomatic benign prostatic hyperplasia. Substantial safety data from clinical trials so far indicate that the drug is well tolerated.

What the reader will gain: Talaporfin sodium has a broad safety profile and a mode of action that could affect growth in treated and untreated tumors.

Take home message: Clinical and preclinical studies indicate that talaporfin sodium treatment may offer a powerful option to synergize current therapies, as well as an alternative monotherapy in treating cancer.     

The clinical development of histone deacetylase inhibitors as targeted anticancer drugs

Importance of the field: Histone deacetylase (HDAC) inhibitors are being developed as a new, targeted class of anticancer drugs.

Area covered in this review: This review focuses on the mechanisms of action of the HDAC inhibitors, which selectively induce cancer cell death.

What the reader will gain: There are 11 zinc-dependent HDACs in humans and the biological roles of these lysine deacetylases are not completely understood. It is clear that these different HDACs are not redundant in their activity. This review focuses on the mechanisms by which HDAC inhibitors can induce transformed cell growth arrest and cell death, inhibit cell mobility and have antiangiogenesis activity. There are more than a dozen HDAC inhibitors, including hydroxamates, cyclic peptides, benzamides and fatty acids, in various stages of clinical trials and many more compounds in preclinical development. The chemically different HDAC inhibitors may target different HDACs.

Take home message: There are extensive preclinical studies with transformed cells in culture and tumor-bearing animal models, as well as limited clinical studies reported to date, which indicate that HDAC inhibitors will be most useful when used in combination with cytotoxic or other targeted anticancer agents.     

Iloperidone,asenapine and lurasidone: a primer on their current status

Introduction: Three newer atypical antipsychotic drugs were FDA-approved in 2009 and 2010 in the following order: iloperidone, asenapine and lurasidone. The three drugs are indicated for the treatment of acute schizophrenia. Asenapine is also approved for treatment of manic or mixed episodes associated with bipolar I disorder, for the maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Areas covered: This review compares and contrasts the current preclinical, clinical, safety and tolerability profiles of the three newer drugs, as reported in published preclinical and clinical studies, product labels, poster presentations and press releases.

Expert opinion: Preclinical studies have reported that the three drugs have variable affinities for a wide range of neurotransmitter receptors, and are active in animal models predictive of antipsychotic activity. Asenapine is the first antipsychotic to be administered sublingually, whereas iloperidone requires titration to minimize orthostatic hypotension. Asenapine and lurasidone are associated with dose-related akathisia, whereas iloperidone is not. The three drugs appear to have relatively benign metabolic profiles. The availability of the three novel antipsychotics should provide additional options for improved treatment of schizophrenia and other psychotic disorders.     

Cobimetinib and vemurafenib for the treatment of melanoma

Introduction: Cobimetinib combined with vemurafenib is a new approved MEK inhibitor for first line treatment of metastatic melanoma patients with BRAF V600 mutations. It improves tumor response rates and progression free survival compared to vemurafenib alone, while decreasing toxicities due to the paradoxical activation of the MAPK signaling pathway.

Areas covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical and preclinical studies on cobimetinib. It also reports ongoing trials evaluating cobimetinib to better understand future developments for this drug.

Expert opinion: The combination of cobimetinib and vemurafenib seems to be more toxic than the combination therapy dabrafenib and trametinib even if these four drugs have never been compared in a randomized trial. The future of this combination depends on its capacity to be combined simultaneously or sequentially with immune based therapies to improve the durability of responses.     

NK-1 as a melanoma target

Introduction: Melanoma expresses both neurokinin-1 (NK-1) receptors and substance P (SP). After binding to the NK-1 receptor, SP induces tumor cell proliferation in melanoma cells, whereas after binding to the same NK-1 receptor, antagonists inhibit melanoma cell proliferation and cause tumor cell death by apoptosis. Thus, the NK-1 receptor could be a new and promising target in melanoma therapy.

Areas covered: This review provides an overview of the underlying mechanism of action of the SP/NK-1 receptor system, and NK-1 receptor antagonists in human melanoma, over the last 7 years.

Expert opinion: In stages III – IV, no effective treatment exists for melanoma and hence there is an urgent need to improve therapy in melanoma patients. The NK-1 receptor is a promising new target in human melanoma treatment, since preclinical assays (most of them in vitro assays) have reported that NK-1 receptor antagonists exert an antitumor action against melanoma. The NK-1 receptor antagonist aprepitant is used in clinical practice and exerts an antitumor action against human melanoma in vitro. In the future, such antitumor action should be tested in human clinical trials. This should be faster compared with less investigated NK-1 receptor antagonists, because a great part of the required safety and characterization studies for aprepitant have already been carried out.     

PCI-32765: a novel Bruton's tyrosine kinase inhibitor for the treatment of lymphoid malignancies

Introduction: There has been a significant paradigm shift in the manner in which lymphoid malignancies are treated and managed. Treatment has been moving away from conventional chemotherapy and towards targeted therapy. The success of new classes of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further searches for novel pathways to inhibit. The Bruton's tyrosine kinase (Btk) pathway is a downstream mediator of the B-cell receptor (BCR) pathway, which is crucial in B-cell production and maintenance, and a potential therapeutic target.

Areas covered: This review will summarize the current knowledge of the Btk pathway and its role in lymphoid malignancies. It will also discuss the present data about PCI-32765 in both the preclinical and clinical setting.

Expert opinion: PCI-32765 is an oral irreversible Btk inhibitor with high potency and both preclinical and clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). Phase I studies have demonstrated that it is well tolerated and has an excellent safety profile. Further studies are ongoing as a single agent and in combination with other targeted and conventional therapies. PCI-32765 is a very promising targeted therapy, and the data from these trials will ultimately decide its future role and success.     

Entinostat for treatment of solid tumors and hematologic malignancies

Introduction: A key feature of malignant cells is inappropriate gene suppression resulting in uncontrolled proliferation, continued cell cycling and a lack of differentiation. Histone deacetylase inhibitors (HDACi) are an emerging class of antineoplastic agents that counteract this effect and thus permit re-expression of silenced genes. Entinostat is an emerging HDACi that has shown promise in multiple preclinical studies. Additionally, Phase I and II clinical trials have begun to demonstrate its potential as a well-tolerated agent with anti-tumor activity.

Areas covered: The pharmacokinetics, pharmacodynamics, mechanisms of action, safety and tolerability, and clinical trials of entinostat are reviewed. Sources for this review included all relevant, publicly available, entinostat-related peer-reviewed publications and meeting abstracts up to March 2011.

Expert opinion: Entinostat is a well-tolerated HDACi that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity. Future clinical trials will likely focus on its use in combination with other agents that are able to exploit the epigenetic changes rendered by deacetylase inhibition.     

The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives

Importance of the field: Breast cancer is one of the leading causes of cancer-related deaths in the world. Despite the significant improvements in the adjuvant treatment strategies of early-stage breast cancer, many patients experience relapse. Bisphosphonates are widely used in the treatment of bone metastasis of solid tumors and multiple myeloma, as well as in osteoporosis. The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast-cancer patients under hormonal treatment – especially with the bisphosphonate zoledronic acid – caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites. A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanisms and antitumoral activity of bisphosphonates.

Areas covered in this review: The current literature on the preclinical and clinical studies into antitumoral effect and adjuvant treatment of bisphosphonates, especially zoledronic acid, are summarized. Data in the literature over the last two decades were also reviewed.

What the reader will gain: The reader will find a summary of preclinical and clinical studies of antitumoral effect and adjuvant treatment with bisphosphonates, in particular zoledronic acid, as well as ongoing trials about adjuvant treatment of breast cancer with zoledronic acid and ibandronate.

Take home message: Current evidence supports zoledronic acid as an effective treatment in adjuvant breast-cancer therapy for hormone-receptor-positive breast-cancer patients when added to hormonotherapy. Uncertainty about effects of zoledronic acid and other bisphosphonates will be clarified after completion of ongoing trials.     

Eribulin mesylate for the treatment of breast cancer

Importance of the field: Breast cancer is the most common cause of cancer-related death among women in the USA, and additional effective and well-tolerated chemotherapeutic agents are urgently needed. Eribulin mesylate (E7389), a synthetic analog of the marine macrolide halichondrin B, is a microtubule inhibitor with a unique tubulin binding site and mechanism of action.

Areas covered in this review: Based on a review of the literature between 2005 and 2010, we present a summary of eribulin and its clinical activity, specifically in metastatic breast cancer.

What the reader will gain: The mechanism of action of eribulin, preclinical data indicating antitumor activity of eribulin and data from Phase I and II clinical trials evaluating the efficacy and tolerability of eribulin are presented.

Take home message: Based on data from Phase I and II clinical trials, we conclude that eribulin seems to have efficacy in metastatic breast cancer, even among women with heavily pretreated and taxane-resistant disease. In addition, eribulin has a manageable side-effect profile, consisting mainly of neutropenia and fatigue, and most notably a low incidence of peripheral neuropathy. With these encouraging results, additional Phase II and III studies are ongoing. Eribulin seems to be a promising new agent for the treatment of metastatic breast cancer.     

The future is today: emerging drugs for the treatment of erectile dysfunction

Importance of the field: Erectile dysfunction (ED) is the most common male sexual dysfunction presented for treatment affecting between 10 and 20% of men. PDE type 5 inhibitors (PDE5I) now account for the largest segment of the ED market. While these drugs are highly efficacious for many men, a relatively large subset of ED patients who do not respond to PDE5I is increasingly recognized.

Areas covered in this review: In this review, we discuss clinical and preclinical evidence supporting various emerging compounds that regulate penile erection both centrally (clavulanic acid, dopamine and melanocortin receptor agonists) and peripherally (novel PDE5I, soluble and particulate guanylil cyclase activators, rho-kinase inhibitors and maxi-K channel openers).

What the reader will gain: The reader will gain a broad understanding of erectile (patho-)physiology and gain insights in the mechanisms of action, efficacy and adverse events of various compounds under development for the treatment of ED.

Take home message: We expect emerging drugs to allow treatment protocols tailored to the specific needs of each individual patient, taking into consideration the efficacy of erectile performance enhancement and the potential for adverse events. This tailored approach may include combination of various emerging drugs to enhance efficacy in difficult-to-treat patients.     

Advances in hepatitis C virus vaccines,part two: advances in hepatitis C virus vaccine formulations and modalities

Introduction: Developing a vaccine against HCV is an important medical and global priority. Unavailability and potential dangers associated with using attenuated HCV viral particles for vaccine preparation have resulted in the use of HCV genes and proteins formulated in novel vaccine modalities.

Areas covered: In part one of this review, advances in basic knowledge for HCV vaccine design were provided. Herein, a detailed and correlated patents (searched by Espacenet) and literatures (searched by Pubmed) review on HCV vaccine formulations and modalities is provided, including: subunit, DNA, epitopic-peptide/polytopic, live vector- and whole yeast-based vaccines. Less-touched areas in vaccine studies such as mucosal, plant-based, and chimeric HBV/HCV vaccines are also discussed. Furthermore, results of preclinical/clinical studies on selected HCV vaccines as well as pros and cons of different strategies are reviewed. Finally, potential strategies for creation and/or improvement of HCV vaccine formulations are discussed.

Expert opinion: Promising outcomes of a few HCV vaccine modalities in phase I/II clinical trials predict the accessibility of at least partially effective vaccines to inhibit or treat the chronic state of HCV infection (specially in combination with standard antiviral therapy). ChronVac-C (plasmid DNA), TG4040 (MVA-based), and GI-5005 (whole yeast-based) might be the most obvious HCV vaccine candidates to be approved in the near future.     

From cell biology to therapy: ENMD-2076 in the treatment of multiple myeloma

Introduction: Multiple myeloma (MM) remains incurable, indicating the need for continued investigation of innovative strategies. Recent progress in molecular biology has advanced the discovery of novel drugs for MM. ENMD-2076 is an orally bioavailable, multi-target kinase inhibitor with multiple mechanisms of action, including anti-proliferative and pro-apoptotic activity, and anti-angiogenic effects.

Areas covered: In this review, the authors summarize the preclinical in vitro and in vivo data that have formed the rationale for clinical investigation of ENMD-2076 in MM. In addition, the authors review the early clinical results of ENMD-2076 in MM and other malignancies, and speculate on potential avenues of future clinical research in the development of this drug for MM.

Expert opinion: There is a strong preclinical rationale for investigating ENMD-2076 in MM that is confirmed by early clinical results in an ongoing Phase I trial in patients with relapsed or refractory MM. Optimal strategies for developing ENMD-2076 in MM will require better elucidation of its mechanism of action, investigation of biomarkers for response and development of rationale synergistic combinations with other active agents.     

A retrospective review of the progress in amyotrophic lateral sclerosis drug discovery over the last decade and a look at the latest strategies

Introduction: Drug discovery for amyotrophic lateral sclerosis (ALS) has experienced a surge in clinical studies and remarkable preclinical milestones utilizing a variety of mutant superoxide dismutase 1 model systems. Of the drugs that were tested and showed positive preclinical effects, none demonstrated therapeutic benefits to ALS patients in clinical settings.

Areas covered: This review discusses the advances made in drug discovery for ALS and highlights why drug development is proving to be so difficult. It also discusses how a closer look at both preclinical and clinical studies could uncover the reasons why these preclinical successes have yet to result in the availability of an effective drug for clinical use.

Expert opinion: Valuable lessons from the numerous preclinical and clinical studies supply the biggest advantage in the monumental task of finding a cure for ALS. Obviously, a single design type for ALS clinical trials has not yielded success. The authors suggest a two-pronged approach that may prove essential to achieve clinical efficacy in the identification of novel targets and preclinical testing in multiple models to identify biomarkers that can function in diagnostic, predictive and prognostic roles, and changes to clinical trial design and patient recruitment criteria. The advancement of technology and invention of more powerful tools will further enhance the above. This will give rise to more sophisticated clinical trials with consideration of a range of criteria from: optimum dose, route of delivery, specific biomarkers, pharmacokinetics, pharmacodynamics and toxicology to biomarkers, timing for trial and patients’ clinical status.     

The CD4-like molecule LAG-3, biology and therapeutic applications

Importance of the field: Promising immunotherapeutic agents targeting co-stimulatory pathways are currently being tested in clinical trials. One player in this array of regulatory pathways is the LAG-3/MHC class II axis. The lymphocyte activation gene-3 (LAG-3) is a negative co-stimulatory receptor that modulates T cell homeostasis, proliferation and activation. A recombinant soluble dimeric form of LAG-3 (sLAG-3–Ig, IMP321) shows adjuvant properties and enhances immunogenicity of tumor vaccines. Recent clinical trials produced encouraging results, especially when the human dimeric soluble form of LAG-3 (hLAG-3–Ig) was used in combination with chemotherapy.

Areas covered in this review: The biological relevance of LAG-3 in vivo. Pre-clinical data demonstrating adjuvant properties, as well as the improvement of tumor immunity by sLAG-3–Ig. Recent advances in the clinical development of the therapeutic reagent IMP321, hLAG-3–Ig, for cancer treatment.

What the reader will gain: This review summarizes preclinical and clinical data on the biological functions of LAG-3.

Take home message: The LAG-3 inhibitory pathway is attracting attention, in the light of recent studies demonstrating its role in T cell unresponsiveness, and Treg function after chronic antigen stimulation. As a soluble recombinant dimer, the sLAG-3–Ig protein acts as an adjuvant for therapeutic induction of T cell responses, and may be beneficial to cancer patients when used in combination therapies.     

Prospects for MEK inhibitors for treating cancer

Introduction: The MAPK pathway is a signaling network that plays a key role in many normal cellular processes and in a large number of human malignancies. One of its effectors, MEK, is essential for the carcinogenesis of different tumors. In recent years, several drugs able to inhibit MEK have been assessed in clinical trials. Trametinib has recently become the first MEK inhibitor licensed for cancer treatment (advanced melanoma).

Areas covered: We comprehensively review the safety and clinical efficacy of the family of MEK inhibitors, either alone or in combination with other drugs. We discuss data ranging from the Phase III trial of trametinib in melanoma to the most recent drugs with early signs of antitumor activity. In addition, we explain the reasons for the unsuccessful results of the early trials with MEK inhibitors and provide a view of their role in cancer treatment in forthcoming years.

Expert opinion: MEK inhibitors are a potentially safe and active treatment option for the treatment of many human malignancies. The information provided by a large series of studies currently ongoing will be very valuable in order to optimize their use. Adequate selection of patients is crucial for achieving successful results with these compounds.     

Patient-derived tumor xenograft models for melanoma drug discovery

ABSTRACT

Introduction: Cutaneous metastatic melanoma (MM) is an aggressive form of skin cancer, with treatment providing cures to a minority of patients. The multiple risk factors that contribute to MM development suggest that cutaneous melanomas embody a repertoire of altered genetic events requiring studies to better understand its biology in order to develop novel therapies.

Areas covered: Patient-derived tumor xenograft (PDTX) mouse models are noted to be superior for novel drug discovery and tumor biology studies due to their ability to maintain tumor heterogeneity and their use as real-time individualized patient models. In this review, the authors highlight the utility of PDTX models in advancing treatment options for patients with MM by creating invaluable preclinical models that exhibit patient-relevant treatment outcomes.

Expert opinion: There is a strong necessity to reassess current approaches in which preclinical experiments are designed and executed in order to minimize unwarranted clinical trials. With rigorously performed preclinical studies, PDTX models have the capability to effectively confirm or deny drug effective outcomes. The ability to do this, however, will demand better aids to guide experimental design, the redefining of preclinical efficacy, and the understanding that these models should be viewed as complementary to other drug prediction and efficacy tools.