Potential dual role of KGF/KGFR as a target option in novel therapeutic strategies for the treatment of cancers and mucosal damages

Introduction: Keratinocyte growth factor (KGF) and its receptor KGFR play a pivotal role in regulating cell proliferation, migration, differentiation and survival, in response to injury and tissue repair. Altered expression of this pathway in cancer opened the way to the development of targeted therapy to achieve KGFR inhibition. Nevertheless, KGF administration has been demonstrated to ameliorate oral mucositis resulting from chemoradiotherapy, besides protecting epithelial cells against radiation-induced damage.

Areas covered: This review focuses on the potential therapeutic interest of KGF/KGFR in two different areas: selective inhibition of KGFR signaling for the treatment of cancers characterized by upregulation of this pathway and administration of KGF to protect epithelial cells from induced damage. The review presents an overview of therapeutic strategies in both directions.

Expert opinion: KGF/KGFR signaling can contribute to enhancing the malignant potential of epithelial cells and to promoting tumorigenesis. On the other hand, the therapeutic use of KGF in cancer patients provides epithelial protection, reducing chemotherapy side effects. FGFRs have become attractive antitumor targets and various inhibitors have been used to contrast tumor cell growth. The identification of KGFR-specific molecules might represent a promising therapeutic strategy that could increase the window of available agents and treatment methods.     

Small molecule c-Met kinase inhibitors: a review of recent patents

Importance of the field: c-Met kinase is the receptor for hepatocyte growth factor. Primarily expressed on epithelial and mesenchymal cells its normal function is associated with wound healing, liver regeneration and embryo development. However, dysregulation of c-Met through overexpression, gene amplification, mutation or a ligand-dependent autocrine/paracrine loop is associated with tumorigenesis. c-Met dysregulation in human cancer patients is typically associated with a poor prognosis, aggressive disease, increased metastasis and shortened patient survival. Targeting the hepatocyte growth factor/c-Met signalling pathway as a means of cancer therapy has, therefore, become increasingly popular with a number of different therapeutic approaches undergoing clinical trials.

Areas covered by this review: This review covers the patent applications for small molecule c-Met kinase inhibitors since 2007, attempts to place them in context from a structural point of view and examines their potential applications in cancer therapy.

What the reader will gain: Readers will gain an overview of the structural types of c-Met inhibitors, the major players in the field and an insight into what is progressing into the clinic.

Take home message: This area is developing rapidly and the results of the various ongoing clinical trials will generate an increased understanding of the potential benefits and pitfalls of c-Met inhibitors as therapeutic agents.     

Investigational platelet-derived growth factor receptor kinase inhibitors in breast cancer therapy

Introduction: Aberrant regulation of platelet-derived growth factors (PDGFs) and their receptors (PDGFR) has been shown to be involved in many solid tumors, including breast cancer. PDGFR-α and PDGFR-β expressions were documented in breast cancer and are correlated with tumor aggressiveness and metastasis. Preclinical evidence further suggests tumor stimulatory roles of PDGFRs expressed by tumor stroma cells and indicates a deleterious effect of stromal PDGFRs on intratumoral drug uptake.

Areas covered: This review summarizes the present understanding of PDGF signaling in breast cancer based on experimental studies and available clinical trials. It also provides a critical discussion of selected ongoing clinical trials in patients with breast cancer involving PDGFR inhibition with tyrosine kinase inhibitors, specifically in endocrine responsive breast cancer.

Expert opinion: An increased molecular understanding of response and resistance mechanisms to endocrine therapy will be essential for therapeutic advances in PDGFR-directed cancer therapy. Future developments in the field will rely on clinical studies where prospective analyses of target expression in breast cancer cells and in the tumor stroma are included. More selective PDGFR inhibitors with reduced side effects will be crucial for combinatorial therapies. Development of sensitive diagnostics is of critical importance for patient selection and monitoring of therapeutic effects.     

Investigational fibroblast growth factor receptor 2 antagonists in early phase clinical trials to treat solid tumors

ABSTRACT

Introduction: Fibroblast growth factor receptor 2 (FGFR2) is a highly conserved transmembrane tyrosine kinase receptor. FGFR2 dysregulation occurs in numerous human solid tumors and overexpression is closely associated with tumor progression. FGFR2 has recently been reported as a therapeutic target for cancer. Several targeted therapies are being investigated to disrupt FGFR2 activity; these include multi-target tyrosine kinase inhibitors (TKIs), pan-FGFR targeted TKIs and FGFR2 monoclonal antibodies.

Areas: This review examines FGFR2 regulation and function in cancer and its potential as a target for cancer treatment.

Expert opinion: Highly specific FGFR2 blockers have not yet been developed and moreover, resistance to FGFR2-targeted therapies is a challenge. More sophisticated patient selection strategies would help improve FGFR2-targeted therapies and combination therapy is considered the most promising approach for cancer patients with FGFR2 alterations.     

Targeting the HGF/Met signaling pathway in cancer therapy

Introduction: Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand-activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis.

Area covered: The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. The authors review Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results.

Expert opinion: Clinical trials with HGF/Met pathway antagonists show that as a class these agents are well tolerated. Although widespread efficacy was not seen in several completed Phase II studies, promising results have been reported in lung, gastric, prostate and papillary renal cancer patients treated with these agents. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment are optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents, and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.     

Zibotentan for the treatment of castrate-resistant prostate cancer

Importance of the field: Patients with prostate cancer who have progression of their disease while on androgen deprivation therapy have limited therapeutic options. Docetaxel is currently the only agent that increases overall survival in patients with metastatic, castration-resistant prostate cancer; additional agents are needed.

Areas covered in this review: This review will describe the importance of endothelin-1 (ET-1) for growth of prostate cancer cells, development of bone metastases, and pain responses; the preclinical data for zibotentan, a specific inhibitor of the ET_A receptor; and the clinical development of atrasentan, a first-generation ET receptor inhibitor, and zibotentan, a more selective inhibitor of the ET_A receptor.

What the reader will gain: Readers will understand the importance of ET-1 as a novel pathway to target for patients with castration-resistant prostate cancer due to its association with prostate cancer growth, metastases to bone, and pain. Readers will learn about the preclinical and clinical development of zibotentan, including the promising Phase II results that have resulted in an extensive Phase III clinical trials program.

Take home message: Modulating the activity of ET-1 through the ET_A receptor is a novel target for treating patients with metastatic, castration-resistant prostate cancer. There are currently three ongoing Phase III trials with zibotentan, a selective ET_A inhibitor, to determine the effect of this agent on overall survival in these patients.     

The potential of fibroblast growth factor/fibroblast growth factor receptor signaling as a therapeutic target in tumor angiogenesis

Introduction: Fibroblast growth factors (FGFs) are endowed with a potent pro-angiogenic activity. Activation of the FGF/FGF receptor (FGFR) system occurs in a variety of human tumors. This may lead to neovascularization, supporting tumor progression and metastatic dissemination. Thus, a compelling biologic rationale exists for the development of anti-FGF/FGFR agents for the inhibition of tumor angiogenesis in cancer therapy.

Areas covered: A comprehensive search on PubMed was performed to identify studies on the role of the FGF/FGFR system in angiogenesis. Endothelial FGFR signaling, the pro-angiogenic function of canonical FGFs, and their role in human tumors are described. In addition, experimental approaches aimed at the identification and characterization of nonselective and selective FGF/FGFR inhibitors and their evaluation in clinical trials are summarized.

Expert opinion: Different approaches can be envisaged to inhibit the FGF/FGFR system, a target for the development of ‘two-compartment’ anti-angiogenic/anti-tumor agents, including FGFR selective and nonselective small-molecule tyrosine kinase inhibitors, anti-FGFR antibodies, and FGF ligand traps. Further studies are required to define the correlation between tumor vascularization and activation of the FGF/FGFR system and for the identification of cancer patients more likely to benefit from anti-FGF/FGFR treatments. In addition, advantages and disadvantages about the use of selective versus non-selective FGF inhibitors remain to be elucidated.     

Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors

Importance of the field: Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the role of these receptor tyrosine kinases (RTKs) in development and progression of cancer remained unexplained. Studies demonstrating that Axl and Mer contribute to cell survival, migration, invasion, metastasis and chemosensitivity justify further investigation of Axl and Mer as novel therapeutic targets in cancer.

Areas covered in this review: Axl and Mer signaling pathways in cancer cells are summarized and evidence validating these RTKs as therapeutic targets in glioblastoma multiforme, NSCLC, and breast cancer is examined. A discussion of Axl and/or Mer inhibitors in development is provided.

What the reader will gain: Potential toxicities associated with Axl or Mer inhibition are addressed. We propose that the probable action of Mer and Axl inhibitors on cells within the tumor microenvironment will provide a therapeutic opportunity to target both tumor cells and the stromal components that facilitate disease progression.

Take home message: Axl and Mer mediate multiple oncogenic phenotypes and activation of these RTKs constitutes a mechanism of chemoresistance in a variety of solid tumors. Targeted inhibition of these RTKs may be effective as anti-tumor and/or anti-metastatic therapy, particularly if combined with standard cytotoxic therapies.     

Vandetanib for the treatment of non-small-cell lung cancer

Introduction: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways.

Areas covered: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens.

Expert opinion: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Hepatocyte growth factor is an attractive target for the treatment of pulmonary fibrosis

Introduction: Pulmonary fibrosis (PF) is a progressive fatal disorder and is characterized by alveolar epithelial injury, myofibroblast proliferation, and extracellular matrix remodeling, resulting in irreversible distortion of lung's architecture. Available therapies are associated with side effects and show restricted efficacy. Therefore, there is an urgent need to find a therapeutic solution to PF. Therapeutic strategies interfering myofibroblast expansion, apoptosis of epithelial and endothelial cells might be beneficial for treatment of PF. Hepatocyte growth factor (HGF), a pleiotropic growth factor, plays an important role in lung development, inflammation, repair, and regeneration. In animal model of PF, administration of recombinant HGF protein or ectopic HGF expression ameliorates fibrosis.

Areas covered: The focus of this review is to highlight HGF as a promising therapeutic approach for the treatment of PF. The review discusses the currently available treatment option for PF as well as highlights the possible beneficial effect of HGF as a drug target.

Expert opinion: HGF with its anti-fibrotic effect provides a promising new therapeutic approach by protecting lung from fibrotic remodeling and also promoting normal regeneration of lung. The development of HGF mimetics may provide a potential attractive therapy for treatment of this devastating and complex disease.     

Clinical translation of folate receptor-targeted therapeutics

Introduction: Folate receptor?α (FR?α) has been established as a membrane marker for ovarian cancer. In addition, it is frequently overexpressed in other major types of epithelial tumors. FR?α-based tumor-targeted therapy and drug carriers have been an active area of laboratory research for more than 20 years. Recently, there has been a great increase in the effort to finally translate this promising technology into the clinic and bring FR-targeted therapeutics into the market.

Areas covered: Two FR-targeted therapeutic agents have moved into Phase III clinical trials, the monoclonal antibody farletuzumab and the low molecular weight vintafolide, combined with etarfolatide as a companion imaging agent, representing two alternative strategies for targeting the FR.

Expert opinion: Each of the two strategies has advantages and disadvantages. Identification of the best target patient population is likely critical to the ultimate success of FR-targeted agents in the clinic. A successful clinical strategy may require the integration between FR expression analysis and an optimal combination of FR-targeted therapy and standard chemotherapy. Advancement into Phase III trials and the ongoing clinical development of several additional folate conjugates are likely to usher in a new era of clinical translation and validation of FR-targeted imaging and therapeutic agents.     

Focal adhesion kinase inhibitors in the treatment of metastatic cancer: a patent review

Introduction: Focal adhesion kinase (FAK) plays a prominent role in integrin signaling. FAK activation increases phosphorylation of Tyr397 and other sites of the protein. FAK-dependent activation of signaling pathways implicated in controlling essential cellular functions including growth, proliferation, survival and migration. FERM (F for the 4.1 protein, ezrin, radixin and moesin) domain-enhanced p53 degradation plays a critical role in proliferation and survival. FAK, overexpressed in metastatic tumors, has emerged as an important therapeutic target for the development of selective inhibitors. FAK inhibitors achieved tumor growth inhibition and induced apoptosis. Strategies targeting FAK inhibition using novel compounds have created an exciting opportunity for anticancer therapy.

Areas covered: This review summarizes the current research with available data from early phase clinical trials and discusses the available small-molecule inhibitors of FAK from patents. The importance of inhibiting FAK activity in cancer patients is discussed.

Expert opinion: Emerging data from clinical trials with orally available small-molecule inhibitors of FAK are promising. Although this approach is appropriate as a targeted therapeutic approach against several metastatic cancer types, several compounds in research are yet to prove their preclinical efficacy. This report lays special emphasis on the available patent data of FAK inhibitors for such targeted molecular therapies. This review summarizes current knowledge about FAK inhibition in cancer therapy.     

Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer

Introduction: Protein tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs and one of the most impressive approaches of targeted cancer therapy. Aberrant activation of tyrosine kinase pathways is among the most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable molecular targets. To date, several inhibitors of tyrosine kinases have been approved and there are hundreds more compounds that are in various stages of development. Because of the deregulation in human malignancies, the ABL1, SRC, the epidermal growth factor receptor and the vascular endothelial growth factor receptor kinases are among the protein kinases that are considered as prime molecular targets for selective inhibition.

Areas covered: This review focuses on most important small-molecule inhibitors that serve as a model for future development. They also provide a broad overview of some of the new approaches and challenges in the field.

Expert opinion: With the exception of a few malignancies seemingly driven by a limited number of genetic lesions, current targeted therapeutic approaches have shown only limited efficacy in advanced cancers. Consequently, more sophisticated strategies, such as identification of pathogenic ‘driver' mutations and optimization of personalized therapies are needed.     

TGF-β: friend or foe? The role of TGF-β/SMAD signaling in epigenetic silencing of ovarian cancer and its implication in epigenetic therapy

Importance of the field: The TGF-β signaling pathway plays an important role in regulating numerous cellular processes including growth inhibition of ovarian surface epithelial (OSE) cells. However, epithelial ovarian cancer is refractory to the inhibitory functions of TGF-β, and yet TGF-β induces metastasis or epithelial–mesenchymal transition (EMT) in advanced ovarian cancer. How TGF-β plays a certain role in one cell but a different role in its malignant counterpart is not fully understood.

Areas covered in this review: The role of TGF-β/SMAD signaling both in normal OSE cells and ovarian cancer as well as how dysregulation of this signaling pathway leads to epigenetic silencing of its downstream targets in ovarian neoplasias are reviewed. The therapeutic implication of this signaling pathway in epigenetic therapy of ovarian cancer are also discussed.

What the reader will gain: The reader will gain insight on how dysregulation of TGF-β signaling alters promoter methylation and histone modifications of TGF-β downstream targets in ovarian cancer.

Take home message: Disruption of TGF-β/SMAD signaling leads to epigenetic silencing of its target genes transiently through histone modifications but permanently by promoter hypermethylation. Targeting the TGF-β signaling pathway may be a novel therapeutic strategy in ovarian cancer.     

c-Jun N-terminal kinases as potential therapeutic targets

Introduction: Proteoglycans are critical molecules involved in multiple physiological cell functions, but also key players in cancer development and progression. In particular, chondroitin sulfate proteoglycan 4 (CSPG4) is recognized as an attractive target for antibody-based approaches because of its high expression on cancer cells in several types of human malignancies and its restricted distribution in normal tissues.

Areas covered: Adoptive transfer of genetically modified T cells is emerging as a powerful therapeutic approach in cancer patients. In this regard, the selection of the appropriate antigen to be targeted in solid tumors becomes a critical aspect in promoting potent antitumor effects while preventing toxicities. This review summarizes the authors’ current knowledge on the expression and function of CSPG4 in normal tissues and malignant tumors, with a particular focus on the potential use of CSPG4 as a target for antigen-specificity redirected T cells.

Expert opinion: T cells expressing a CSPG4-specific chimeric antigen receptor (CAR) offer the possibility to target a broad spectrum of solid tumors for which no curative treatment is currently available. In addition, since CSPG4 is also selectively up-regulated on tumor-associated pericytes, targeting this antigen may also contribute to tumor regression via inhibition of neoangiogenesis. Preclinical experiments to date justify the clinical translation of CSPG4-specific CAR-T cells.     

Hsp90 as a therapeutic target in patients with oesophageal carcinoma

Importance of the field: Oesophageal carcinoma has a poor prognosis with a 5-year overall survival rate of only 10 – 20%. The disease is often diagnosed at a late stage, when dissemination may already have occurred, contributing to the poor prognosis. However, recent developments in targeted therapy now offer new possibilities in the treatment arsenal. Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation, thus promoting cell growth and survival. Hsp90 has been found to be abundantly expressed in oesophageal cancer and may serve as a therapeutic target in the treatment of this disease.

Areas covered in this review: We have summarised available data concerning the role of Hsp90 in oesophageal carcinoma as well as available information on other tumour types.

What the reader will gain: To be able to elaborate on the molecular mechanisms of action of Hsp90 and discuss state-of-the-art of clinical trials involving Hsp90 inhibitors in malignancies, with a special emphasis on oesophageal cancer.

Take home message: Preclinical studies on Hsp90 inhibition in oesophageal cancer are promising and it is anticipated that in the near future clinical trials with Hsp90 inhibitors will be initiated also for oesophageal cancer, using the experience from other trials.     

Does Axl have potential as a therapeutic target in pancreatic cancer?

ABSTRACT

Introduction: Pancreatic cancer is a leading cause of cancer-related death. Metastasis, therapy resistance, and immunosuppression are dominant characteristics of pancreatic tumors. Strategies that enhance the efficacy of standard of care and/or immune therapy are likely the most efficient route to improve overall survival in this disease.

Areas covered: Axl, a member of the TAM (Tyro3, Axl, MerTK) family of receptor tyrosine kinases, is involved in cell plasticity, chemoresistance, immune suppression, and metastasis in various cancers, including pancreatic cancer. This review provides an overview of Axl and its function in normal conditions, summarizes the regulation and function of Axl in cancer, and highlights the contribution of Axl to pancreatic cancer as well as its potential as a therapeutic target.

Expert opinion: Axl is an attractive therapeutic target in pancreatic cancer because it contributes to many of the roadblocks that hamper therapeutic efficacy. Clinical evidence supporting Axl inhibition in pancreatic cancer is currently limited; however, multiple clinical trials have been initiated or are in the planning phase to test the effect of inhibiting Axl in conjunction with standard therapy in pancreatic cancer patients. We anticipate that these studies will provide robust validation of Axl as a therapeutic target in pancreatic cancer.     

MACC1 – a novel target for solid cancers

Introduction: The metastatic dissemination of primary tumors is directly linked to patient survival in many tumor entities. The previously undescribed gene metastasis-associated in colon cancer 1 (MACC1) was discovered by genome-wide analyses in colorectal cancer (CRC) tissues. MACC1 is a tumor stage-independent predictor for CRC metastasis linked to metastasis-free survival.

Areas covered: In this review, the discovery of MACC1 is briefly presented. In the following, the overwhelming confirmation of these data is provided supporting MACC1 as a new remarkable biomarker for disease prognosis and prediction of therapy response for CRC and also for a variety of additional forms of solid cancers. Lastly, the potential clinical utility of MACC1 as a target for prevention or restriction of tumor progression and metastasis is envisioned.

Expert opinion: MACC1 has been identified as a prognostic biomarker in a variety of solid cancers. MACC1 correlated with tumor formation and progression, development of metastases and patient survival representing a decisive driver for tumorigenesis and metastasis. MACC1 was also demonstrated to be of predictive value for therapy response. MACC1 is a promising therapeutic target for anti-tumor and anti-metastatic intervention strategies of solid cancers. Its clinical utility, however, must be demonstrated in clinical trials.     

Modulators of the urokinase-type plasminogen activation system for cancer

Importance of the field: The serine protease urokinase-type plasminogen activator (uPA) and its receptor uPAR as well as two specific inhibitors, the plasminogen activator inhibitor type-1 (PAI-1) and type-2 (PAI-2), are involved in the control of extracellular matrix turnover and tumor growth. Data accumulating over the past 20 years have made increasingly clear that the uPA system has a multifunctional role in neoplastic evolution, affecting cancer cell proliferation, tumor angiogenesis, adhesion and migration.

Areas covered in this review: Several therapeutic strategies inhibiting the uPA system have been or are currently being developed for suppression of tumor growth. This review examines the role of the uPA system in tumor progression and assesses the various therapeutic strategies developed to selectively exploit this system.

What will the reader gain: We focus on the therapeutic developments of the last 15 years. In addition to antibodies and recombinant uPA- or uPAR-derived proteins, various antagonistic peptides as well as small molecules have been designed and synthesized that inhibit the uPA system, leading to reduced tumor progression.

Take home message: The multifunctional potential of the uPA system in cancer has rendered this system an attractive novel target for anticancer therapy. A few novel tumor biology-based therapeutic strategies reported here, opening new ways for patient-optimized and individualized cancer therapy. It may be the right time to evaluate the hypothesis that the uPA system plays a pivotal role in cancer progression and that targeting this system will lead to clinical benefit in cancer patients.