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FGFR
FGFR FGFR(14)
FGFs have a wide variety of functions, including stimulating myeloid progenitors. FGFs comprise the largest family of growth factor ligands with 23 members.(7) Alternate splicing of four FGFR genes results in the production of over 48 different isoforms. These isoforms vary in their ligand binding properties and kinase domains, but all share a common extracellular region composed of three Ig-like domains (D1-D3).(8) Interactions with FGFs occur via FGFR domains D2 and D3. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor. A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic TYK domain, and one isoform only contains the extracellular domains D1 and D2.(9)
bFGFRs comprise a subfamily of RTKs that are master regulators of a broad spectrum of cellular and developmental processes, including apoptosis, proliferation, migration and angiogenesis.(10) bFGFRs are glycoproteins composed of extracellular Ig-like domains, a hydrophobic helix transmembrane region, and a cytoplasmic part containing the TYK domain. They transduce signals from their high-affinity ligands (BFGFs) to RAS/MAPK and PI3K/AKT pathways through BFGFR substrate 2, and also to the diacylglycerol/PKC pathway through phospholipase Cg.(11, 12) The BFGFR family consists of four members-BFGFR1, BFGFR2, BFGFR3, and BFGFR4. The bFGF receptors are, as their name implies, receptors that bind to members of the bFGF family of proteins. These receptors bind bFGFs, members of the largest family of growth factor ligands, comprising 22 members.(13)bFGF1/2 exemplifies angiogenesis-initiating signaling as it binds to an endothelial transmembrane TYK receptor.(1, 2) Anti-angiogenic properties of type 1 IFN has been attributed, in part, to inhibition of bFGF expression.(3) Cu is a co-factor required for the angiogenic mediator bFGF.(4) The amino-terminal end of TSP1 contains a tryptophan-rich motif that blocks bFGF driven angiogenesis.(5)
Gene amplification and over-expression of BFGFRs have been observed in a variety of human cancers: BFGFR1 over-expression in urothelial carcinoma and luminal B-type BCs, and BFGFR2 over-expression in BC and gastric cancer. BFGFR1 amplification may be a major contributor to poor prognosis in luminal-type BCs. Missense mutations of BFGFRs have also been observed in many human cancers: BFGFR2 mutations in BC, gastric cancer, lung cancer, ovarian cancer, and endometrial uterus cancer, and BFGFR3 mutations in urothelial carcinoma.(11)


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References

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.

2. Bogenrieder T HM. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene. 2003;22:6524-36.

3. Kiladjian JJ MR, Hoffman R. The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood. 2011;117(18):4706-15. PMCID: 21389325.

4. Chen D, Dou QP. New uses for old copper-binding drugs: converting the pro-angiogenic copper to a specific cancer cell death inducer. 2008.

5. Iruela-Arispe ML, Lombardo M, Krutzsch HC, Lawler J, Roberts DD. Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats. Circulation. 1999;100(13):1423-31.

6. VEGF. [cited]; Available from: http://en.wikipedia.org/wiki/VEGF.

7. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol. 2001;2(3):1-12.

8. Coutts JC, Gallagher JT. Receptors for fibroblast growth factors. Immunology and cell biology. 1995;73(6):584-90.

9. Receptor_tyrosine_kinase. [cited]; Available from: http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase.

10. Acevedo VD IM, Spencer DM. Paths of FGFR-driven tumorigenesis. Cell Cycle. 2009;8(4). PMCID: 19182515.

11. Takeuchi K IF. Receptor tyrosine kinases and targeted cancer therapeutics. Biol Pharm Bull. 2011;34(12):1774-80. PMCID: 22130229.

12. Ornitz D. M. IN. Genome Biol. 2001;2:3005.

13. Wolf K, Schulz C, Riegger G, Pfeifer M. Tumour necrosis factor?? induced CD70 and interleukin?7R mRNA expression in BEAS?2B cells. European Respiratory Journal. 2002;20(2):369-75.

14. Alitalo K. The fatal detachment. Nature Cell Biology. 2001;3:E157 - E9.

News
3:43 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: FGFR, PI3K, CLL
There have been significant advances in our understanding of the pathogenesis of chronic lymphocytic leukemia (CLL) over the last decade, which has been accompanied by a rapid increase in treatment options. Inhibitors of BCRsignaling such as ibrutinib and idelalisib, and pro-apoptotic agents such as ABT- 199 have shown great promise in initial clinical trials and have been at the forefront of recent developments. However, despite the encouraging early data, these agents do not appear to represent a “cure” for CLL and mechanisms of resistance to these agents have already been identified. In light of these considerations there remains a need for alternative treatment strategies. Lenalidomide, a second-generation derivative of thalidomide, has been demonstrated to have significant clinical activity in CLL. Its effect appears to be mediated by reduction of CLL-cell proliferation, improvement of anti-tumor immune responses and reduction of pro-tumoral factors in the CLL microenvironment. This review discusses our current understanding of the mechanism of action of lenalidomide on both healthy cells and in CLL. It also summarises the published clinical trial experience with this drug, and proposes an ongoing role for this agent in the CLL armamentarium.
Contributors : Aik C Tan ; Paul Huang
Series Type : Genome variation profiling by array
Organism : Homo sapiens

Malignant rhadboid tumors (MRTs) are lethal paediatric cancers characterised by a deficiency in the SWI/SNF subunit SMARCB1. Here we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy.
Genome variation profiling of A204 parental and acquired resistance cell line

Friday, September 16, 2016 4:27 PM|Yanqing Huang, Chengliu Jin, Tomoaki Hamana, Junchen Liu, Cong Wang, Lei An, Wallace L. McKeehan, Fen Wang|International Journal of Biological Sciences|Labels: FGFR, prostate cancer

Bone metastasis is the major cause of morbidity and mortality of prostate cancer (PCa). Fibroblast growth factor 9 (FGF9) has been reported to promote PCa bone metastasis. However, the mechanism by which overexpression of FGF9 promotes PCa progression and metastasis is still unknown. Herein, we report that transgenic mice forced to express FGF9 in prostate epithelial cells (F9TG) developed high grade prostatic intraepithelial neoplasia (PIN) in an expression level- and time-dependent manner. Moreover, FGF9/TRAMP bigenic mice (F9TRAMP) grew advanced PCa earlier and had higher frequencies of metastasis than TRAMP littermates. We observed tumor microenvironmental changes including hypercellularity and hyperproliferation in the stromal compartment of F9TG and F9TRAMP mice. Expression of TGFβ1, a key signaling molecule overexpressed in reactive stroma, was increased in F9TG and F9TRAMP prostates. Both in vivo and in vitro data indicated that FGF9 promoted TGFβ1 expression via increasing cJun-mediated signaling. Moreover, in silico analyses showed that the expression level of FGF9 was positively associated with expression of TGFβ1 and its downstream signaling molecules in human prostate cancers. Collectively, our data demonstrated that overexpressing FGF9 in PCa cells augmented the formation of reactive stroma and promoted PCa initiation and progression.

Thursday, September 15, 2016 7:42 AM|Skinner, H. D., Giri, U., Yang, L., Woo, S. H., Story, M. D., Pickering, C. R., Byers, L. A., Williams, M. D., El-Naggar, A., Wang, J., Diao, L., Shen, L., Fan, Y. H., Molkentine, D. P., Beadle, B. M., Meyn, R. E., Myers, J. N., Heymach, J. V.|Clinical Cancer Research current issue|Labels: FAK, FGFR, HNN

Purpose: Head and neck squamous cell carcinoma (HNSCC) is commonly treated with radiotherapy, and local failure after treatment remains the major cause of disease-related mortality. To date, human papillomavirus (HPV) is the only known clinically validated, targetable biomarkers of response to radiation in HNSCC.

Experimental Design: We performed proteomic and transcriptomic analysis of targetable biomarkers of radioresistance in HPV-negative HNSCC cell lines in vitro, and tested whether pharmacologic blockade of candidate biomarkers sensitized cells to radiotherapy. Candidate biomarkers were then investigated in several independent cohorts of patients with HNSCC.

Results: Increased expression of several targets was associated with radioresistance, including FGFR, ERK1, EGFR, and focal adhesion kinase (FAK), also known as PTK2. Chemical inhibition of PTK2/FAK, but not FGFR, led to significant radiosensitization with increased G2–M arrest and potentiated DNA damage. PTK2/FAK overexpression was associated with gene amplification in HPV-negative HNSCC cell lines and clinical tumors. In two independent cohorts of patients with locally advanced HPV-negative HNSCC, PTK2/FAK amplification was highly associated with poorer disease-free survival (DFS; P = 0.012 and 0.034). PTK2/FAK mRNA expression was also associated with worse DFS (P = 0.03). Moreover, both PTK2/FAK mRNA (P = 0.021) and copy number (P = 0.063) were associated with DFS in the Head and Neck Cancer subgroup of The Cancer Genome Atlas.

Conclusions: Proteomic analysis identified PTK2/FAK overexpression is a biomarker of radioresistance in locally advanced HNSCC, and PTK2/FAK inhibition radiosensitized HNSCC cells. Combinations of PTK2/FAK inhibition with radiotherapy merit further evaluation as a therapeutic strategy for improving local control in HPV-negative HNSCC. Clin Cancer Res; 22(18); 4643–50. ©2016 AACR.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: FGFR, childhood cancer, GIST, sarcoma
Although regorafenib was approved for use in patients who had progressive GIST despite imatinib and/or sunitinib on the basis of phase II and phase III data, it has not been examined in a systematic fashion in patients with other forms of sarcoma. Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and evidence of activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like sarcoma, there is precedent to examine SMOKIs (small molecule oral kinase inhibitors) such as regorafenib in sarcomas other than GIST. It is also recognized that SMOKIs (small molecule oral kinase inhibitors)such as regorafenib, sorafenib, pazopanib, and sunitinib have overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most of these SMOKIs (small molecule oral kinase inhibitors) block vascular endothelial growth factor and platelet derived growth factors receptors (VEGFRs and PDGFRs), speaking to a common mechanism of action of several of these agents.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: FGFR, MM, clinical trial
The purpose of this study is to determine if adding elotuzumab to pomalidomide and low-dose dexamethasone is a more effective treatment of relapsed and refractory multiple myeloma compared to pomalidomide and low-dose dexamethasone alone.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: FGFR, MM, clinical trial
This is a dose finding pilot study to evaluate the safety and determine the maximum tolerated dose of the combination of carfilzomib and pomalidomide with dexamethasone (CPD) in patients with relapsed or refractory multiple myeloma followed by a phase II expansion at the MTD to evaluate efficacy. The study will explore the efficacy of CPD including overall response, time to progression, progression free survival, and time to next therapy.
Tuesday, September 13, 2016 8:19 PM|Si Shi, Xingyu Li, Bo You, Ying Shan, Xiaolei Cao, Yiwen You|Journal of Cancer (RSS 2.0)|Labels: FGFR, pharyngeal

Background: FGF receptor (FGFR) family can be activated by FGFs and play important roles in regulating cell growth, differentiation, migration and angiogenesis. Recent studies suggested that FGFR4 could regulate several processes including tumor progression. Nasopharyngeal carcinoma (NPC) is a malignancy with a high occurrence in Southeast Asia and Southern China. However, the molecule mechanism and the potential roles of FGFR4 in NPC remain unknown

Methods: Immunohistochemistry and western blot were used to investigate the expression of FGFR4 in NPC samples. Then we used statistical analysis to evaluate the diagnostic value and the associations of FGFR4 expression with clinical parameters. In vitro studies, the effects of FGFR4 on proliferation and migration of NPC cell line CNE2 were measured by the starvation-refeeding experiment, CCK8 assay, wounding healing assay and transwell migration assay. The changes of the epithelial-mesenchymal transition (EMT) markers in CNE2 cells after knocking down the expression of FGFR4 were measured by Western blot and immunofluorescence analysis.

Results: FGFR4 was overexpressed in NPC as compared with the inflammatory tissues. High expression of FGFR4 was correlated with Ki67 expression, clinical stages and prognosis in NPC patients (P<0.05).While in vitro, the upregulation of FGFR4 was accompanied with CNE2 cells released from serum starvation. Moreover, it could increase cell proliferation and migration by regulating EMT markers in CNE2 cells.

Conclusion: Our data suggested that FGFR4 might induce NPC progression and act as a potential therapeutic target in NPC.

Tuesday, September 13, 2016 2:05 PM|Deanna J. Fall, Holly Stessman, Sagar S. Patel, Zohar Sachs, Brian G. Van Ness, Linda B. Baughn, Michael A. Linden|Journal of Cancer|Labels: FGFR, MM, biomarker diagnostic

Multiple myeloma (MM) is an incurable malignant neoplasm hallmarked by a clonal expansion of plasma cells, the presence of a monoclonal protein in the serum and/or urine (M-spike), lytic bone lesions, and end organ damage. Clinical outcomes for patients with MM have improved greatly over the last decade as a result of the re-purposing of compounds such as thalidomide derivatives, as well as the development of novel chemotherapeutic agents including first and second generation proteasome inhibitors, bortezomib (Bz) and carfilzomib. Unfortunately, despite these improvements, the majority of patients relapse following treatment. While Bz, one of the most commonly used proteasome inhibitors, has been successfully incorporated into clinical practice, some MM patients have de novo resistance to Bz, and the majority of the remainder subsequently develop drug resistance following treatment. A significant gap in clinical care is the lack of a reliable clinical test that would predict which MM patients have or will subsequently develop Bz resistance. Thus, as Bz resistance remains a significant challenge, research efforts are needed to identify novel biomarkers of early Bz resistance, particularly when an early therapeutic intervention can be initiated. Recent advances in MM research indicate that genomic data can be extracted to identify novel biomarkers that can be utilized to select more effective, personalized treatment protocols for individual patients. Computationally integrating large patient databases with data from whole transcriptome profiling and laboratory-based models can potentially revolutionize our understanding of MM disease mechanisms. This systems-wide approach can provide rational therapeutic targets and novel biomarkers of risk and treatment response. In this review, we discuss the use of high-content datasets (predominantly gene expression profiling) to identify novel biomarkers of treatment response and resistance to Bz in MM.

Tuesday, September 13, 2016 2:05 PM|Guillemette Fouquet, Benjamin Hebraud, Sylvain Garciaz, Anne Marie Stoppa, Murielle Roussel, Denis Caillot, Marie Lorraine Chrétien, Bertrand Arnulf, Raphael Szalat, Laurent Garderet, Lina Benajiba, Brigitte Pegourie, Caroline Regny, Bruno Royer, Alexis Caulier, Cyrille Touzeau, Benoit Tessoulin, Jean Paul Fermand, Thierry Facon, Michel Attal, Hervé Avet Loiseau, Philippe Moreau, Xavier Leleu|Journal of Cancer|Labels: FGFR, MM

The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen.

We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure.

Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH.

This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.

Thursday, September 1, 2016 10:05 PM|Brown, W. S., Tan, L., Smith, A., Gray, N. S., Wendt, M. K.|Molecular Cancer Therapeutics current issue|Labels: FGFR, breast cancer

Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial–mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1–4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096–106. ©2016 AACR.

Thursday, August 25, 2016 10:00 AM|Sanchorawala, V., Shelton, A. C., Lo, S., Varga, C., Sloan, J. M., Seldin, D. C.|Blood CLINICAL TRIALS AND OBSERVATIONS|Labels: FGFR

The objectives of a phase 1/2 trial of pomalidomide with dexamethasone for the treatment of light chain (AL) amyloidosis were to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose, and hematologic and clinical response. A 3+3 dose-escalation phase (15 patients) was followed by an expansion cohort (12 patients) enrolled at the MTD. Pomalidomide was administered at 2 and 3 mg on days 1 to 28 (cohorts 1 and 2) and 4 mg on days 1 to 21 (cohort 3) every 28 days, with weekly dexamethasone at a dose of 20 mg. Twenty-seven patients with previously treated AL were enrolled, 15 during dose escalation (6 at 2 mg, 3 at 3 mg, and 6 at 4 mg) and 12 during dose expansion (all at 4 mg). One patient experienced dose-limiting toxicity at 4 mg; the MTD was determined as 4 mg. The most common grade ≥3 drug-related adverse events included myelosuppression and fatigue. Overall, hematologic response (HR) was 50% in 24 evaluable patients. The median time to best HR was 3 cycles, and median duration of HR was 15 months. Median overall survival has not yet been reached, with a median follow-up of 17.1 months and median event-free survival of 17.8 months. This trial was registered at www.clinicaltrials.gov as #NCT01570387.

Wednesday, August 17, 2016 1:13 PM|Chudasama, P., Renner, M., Straub, M., Mughal, S. S., Hutter, B., Kosaloglu, Z., Schwessinger, R., Scheffler, M., Alldinger, I., Schimmack, S., Persigehl, T., Kobe, C., Jäger, D., von Kalle, C., Schirmacher, P., Beckhaus, M.-K., Wolf, S., Heining, C., Gröschel, S., Wolf, J., Brors, B., Weichert, W., Glimm, H., Scholl, C., Mechtersheimer, G., Specht, K., Fröhling, S.|Clinical Cancer Research Online First Articles|Labels: FGFR, leiomyosarcoma, sarcoma

Purpose: Altered FGFR1 signaling has emerged as therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties and potential as drug target of FGFR1 in STS. Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by fluorescence in situ hybridization, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis. Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; Cohort 1), 13 of 79 (16.5%; Cohort 2), and 80 of 254 (31.5%; Cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, Cohort 2) and 39 of 254 (15.4%; Cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway. Conclusions: These data identify FGFR1 as driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as therapeutic option in this challenging group of diseases.

Monday, August 1, 2016 10:05 PM|Pearson, A., Smyth, E., Babina, I. S., Herrera-Abreu, M. T., Tarazona, N., Peckitt, C., Kilgour, E., Smith, N. R., Geh, C., Rooney, C., Cutts, R., Campbell, J., Ning, J., Fenwick, K., Swain, A., Brown, G., Chua, S., Thomas, A., Johnston, S. R. D., Ajaz, M., Sumpter, K., Gillbanks, A., Watkins, D., Chau, I., Popat, S., Cunningham, D., Turner, N. C.|Cancer Discovery recent issues|Labels: FGFR, MapK

FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy.

Significance: Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838–51. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 803

Thursday, July 28, 2016 1:46 PM|Onclive Colorectal Cancer Articles|Labels: FGFR, PDGF, VEGF, CRC
Axel Grothey, MD, discusses both the LUME-1 and LUME-2 trials, the differences between left and right tumors in colorectal cancer, and how that information could potentially be used in diagnosis and treatment.
Thursday, July 28, 2016 8:48 AM|Verheijen, R. B., Bins, S., Mathijssen, R. H. J., Lolkema, M., van Doorn, L., Schellens, J. H. M., Beijnen, J. H., Langenberg, M. H., Huitema, A. D., Steeghs, N.|Clinical Cancer Research Online First Articles|Labels: FGFR

Purpose: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median PFS and tumor shrinkage appears in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically-guided individualized dosing. Experimental Design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At week 3, 5 and 7 the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was < grade 3. Results: In total, 17 patients had at least one Cmin <20 mg/L at week 3, 5 and 7. Of these, 10 were successfully treated with a pharmacokinetically-guided dose escalation, leading to daily dosages ranging from 1000 to 1800 mg daily. Cmin in these patients increased significantly from 13.2 (38.0%) mg/L (mean (CV%)) to 22.9 mg/L (44.9%). Thirteen patients had all Cmin levels {greater than or equal to}20 mg/L. Of these, nine patients with a high Cmin of 51.3 mg/L (45.1%) experienced {greater than or equal to} grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients Cmin remained above the threshold at 28.2 mg/L (25.3%). Conclusions: A pharmacokinetically-guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes such as progression free survival.

Thursday, July 28, 2016 7:56 AM|Kumar, D., Vishwakarma, V., New, J., Gutierrez, W., Chavan, H., Kasturi, P., Tawfik, O., Girod, D., Houten, B. V., Leef, G., Joshi, R., Shelton, S., Straub, J., Shnayder, Y., Kakarala, K., Tsue, T., Lin, F., Dasari, S., Thomas, S.|Cancer Research recent issues|Labels: FGFR, HNN
Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC), which affects 50,000 new patients annually in the United States, is associated with less than 50% 5-year survival. HNSCC tumors display increased glycolysis, even in the presence of oxygen. Consequently, there is an increase in lactic acid (LA) production. However, the effect of lactic acid in the tumor microenvironment and the mechanisms whereby HNSCC tumors survive in highly acidic conditions remain unknown. HNSCC consist of up to 80% tumor-associated fibroblasts (TAFs). We previously reported that activation of receptor tyrosine kinase, c-Met, by TAF-secreted hepatocyte growth factor (HGF) contributes to HNSCC progression (1,2). The mechanism associated with tumor-stroma metabolic symbiosis is not well understood. On this basis, we hypothesized that TAF-secreted HGF regulates HNSCC glycolysis. We demonstrate that HNSCC-secreted basic fibroblast growth factor (bFGF) induces oxidative phosphorylation (OXPHOS) in TAFs. In addition, bFGF regulates secretion of HGF from TAFs. TAF-secreted HGF increases HNSCC glycolysis and induces bFGF secretion from HNSCC. Thus, HNSCC and TAFs engage in reciprocal signaling through paracrine effects of HGF and bFGF. Inhibition of c-Met with small molecule inhibitor PF-02341066 or specific knockdown with c-Met siRNA decreased TAF-facilitated HNSCC glycolysis, lactic acid production and bFGF expression. In addition, inhibition of FGFR with small molecule inhibitor AZD-4547 decreased OXPHOS and HGF expression in TAFs. Inhibition of FGFR also reduced HNSCC-stimulated phosphorylation of p42/44 mitogen activated protein kinase, proliferation and migration in TAFs. Further, we tested the efficacy of AZD-4547 in combination with c-Met inhibitor PF-02341066 in mitigating TAF-induced HNSCC growth in vitro and in vivo. Combined treatment with AZD-4547 and PF-02341066 significantly inhibited TAF-induced proliferation of HNSCC in vitro compared to the vehicle control treated cells (p<0.001). Further, combined treatment significantly reduced growth of admixed HNSCC and TAF xenograft tumors (p<0.001). Our cumulative findings underscore the therapeutic potential of combinatorial treatment with PF-02341066 and AZD-4547 in HNSCC. The therapeutic approach developed in this study may be a feasible in HNSCC.1. Wheeler SE, Shi H, Lin F, Dasari S, Bednash J, Thorne S, et al. Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models. Head 36(3):385-92.2. Knowles LM, Stabile LP, Egloff AM, Rothstein ME, Thomas SM, Gubish CT, et al. HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15(11):3740-50.Citation Format: Dhruv Kumar, Vikalp Vishwakarma, Jacob New, Wade Gutierrez, Hemant Chavan, Partha Kasturi, Ossama Tawfik, Douglas Girod, Bennett Van Houten, George Leef, Radhika Joshi, Shary Shelton, Jeffrey Straub, Yelizaveta Shnayder, Kiran Kakarala, Terance Tsue, Fangchen Lin, Sumana Dasari, Sufi Thomas. Targeting tumor-stroma metabolic symbiosis for head and neck cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B37.
Wednesday, July 20, 2016 9:31 AM|Paino, T., Garcia-Gomez, A., Gonzalez-Mendez, L., San Segundo, L., Hernandez-Garcia, S., Lopez-Iglesias, A.-A., Algarin, E. M., Martin-Sanchez, M., Corbacho-Gonzalez, D., Ortiz-de-Solorzano, C., Corchete, L., Gutierrez, N. C., Mateos, M. V., Garayoa, M., Ocio, E. M.|Clinical Cancer Research Online First Articles|Labels: FGFR, MM

Purpose: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models. Experimental Design: In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies. Results: PIM447 is cytotoxic for myeloma cells due to cell cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI=0.002), lenalidomide + dexamethasone (CI=0.065) and pomalidomide + dexamethasone (CI=0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma. Conclusions: Our results demonstrate dual anti-tumoral and bone protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma.

Thursday, July 14, 2016 10:05 PM|Srivastava, A. K., Hollingshead, M. G., Weiner, J., Navas, T., Evrard, Y. A., Khin, S. A., Ji, J. J., Zhang, Y., Borgel, S., Pfister, T. D., Kinders, R. J., Bottaro, D. P., Linehan, W. M., Tomaszewski, J. E., Doroshow, J. H., Parchment, R. E.|Clinical Cancer Research recent issues|Labels: FGFR, MET

Purpose: Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect.

Experimental Design: Sandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/1235, pY1235, and pY1356. Using pMET:MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and -compensated (VEGFR blockade) models.

Results: By limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET:MET, pY1235-MET:MET, and pY1356-MET:MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET:MET and pY1356-MET:MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation.

Conclusions: These validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field. Clin Cancer Res; 22(14); 3683–94. ©2016 AACR.

Monday, July 11, 2016 1:55 PM|Liu, H., Ai, J., Shen, A., Chen, Y., Wang, X., Peng, X., Chen, H., Shen, Y., Huang, M., Ding, J., Geng, M.|Clinical Cancer Research Online First Articles|Labels: FGFR, MET

Purpose: Lately, emerging evidence has suggested that oncogenic kinases are associated with specific downstream effectors to govern tumor growth, suggesting potential translational values in kinase-targeted cancer therapy. Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is one of the most investigated kinases in molecularly targeted cancer therapy. Herein, we investigated whether there exists key downstream effector(s) that converges FGFR signaling and determines the therapeutic response of FGFR-targeted therapy. Experimental Design: A range of assays was used to assess the role of c-Myc in FGFR aberrant cancers and its translational relevance in FGFR-targeted therapy, including assessment of drug sensitivity using cell viability assay, signaling transduction profiling using immunoblotting, and in vivo antitumor efficacy using cancer cell line based xenografts and patient-derived xenografts models. Results: We discovered that c-Myc functioned as the key downstream effector that preceded FGFR-MEK/ERK signaling in FGFR aberrant cancer. Disruption of c-Myc overrode the cell proliferation driven by constitutively active FGFR. FGFR inhibition in FGFR-addicted cancer facilitated c-Myc degradation via phosphorylating c-Myc at threonine 58. Ectopic expression of undegradable c-Myc mutant conferred resistance to FGFR inhibition both in vitro and in vivo. c-Myc level alteration stringently determined the response to FGFR inhibitors, as demonstrated in FGFR responsive cancer subset, as well as cancers bearing acquired or de novo resistance to FGFR inhibition. Conclusions: This study reveals a stringent association between FGFR and the downstream effector c-Myc in FGFR dependent cancers, and suggests the potential therapeutic value of c-Myc in FGFR-targeted cancer therapy.

Wednesday, June 29, 2016 6:00 PM|Wen-Ya Zhou, Hong Zheng, Xiao-Ling Du, Ji-Long Yang|Cancer Biology & Medicine|Labels: FGFR
The fibroblast growth factor receptor (FGFR) family plays important roles in regulating cell growth, proliferation, survival,differentiation and angiogenesis. Deregulation of the FGF/FGFR signaling pathway has been associated with multiple developmentsyndromes and cancers, and thus therapeutic strategies targeting FGFs and FGFR in human cancer are currently being explored.However, few studies on the FGF/FGFR pathway have been conducted in sarcoma, which has a poor outcome with traditionaltreatments such as surgery, chemotherapy, and radiotherapy. Hence, in the present review, we provide an overview of the role ofthe FGF/FGFR pathway signal in sarcoma and FGFR inhibitors, which might be new targets for the treatment of sarcomasaccording to recent research.
CONCLUSIONSTreatment with dovitinib demonstrated modest efficacy in patients with advanced SCC with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in patients with SCC are warranted. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Thursday, June 16, 2016 3:00 PM|Cancer|Cancer via MedWorm.com|Comments|Labels: FGFR, lung cancer
In contrast to targeted therapy development in lung adenocarcinoma, trials targeting fibroblast growth factor receptor 1 (FGFR1) in squamous cell lung cancers generally have been disappointing. Gene amplification or overexpression of this target may not be a sufficiently robust predictor of efficacy for FGFR1 inhibitors. See also pages 000‐000. (Source: Cancer)
Wednesday, June 1, 2016 8:50 PM|Peter Stopfer|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: FGFR, PDGF, VEGF

Pharmacokinetic properties of nintedanib in healthy volunteers and patients with advanced cancer
Claudia Dallinger Dirk Trommeshauser, Kristell Marzin, Andre Liesener, Rolf Kaiser, Peter Stopfer
Journal of Clinical Pharmacology, Vol. , No. (2016) pp. -
Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef®) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma NSCLC after first‐line chemotherapy, and as monotherapy (Ofev®) in the USA and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single‐ and multiple‐doses and intravenous (i.v.) administration were assessed using three datasets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of four studies that enrolled a total of 113 healthy volunteers; (3) a pooled data analysis of four studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean: 1390 mL/min) and a high volume of distribution at steady state (Vss = 1050 L). Urinary excretion of i.v. nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after i.v. administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to i.v. dosing (4‐hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first‐pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice‐daily dosing. Nintedanib's PK was time‐independent; accumulation after repeated administration was negligible. This article is protected by copyright. All rights reserved