Beyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway and Antiangiogenesis
TL;DR: Although agents targeting FGF signaling are early in development, the potential to target both the VEGF and FGF pathways may translate into improvements in the clinical care of cancer patients.
Abstract: Fibroblast growth factor (FGF) signaling regulates cell proliferation, differentiation, survival, angiogenesis, and wound healing. Compelling evidence for deregulated FGF signaling in tumorigenesis continues to emerge, and a growing body of research suggests that FGF may also play an integral role in the resistance to anti-VEGF therapy. Although agents targeting FGF signaling are early in development, the potential to target both the VEGF and FGF pathways may translate into improvements in the clinical care of cancer patients.
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Journal Article•
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore
PL02-05
All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.
2,737 citations
TL;DR: Whole exome/transcriptome sequencing will be introduced to the clinical laboratory as the companion diagnostic platform facilitating patient selection for FGFR‐targeted therapeutics in the era of personalized medicine.
Abstract: Fibroblast growth factors (FGFs) are involved in a variety of cellular processes, such as stemness, proliferation, anti-apoptosis, drug resistance, and angiogenesis. Here, FGF signaling network, cancer genetics/genomics of FGF receptors (FGFRs), and FGFR-targeted therapeutics will be reviewed. FGF signaling to RAS-MAPK branch and canonical WNT signaling cascade mutually regulate transcription programming. FGF signaling to PI3K-AKT branch and Hedgehog, Notch, TGFβ, and noncanonical WNT signaling cascades regulate epithelial-to-mesenchymal transition (EMT) and invasion. Gene amplification of FGFR1 occurs in lung cancer and estrogen receptor (ER)-positive breast cancer, and that of FGFR2 in diffuse-type gastric cancer and triple-negative breast cancer. Chromosomal translocation of FGFR1 occurs in the 8p11 myeloproliferative syndrome and alveolar rhabdomyosarcoma, as with FGFR3 in multiple myeloma and peripheral T-cell lymphoma. FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes, respectively, due to interstitial deletions in glioblastoma multiforme. Missense mutations of FGFR2 are found in endometrial uterine cancer and melanoma, and similar FGFR3 mutations in invasive bladder tumors, and FGFR4 mutations in rhabdomyosarcoma. Dovitinib, Ki23057, ponatinib, and AZD4547 are orally bioavailable FGFR inhibitors, which have demonstrated striking effects in preclinical model experiments. Dovitinib, ponatinib, and AZD4547 are currently in clinical trial as anticancer drugs. Because there are multiple mechanisms of actions for FGFR inhibitors to overcome drug resistance, FGFR-targeted therapy is a promising strategy for the treatment of refractory cancer. Whole exome/transcriptome sequencing will be introduced to the clinical laboratory as the companion diagnostic platform facilitating patient selection for FGFR-targeted therapeutics in the era of personalized medicine.
448 citations
TL;DR: This review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents.
Abstract: The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies. Recently, the field of FGFR targeting has exponentially progressed thanks to the development of novel agents inhibiting FGFs or FGFRs, which had manageable safety profiles in early-phase trials. Promising treatment efficacy has been observed in different types of malignancies, particularly in tumors harboring aberrant FGFR signaling, thus offering novel therapeutic opportunities in the era of precision medicine. The most exciting challenges now focus on selecting patients who are most likely to benefit from these agents, increasing the efficacy of therapies with the development of novel potent compounds and combination strategies, and overcoming toxicities associated with FGFR inhibitors. After examination of the basic and translational research studies that validated the oncogenic potential of aberrant FGFR signaling, this review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents.
386 citations
Cites background from "Beyond VEGF: Inhibition of the Fibr..."
...FGFs—and especially FGF2—are among the earliest identified proangiogenic factors, and they have a direct effect on tumor angiogenesis at all steps of angiogenesis (5, 57, 58)....
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TL;DR: Efforts are being pursued to develop selective approaches for use against FGF/FGFR by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clinical trials to address these different issues.
Abstract: The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clinical trials to address these different issues.
357 citations
TL;DR: Extended access to next-generation sequencing platforms will facilitate the identification of diseases in which somatic FGFR(1-4) mutations, amplifications and fusions are potentially driving cancer cell viability, further strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application ofFGFR inhibitors.
306 citations
Cites background from "Beyond VEGF: Inhibition of the Fibr..."
...The FGFR pathway was primarily studied in cancer as a direct promoter of endothelial cell proliferation and tumor neoangiogenesis, having complementary and synergistic effects with the vascular endothelial growth factor (VEGF) signaling [1, 2]....
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...FGFR pathway activation has been shown to mediate resistance to anti-VEGF therapy [1, 3]....
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References
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TL;DR: The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
Abstract: background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. methods Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. results The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progressionfree survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. conclusions The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
10,161 citations
"Beyond VEGF: Inhibition of the Fibr..." refers background in this paper
...combination with cytotoxic therapy and minimal activity as single agents with rare exceptions (75, 99)....
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...cacious inpreclinical cancermodels and in clinical trials (74, 75)....
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TL;DR: This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds and reports on genetic studies addressing the functions of endogenous growth factors in the wound repair process.
Abstract: Werner, Sabine, and Richard Grose. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev 83: 835–870, 2003; 10.1152/physrev.00032.2002.—Cutaneous wound healing is a complex proce...
3,234 citations
"Beyond VEGF: Inhibition of the Fibr..." refers background in this paper
...first areas where FGF signaling was shown to be important (55, 56)....
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TL;DR: The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC.
Abstract: Purpose To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC).
2,767 citations
"Beyond VEGF: Inhibition of the Fibr..." refers background in this paper
...combination with cytotoxic therapy and minimal activity as single agents with rare exceptions (75, 99)....
[...]
Journal Article•
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore
PL02-05
All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.
2,737 citations
Wellcome Trust Sanger Institute1, European Bioinformatics Institute2, Harvard University3, Ludwig Institute for Cancer Research4, Erasmus University Rotterdam5, University of Pennsylvania6, University of Sydney7, Institute of Cancer Research8, University of Cambridge9, QIMR Berghofer Medical Research Institute10, Van Andel Institute11, University of Hong Kong12
TL;DR: More than 1,000 somatic mutations found in 274 megabases of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers reveal the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
Abstract: Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
2,732 citations