Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

Introduction: Thyroid cancer is an emerging public health concern. In the USA, its incidence has doubled in the past decade, making it the eighth most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options.

Areas covered: Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers.

Expert opinion: Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity-modulated radiation therapy appears to extend survival for patients with locoregionally confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.     

Emerging drugs and therapeutics for systemic sclerosis

Introduction: Treatment of systemic sclerosis (SSc) is challenging despite advances in medical therapeutics for other rheumatologic diseases. Significant disease modifying therapy is lacking for most patients with SSc, due to the heterogeneous multisystem nature of SSc and its complex pathophysiology. The emergence of organ based management strategies has provided guidance in patient care as well as research and drug development.

Areas covered: Design and development of new compounds focused on the underlying fibrotic disease processes have been sparse. Therefore, organ based strategies with targeted approaches have been directed towards the most devastating and life threatening features of systemic sclerosis. These include pulmonary arterial hypertension, interstitial lung disease, peripheral vasculopathy and skin thickening. In this context, new treatment regimens using older drugs as well as discovery of novel compounds based on recent insights of the disease pathophysiology are discussed.

Expert opinion: Systemic sclerosis is a heterogeneous rare disease that carries a high burden of morbidity and mortality. Organ based management strategies have improved the natural history of systemic sclerosis using targeted interventions or strategies, particularly vascular features. However, more research is required to better understand disease mechanisms, including an ultimate unifying pathway that explains the multisystem nature of systemic sclerosis.     

Emerging peptide therapeutics for inflammatory diseases

Steroids are the best known anti-inflammatory drugs and have been in use for more than 50 years. Their chronic use however was limited by safety concerns. Non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors although devoid of steroid side effects often possess gastrointestinal side effects. In addition recent data suggest that chronic use of some Cox inhibitors is associated with cardiovascular risk. Currently biologics represent the best option for many inflammatory diseases where TNFalpha is the main culprit. These include rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease and psoriasis. A wealth of information is now available on the role of different cytokines and adhesion molecules in the origin and progression of inflammatory diseases. With the success of protein therapeutics such as Etanercept (Enbrel), which binds TNFalpha and inhibits its activity, research has been focused on developing small peptides that can interfere with cytokines or specific cell surface molecules and inhibit the inflammatory reactions. Here we review these peptides that are in discovery and development phases and their potential in the treatment of inflammatory diseases.     

Emerging therapeutics for primary peritoneal cancer

INTRODUCTION: Primary peritoneal cancer describes a malignancy that originates from the peritoneal lining of the abdomen. The diagnosis is clearest when the ovaries are uninvolved; however, this is rarely the case and, as such, the declaration is often made pathologically by extrinsic or secondary involvement of the ovaries. The disease shares nearly all of the clinicopathologic features of primary ovarian cancer, most importantly, a molecular homology, which has made it unfruitful for considering it a different entity. Because of this, both standard of care treatment algorithms and contemporary drug development protocols nearly uniformly consider these cancers as primary ovarian cancers. AREAS COVERED: A Medline search was performed as well as a review of trials presented in the National Cancer Institute clinical trials website (http://www.Clinicaltrials.gov). We also reviewed abstracts presented at recent oncology congresses, such as the 2010 Annual meetings of the Society of Gynecologic Oncologists and the American Society of Clinical Oncology. The purpose of this review is to highlight areas of current drug development for patients with primary peritoneal carcinoma. While there are numerous investigational agents being evaluated which follow patients with this disease, our review focuses on the most promising agents that are in mature clinical development. In addition, given the recent positive Phase III data of bevacizumab in the first-line setting for patients with this disease, we consider changes that we can anticipate in this field. EXPERT OPINION: Numerous novel agents are being explored in this disease with the majority focusing on direct and indirect perturbations of tumor angiogenesis. Based on ongoing and recently completed investigations, targeted therapies are likely to become part of the armamentarium of first-line and recurrent treatment for patients with peritoneal cancers. Future studies of pathway-specific targeting will probably include pretreatment biomarker selection or eligibility criteria as well as combinatorial strategies.     

Emerging targeted therapies for glioma

Introduction: Gliomas are the most common malignant primary brain tumors in adults. Despite aggressive treatment with surgery, radiation and chemotherapy, these tumors are incurable and invariably recur. Molecular characterization of these tumors in recent years has advanced our understanding of gliomagenesis and offered an array of pathways that can be specifically targeted.

Areas covered: The most commonly dysregulated signaling pathways found in gliomas will be discussed, as well as the biologic importance of these disrupted pathways and how each may contribute to tumor development. Our knowledge regarding these pathways are most relevant to Grade IV glioma/glioblastoma, but we will also discuss genomic categorization of low grade glioma. Further, drugs targeting single pathways, which have undergone early phase clinical trials will be reviewed, followed by an in depth discussion of emerging treatments on the horizon, which will include inhibitors of Epidermal Growth Factor Receptor (EGFR) and receptor tyrosine kinases, Phosphoinositide-3-Kinase (PI3K), angiogenesis, cell cycle and mutant Isocitrate Dehydrogenase (IDH) mutations.

Expert opinion: Results from single agent targeted therapy trials have been modest. Lack of efficacy may stem from a combination of poor blood brain barrier penetration, the genetically heterogeneous make-up of the tumors and the emergence of resistance mechanisms. These factors can be overcome by rational drug design that capitalizes on ways to target critical pathways and limits upregulation of redundant pathways.     

Emerging targeted therapies for melanoma

Introduction: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development.

Areas covered: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials.

Expert opinion: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.     

Emerging targeted treatments for malignant glioma

This paper focuses on the medical management of malignant gliomas, which is currently undergoing change. It suggests that as surgery and radiotherapy are of limited benefit in the treatment of these tumours, medical therapies may have the potential to offer a better alternative. The current therapies for glioma and the targeted agents in clinical trials are reviewed. There is a general acceptance that temozolomide in combination with radiotherapy is replacing radiotherapy alone as first-line therapy in high-grade astrocytic gliomas. Within the realms of clinical research, it can be seen that there is a shift away from therapies targeting the end effect of deregulated cell-cycle control, to targeting specific and individual genetic aberrations in tumours. Finally, the paper questions current clinical trial methodology and tentatively suggests ways in which this may be improved.     

Emerging targeted treatments for malignant glioma

This paper focuses on the medical management of malignant gliomas, which is currently undergoing change. It suggests that as surgery and radiotherapy are of limited benefit in the treatment of these tumours, medical therapies may have the potential to offer a better alternative. The current therapies for glioma and the targeted agents in clinical trials are reviewed. There is a general acceptance that temozolomide in combination with radiotherapy is replacing radiotherapy alone as first-line therapy in high-grade astrocytic gliomas. Within the realms of clinical research, it can be seen that there is a shift away from therapies targeting the end effect of deregulated cell-cycle control, to targeting specific and individual genetic aberrations in tumours. Finally, the paper questions current clinical trial methodology and tentatively suggests ways in which this may be improved.     

Molecular pathophysiology and targeted therapeutics for muscular dystrophy.

Experimental therapeutics of the muscular dystrophies has made impressive advances on several fronts. Adeno-associated virus has emerged as the clear 'vector of choice' for muscle gene delivery, with successful functional rescue of dystrophic muscle in rodent models. Correction of the dystrophin gene mutation in a dog model has been reported, and several reports of progress on myogenic stem cell characterization are resurrecting cell transplantation as a possible therapeutic approach. The downstream consequences of dystrophin deficiency are being defined quickly using microarray experiments, and drugs targeting specific biochemical pathways are being tested rapidly in animal models. Such targeted drug discoveries, which are discussed in this article, have begun to be implemented in human clinical trials.     

Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise

There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastasis. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.     

Emerging antibody-drug conjugates for treating lymphoid malignancies

Introduction: Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of cytotoxic the drug within or near the neoplastic cells with reduced systemic effects.

Areas covered: A literature review was conducted of the MEDLINE database PubMed for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs. Publications from 2000 through April 2017 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles.

Expert opinion: Newer ADCs show promise as treatment for several hematologic malignancies, especially lymphoma, multiple myeloma, and leukemia. However, definitive data from ongoing and future clinical trials will aid in better defining the status of these agents in the treatment of these diseases.     

Strategies for the targeted delivery of therapeutics for osteosarcoma

Background: Conventional therapy for osteosarcoma has reached a plateau of 60 – 70%, a 5-year survival rate that has changed little in two decades, highlighting the need for new approaches. Objective: To review the alternative means of delivering effective therapy for osteosarcoma that reach beyond the central venous catheter. Methods: Drawing on the author's own experiences providing care to high-risk osteosarcoma patients and reviewing the last two decades of literature describing sarcoma therapy, available information is summarized about potential osteosarcoma treatments that deliver therapy by a less conventional route. Results/conclusions: Intra-arterial chemotherapy has a limited impact on survival, but may help to achieve a better limb salvage. Intrapleural chemotherapy is important for managing malignant effusions. The development of inhalation therapies, treatments that target new bone formation such as bisphosphonates, chemically targeted radiation and antibody-based therapies all have potential to improve osteosarcoma therapy.     

Nucleic acid therapeutics: concepts for targeted delivery to solid tumors

Solid tumors form a heterogeneous group of diseases, although common features such as hyperproliferation, overexpression of certain growth factor receptors and deregulated vessel formation including leaky vasculature give the opportunity to target macromolecular drug and nucleic acid carriers to tumor tissue. Similar to other macromolecular drugs, nucleic acid carriers have to be designed to enable tumor targeting after systemic injection. Chemical modification of nucleic acids makes them resistant towards enzymatic degradation. Cationic lipids or polycations condense nucleic acids into small, virus-like structures and the surface modification with hydrophilic polymers allows passive accumulation in tumor tissue; tumor cell binding ligands allow cellular targeting. To avoid toxic side effects, biodegradable and biocompatible carriers were designed. The design of thermoresponsive gene carriers allowed their selective tumor accumulation by locoregional hyperthermia. As a therapeutic concept, tumor-specific delivery of antitumoral RNA was realized in an orthotopic brain tumor model. The combination of gene- and radio-therapy enabled selective accumulation of radionuclides in tumors and boosted antitumoral effects. Hence, combining a smart delivery concept for nucleic acids with a suitable therapeutic strategy will allow successful treatment of otherwise incurable malignant diseases.     

HGF/c-MET targeted therapeutics: novel strategies for cancer medicine

The hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-MET) receptor tyrosine kinase (RTK) pathway plays a pleotropic role in cell proliferation, migration, invasion, angiogenesis and survival. Although it has critical physiological functions in embryonic development and tissue repair, this signaling cascade is frequently deregulated in a wide range of tumors. Aberrant HGF/c-MET signaling, driven by various mechanisms, including constitutive activation and over-expression, has multifunctional effects in oncogenesis and is implicated in the acquisition of an aggressive phenotype with metastatic potential. The central role of c-MET activity in cancer progression, as well as disparities between quiescent HGF/c-MET signaling in normal tissue and overexpression in tumor may provide a degree of tumor selectivity for therapeutic intervention, making HGF or c-MET inhibition an attractive proposition in oncology. This review focuses on the underlying oncogenic role of aberrant HGF/c-MET signaling in malignant progression, as well as recent preclinical and clinical data on the different strategies employed in inhibiting HGF/c-MET function.     

Brain drug delivery technologies: novel approaches for transporting therapeutics

The blood-brain barrier (BBB) denies many therapeutic agents access to brain tumours and other diseases of the central nervous system (CNS). Despite remarkable advances in our understanding of the mechanisms involved in the development of the brain diseases and the actions of neuroactive agents, drug delivery to the brain remains a challenge. For more than 20 years, extensive efforts have been made to enhance delivery of therapeutic molecules across vascular barriers of the CNS. The current challenge is to develop drug-delivery strategies that will allow the passage of drug molecules through the BBB in a safe and effective manner, and this review will provide an insight into some of the strategies developed to enhance drug delivery across the BBB.     

Receptor tyrosine kinases and targeted cancer therapeutics

The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.