Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor

Neoplastic transformation is often related to abnormal activation of growth factor receptors and their signaling pathways. The concept of targeting specific tumorigenic receptors and/or signaling molecules has been validated by the development and successful clinical application of drugs acting against the epidermal growth factor receptor 2 (HER2/neu, Erb2), the epidermal growth factor receptor 1 (EGFR, HER1), the Brc-Abl kinase, the platelet-derived growth factor receptor, and c-kit. This review will focus on the next promising therapeutic target, the insulin-like growth factor I receptor (IGF-IR). IGF-IR has been implicated in a number of neoplastic diseases, including several common carcinomas. From a pharmaceutical standpoint, of particular importance is that IGF-IR appears to be required for many transforming agents (genetic, viral, chemical) to act, but is not obligatory for the function of normal adult cells. The tumorigenic potential of IGF-IR is mediated through its antiapoptotic and transforming signaling, and in some cases through induction of prometastatic pathways. Preclinical studies demonstrated that downregulation of IGF-IR reversed the neoplastic phenotype and sensitized cells to antitumor treatments. The strategies to block IGF-IR function employed anti-IGF-IR antibodies, small-molecule inhibitors of the IGF-IR tyrosine kinase, antisense oligodeoxynucleotides and antisense RNA, small inhibitory RNA, triple helix, dominant-negative mutants, and various compounds reducing ligand availability. The experience with these strategies combined with the knowledge gained with current anti-growth factor receptor drugs should streamline the development of anti-IGF-IR therapeutics.     

Distant metastasis in breast cancer: molecular mechanisms and therapeutic targets

Distant metastasis is responsible for the death of nearly 45,000 women per year in the US alone. At present, we have no clear understanding about the genetic events that govern the ability of breast cancer cells to settle at and colonize in specific sites in the body. This information is critical for developing therapeutic strategies that would target the tumor cells and their supporting environment at distant sites. This review will discuss investigations on 1) the steps of the metastatic pathway, 2) innovative technologies such as radiologic imaging and molecular manipulations of cells that would help us to study metastasis in real time, 3) strengths and weaknesses of current models for studying metastasis, and 4) how best to design large comprehensive gene searches during metastatic progression of breast cancer. These advances will enable the development of therapies targeted towards blocking the outgrowth of metastatic cells.     

Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics

Evaluation of: Turner N, Pearson A, Sharpe R et al.FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70(5), 2085–2094 (2010).

FGF receptor (FGFR) family members are aberrantly activated during carcinogenesis due to gene amplification, chromosomal translocation and missense mutation. FGFR1 is preferentially amplified in estrogen receptor-positive breast cancer, whereas FGFR2 is amplified in triple-negative breast cancer and diffuse-type gastric cancer. Gene amplification of FGFRs results in ligand-independent FGFR signaling to RAS–ERK, PI3K–AKT and JAK–STAT cascades due to the overexpression of wild-type or C-terminally deleted FGFRs. Cediranib, TKI258, Ki23057, MK-2461 and brivanib are broad-range tyrosine kinase inhibitors targeting FGFRs and other receptors. Clinical application of small-molecule FGFR inhibitors could improve the prognosis of FGFR-driven cancer patients. Diagnostic detection of tumors with FGFR genetic alterations in primary lesion, peritoneal effusion, pleural effusion and bone marrow is necessary to select patients for FGFR-targeted therapeutics.     

Fibroblast growth factor signaling in non-small-cell lung cancer

Despite recent progress in the treatment on non-small cell lung cancer (NSCLC), outcomes remain suboptimal. Treatment advances that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signaling pathways highlight the need to understand the multiple convergent growth factor signaling pathways involved in the pathogenesis of NSCLC. Signaling through fibroblast growth factors (FGF), long recognized for its pro-angiogenic activity, has recently emerged as a contributing factor in the pathogenesis and progression of NSCLC through an autocrine signaling loop. In addition, this pathway may function as a mechanism of resistance to anti-EGFR and anti-VEGF treatment. Clinical experience with FGF receptor (FGFR) inhibitors is mounting, and more specific inhibitors of this signaling pathway are in development. This review describes the structure of the FGF signaling pathway, delineates its dual roles in angiogenesis and proliferation in NSCLC, evaluates FGF ligand and receptor expression as prognostic biomarkers in NSCLC, and discusses the development of FGF pathway inhibitors for the treatment of lung malignancies.     

Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors

Bladder cancer presents several challenges in clinical management. For the large group of noninvasive tumors, key problems are the development of multiple recurrences that require long-term surveillance and a lack of effective therapies to prevent recurrence. For the smaller group of poor prognosis patients with invasive disease, novel therapies are urgently needed. The identification of mutations of FGF receptor 3 (FGFR3) in most noninvasive bladder tumors and the recent finding of overexpression of this receptor not only in superficial tumors but also in many invasive bladder cancers has generated optimism that therapies targeting this receptor tyrosine kinase may have major application in the treatment of urothelial cancers. There is little information on the other members of this receptor family apart from FGFR2, which is implicated as a tumor suppressor. Recent preclinical evaluations of FGFR3 as a therapeutic target have provided a strong impetus for the development of targeted agents for clinical use.     

Tyrosine kinase signalling in breast cancer: Fibroblast growth factors and their receptors

The fibroblast growth factors [Fgfs (murine), FGFs (human)] constitute a large family of ligands that signal through a class of cell-surface tyrosine kinase receptors. Fgf signalling has been associated in vitro with cellular differentiation as well as mitogenic and motogenic responses. In vivo, Fgfs are critical for animal development, and some have potent angiogenic properties. Several Fgfs have been identified as oncogenes in murine mammary cancer, where their deregulation is associated with proviral insertions of the mouse mammary tumour virus (MMTV). Thus, in some mammary tumours of MMTV-infected mouse strains, integration of viral genomic DNA into the somatic DNA of mammary epithelial cells was found to have caused the inappropriate expression of members of this family of growth factors. Although examination of human breast cancers has shown an altered expression of FGFs or of their receptors in some tumours, their role in the causation of breast disease is unclear and remains controversial.     

Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience

Background FGFR3-altered urothelial cancer (UC) correlates with a non-T cell-inflamed phenotype and has therefore been postulated to be less responsive to immune checkpoint blockade (ICB). Preclinical work suggests FGFR3 signalling may suppress pathways such as interferon signalling that alter immune microenvironment composition. However, correlative studies examining clinical trials have been conflicting as to whether FGFR altered tumours have equivalent response and survival to ICB in patients with metastatic UC. These findings have yet to be validated in real world data, therefore we evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance.Methods 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014 to 2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing, were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3-alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients.Results Our findings from this dataset confirm that FGFR3-altered (n = 17) and wild type (n = 86) bladder cancers are equally responsive to ICB (12 vs 19%, p = 0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumours have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response.Conclusions Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumours have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.Subject terms: Bladder cancer, Cancer immunotherapy     

Breast cancer: molecular mechanisms of underlying resistance and therapeutic approaches

Breast cancer (BC) affects over 250,000 women in the US each year. Drug-resistant cancer cells are responsible for most breast cancer fatalities. Scientists are developing novel chemotherapeutic drugs and targeted therapy combinations to overcome cancer cell resistance. Combining drugs can reduce the chances of a tumor developing resistance to treatment. Clinical research has shown that combination chemotherapy enhances or improves survival, depending on the patient’s response to treatment. Combination therapy is a highly successful supplemental cancer treatment. This review sheds light on intrinsic resistance to BC drugs and the importance of combination therapy for BC treatment. In addition to recurrence and metastasis of BC, the article discussed biomarkers for BC.     

Prostaglandin E2 EP receptors as therapeutic targets in breast cancer

Prostaglandins are lipid compounds that mediate many physiological effects. Prostaglandin E2 (PGE(2)) is the most abundant prostanoid in the human body, and synthesis of PGE(2) is driven by cyclooxygenase enzymes including COX-2. Both elevated expression of COX-2 and increased PGE(2) levels have been associated with many cancers including breast cancer. PGE(2) exerts its effect by binding to the E series of prostaglandin receptors (EP) which are G protein-coupled receptors. Four EP receptor subtypes exist, EP1-4, and each is coupled to different intracellular signaling pathways. As downstream effectors of the COX-2 pathway, EP receptors have been shown to play a role in breast and other malignancies and in cancer metastasis. The role of each EP receptor in malignant behavior is complex and involves the interplay of EP receptor signaling on the tumor cell, on stromal cells, and on host immune effector cells. While preclinical and epidemiological data support the use of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors (COXibs) for the prevention and treatment of malignancy, toxicities due to COXibs as well as less than promising results from clinical trials have laboratories seeking alternative targets. As knowledge concerning the role of EP receptors in cancer grows, so does the potential for exploiting EP receptors as therapeutic targets for the treatment or prevention of cancer and cancer metastasis.     

Growth factor receptors in breast cancer: potential for therapeutic intervention

Increased expression and activation of receptor tyrosine kinases occurs frequently in human breast carcinomas. Several therapies targeting these receptors are currently in clinical trials. Therapeutic strategies include blockade of individual receptors with monoclonal antibodies and inhibition of tyrosine kinase function. Trastuzumab is the first of these biologic therapies to be approved for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. Novel trastuzumab-based combinations are being investigated in patients with advanced breast cancer. Large clinical trials have also been launched in the adjuvant setting. Small molecules that inhibit specific tyrosine kinases (e.g., epidermal growth factor receptor, HER2) are in phase I and phase II clinical trials. Other growth-factor-targeted drugs that have reached clinical development include STI571 and antibodies directed at the insulin-like growth factor pathway. Biologic therapies directed against these important receptors are promising. In this review we discuss challenges and opportunities for the development of growth-factor-targeted approaches for the treatment of breast cancer.     

Fibroblast growth factor receptor 1 oncogene partner as a novel prognostic biomarker and therapeutic target for lung cancer

To screen candidate molecules that might be useful as diagnostic biomarkers or for development of novel molecular-targeting therapies, we previously carried out gene-expression profile analysis of 101 lung carcinomas and detected an elevated expression of FGFR1OP (fibroblast growth factor receptor 1 oncogene partner) in the majority of lung cancers. Immunohistochemical staining using tumor tissue microarrays consisting of 372 archived non-small cell lung cancer (NSCLC) specimens revealed positive staining of FGFR1OP in 334 (89.8%) of 372 NSCLCs. We also found that the high level of FGFR1OP expression was significantly associated with shorter tumor-specific survival times ( P <  0.0001 by log-rank test). Moreover, multivariate analysis determined that FGFR1OP was an independent prognostic factor for surgically treated NSCLC patients ( P <  0.0001). Treatment of lung cancer cells, in which endogenous FGFR1OP was overexpressed, using FGFR1OP siRNA, suppressed its expression and resulted in inhibition of the cell growth. Furthermore, induction of FGFR1OP increased the cellular motility and growth-promoting activity of mammalian cells. To investigate its function, we searched for FGFR1OP-interacting proteins in lung cancer cells and identified ABL1 (Abelson murine leukemia viral oncogene homolog 1) and WRNIP1 (Werner helicase interacting protein 1), which was known to be involved in cell cycle progression. FGFR1OP significantly reduced ABL1-dependent phosphorylation of WRNIP1 and resulted in the promotion of cell cycle progression. Because our data imply that FGFR1OP is likely to play a significant role in lung cancer growth and progression, FGFR1OP should be useful as a prognostic biomarker and probably as a therapeutic target for lung cancer. ( Cancer Sci 2007; 98: 1902–1913)     

Fibroblast growth factor signalling influences homologous recombination-mediated DNA damage repair to promote drug resistance in ovarian cancer

Background Ovarian cancer patients frequently develop chemotherapy resistance, limiting treatment options. We have previously shown that individuality in fibroblast growth factor 1 (FGF1) expression influences survival and chemotherapy response.Methods We used MTT assays to assess chemosensitivity to cisplatin and carboplatin following shRNA-mediated knockdown or heterologous over-expression of FGF1 (quantified by qRT-PCR and immunoblot analysis), and in combination with the FGFR inhibitors AZD4547 and SU5402, the ATM inhibitor KU55933 and DNA-PK inhibitor NU7026. Immunofluorescence microscopy was used to quantify the FGF1-dependent timecourse of replication protein A (RPA) and γH2AX foci formation.Results Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7026 re-sensitised resistant cells. FGF1 expression influenced the timecourse of damage-induced RPA and γH2AX nuclear foci formation.Conclusion Drug resistance arises from FGF1-mediated differential activation of high-fidelity homologous recombination DNA damage repair. FGFR and ATM inhibitors reverse platinum drug resistance, highlighting novel combination chemotherapy approaches for future clinical trial evaluation.Subject terms: Ovarian cancer, Growth factor signalling     

NF-kappaB and cancer: mechanisms and targets

In addition to being a central coordinator of immune responses, NF-kappaB signaling also plays a critical role in cancer development and progression and it may determine the response to therapy. NF-kappaB activation was shown to provide a critical mechanistic link between inflammation and cancer and is a major factor that controls the ability of both preneoplastic and malignant cells to resist apoptosis-based tumor surveillance mechanisms. NF-kappaB may also be involved in regulation of tumor angiogenesis and invasiveness. Importantly, NF-kappaB and the signaling pathways that mediate its activation have become attractive targets for development of new chemopreventive and chemotherapeutic approaches.     

Fibroblast growth factor receptor 4 mutation and polymorphism in Japanese lung cancer

We investigated the FGFR4 mutation status at the kinase domain and FGFR4 single nucleotide polymorphism (SNP) at codon 388 in surgically treated non-small cell lung cancer (NSCLC) cases. The presence or absence of FGFR4 mutations of kinase domains was analyzed by direct sequences (n=147), and the presence of FGFR4 Arg388 allele was analyzed by genotyping assay using LightCycler hybridization probes (n=387). FGFR4 mutations were not present in our lung cancer patients. In 61.8% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between the FGFR4 genotype and clinicopathological features such as gender, smoking status and pathological subtypes. EGFR mutation status was not correlated with the FGFR4 genotype of lung cancers. In node-negative patients, the FGFR4 genotype was not correlated with disease outcome, while in the node-positive patients FGFR4 Arg388 was significantly associated with worse survival. This association was not attributed to patient response to adjuvant chemotherapy. Therefore, the role of FGFR4 polymorphism is a prognostic marker for advanced NSCLC in Japanese patients.     

Epidermal growth factor receptor structural alterations in gastric cancer

Background  

EGFR overexpression has been described in many human tumours including gastric cancer. In NSCLC patients somatic EGFR mutations, within the kinase domain of the protein, as well as gene amplification were associated with a good clinical response to EGFR inhibitors. In gastric tumours data concerning structural alterations of EGFR remains controversial. Given its possible therapeutic relevance, we aimed to determine the frequency and type of structural alterations of the EGFR gene in a series of primary gastric carcinomas.     

Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: Current options and emerging strategies

Prostate cancer is androgen-dependent in its early stages and androgen deprivation therapy represents the most effective first-line therapeutic approach. However, after an initial remission, prostate cancer progresses towards the castration resistant prostate cancer (CRPC) stage, with increased malignancy and resistance to conventional chemotherapy.     

c-Met and hepatocyte growth factor: Potential as novel targets in cancer therapy

Receptor tyrosine kinases have come to fruition as therapeutic targets in a variety of malignancies. In this group of targets, the c-Met receptor tyrosine kinase plays an important role in increased cell growth, reduced apoptosis, altered cytoskeletal function, increased metastasis, and other biologic changes. The ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor. Met is overexpressed and mutated in a variety of malignancies, among which germline mutations are of particular interest. Most mutations of Met have been found in the juxtamembrane, the tyrosine kinase, and the semaphorin domain. Met gain-of-function mutations lead to deregulated or prolonged tyrosine kinase activity, which is instrumental to its transforming activity. This review summarizes the biologic functions regulated by Met and its structural requirements as well as related developments in targeted therapy. Treatment approaches, including antagonism of HGF binding to Met, targeting of RNA and the Met protein, and inhibition of the tyrosine kinase domain of Met, are highlighted. Targeting of the HGF/Met pathway, alone or in combination with standard therapies, is likely to improve current therapies in Met-dependent malignancies.