FGFR1 mRNA Research Articles

Comprehensive biomarker analyses identifies HER2, EGFR, MET RNA expression and thymidylate synthase 5'UTR SNP as predictors of benefit from S-1 adjuvant chemotherapy in Japanese patients with stage II/III gastric cancer.

Purpose: A comprehensive molecular analysis was conducted to identify prognostic and predictive markers for adjuvant S-1 chemotherapy in stage II/III Japanese gastric cancer (GC) patients and to evaluate their potential suitability for alternative cytotoxic or targeted drugs.Experimental Design: We investigated genetic polymorphisms of enzymes potentially involved in 5-fluoruracil (5-FU) metabolism as well as platinum resistance, previously identified genomic subtypes potentially predicting 5-FU benefit, and mRNA expression levels of receptor tyrosine kinases and KRAS as potential treatment targets in a single institution cohort of 252 stage II/III GC patients treated with or without S-1 after D2 gastrectomy.Results: 88% and 62% GC had a potentially 5-FU sensitive phenotype by SNP analyses of TS 3'UTR, and TS 5'UTR, respectively. 24%, 46%, 40%, 5%, and 44% GC had a potentially platinum sensitive phenotype by SNP analyses of GSTP1, ERCC1 rs11615, ERCC1 rs3212986, ERCC2, and XRCC1, respectively. High HER2, EGFR, FGFR2, or MET mRNA expression was observed in 49%, 66%, 72%, and 54% GC, respectively. High HER2 expression was the only significant prognosticator (HR=3.912, 95%CI: 1.706-8.973, p=0.0005). High HER2 (p=0.031), low EGFR (p=0.124), high MET (p=0.165) RNA expression, and TS 5'UTR subtype 2R/2R, 2R/3C, or 3C (p=0.058) were significant independent predictors for S-1 resistance.Conclusions: The present study suggests that platinum-based or RTK targeted agents could be alternative treatment options for a substantial subgroup of Japanese GC patients currently treated with S-1. HER2, EGFR, MET, and TS 5'UTR SNP appear to be promising predictive markers for S-1 resistance warranting validation in an independent GC series.

1056PD - Phase I experience with rogaratinib in patients with head and neck cancer selected based on FGFR mRNA overexpression

1056PD - Phase I experience with rogaratinib in patients with head and neck cancer selected based on FGFR mRNA overexpression

925TiP - Phase Ib/II study to evaluate the safety, tolerability and pharmacokinetics of rogaratinib in combination with atezolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer and FGFR mRNA overexpression

925TiP - Phase Ib/II study to evaluate the safety, tolerability and pharmacokinetics of rogaratinib in combination with atezolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer and FGFR mRNA overexpression

Preselection of Lung Cancer Cases Using FGFR1 mRNA and Gene Copy Number for Treatment With Ponatinib

IntroductionPreclinically, high epidermal growth factor receptor 1 (FGFR1) messenger RNA (FGFR1-MRNA) and FGFR1 amplification (FGFR1-AMP) predicted sensitivity to fibroblast growth factor receptor inhibitors in non–small-cell lung cancer and small-cell lung cancer cell lines. KRAS mutations did not preclude sensitivity. Patients and MethodsMetastatic EGFR- and ALK-negative lung cancers were screened for FGFR1-MRNA by in-situ hybridization (ISH) and FGFR1-AMP by silver in-situ hybridization (SISH). Patients with positive findings were offered ponatinib, a multi–kinase inhibitor of FGFR1-4. Differences in overall survival (OS) between cohorts were assessed by the log-rank test. Association of FGFR1 positivity with clinicopathologic features were assessed by Fisher exact test and Kruskal-Wallis rank sum test. ResultsA total of 171 cases were prescreened: 9 (7.3%) of 123 SISH+; 53 (42.1%) of 126 ISH+; and 6 cases concordantly positive for SISH and ISH. SISH+ cases had fewer coincident KRAS mutations (P = .03) than SISH− cases, and ISH+ cases had worse OS (P = .020) than ISH− cases. Data distributions suggested a distinct higher positivity cut point for FGFR1 ISH (≥ 20%), occurring in 29 (23%) of 126 cases, was associated with small-cell lung cancer histology (P = .022), soft tissue metastases (P = .050) and shorter OS (P = .031). Four patients received ponatinib on study: All ISH+ by the initial cut point, 2 of 4 by higher cut point, 1 of 4 SISH+. Tolerability was poor. The best response for the 2 higher ISH cases was stable disease and progressive disease for the 2 lower ISH cases. ConclusionElevated FGFR1-MRNA is more common than FGFR1-AMP and associated with worse OS. Higher FGFR1 mRNA expression may be associated with a specific phenotype and is worthy of further exploration. Ponatinib's poor tolerance suggests further fibroblast growth factor receptor exploration in ISH+ cases should utilize more selective FGFR1 inhibitors.

FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis.

ObjectivesMetastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established.MethodsWe investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors (FGFR1-4) and their ligands (FGF3, 4 and 19) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression in situ. Results were correlated with clinico-pathologic data and molecular subtypes.ResultsPrimary tumors showed FGFR1 (6.3%) and FGF3,4,19 (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed FGFR1 amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither FGFR2-4 amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also FGFR1 amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111).ConclusionsWe provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.

Monoclonal antibody targeting of fibroblast growth factor receptor 1c causes cardiac valvulopathy in rats

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF-FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves.

Abstract 4779: Rogaratinib, a small molecule pan-FGFR inhibitor potently inhibits FGFR4-phosphorylation and exerts anti-tumor efficacy in vivo and in vitro

Abstract Fibroblast growth factor signaling plays an essential role in many physiological processes, including cell proliferation, survival, differentiation, migration, and apoptosis Over-activation of the pathway can lead to the development of various cancers. There are four different FGFR subtypes with over 20 ligands providing a very complex network of interactions and signaling. FGFR4 plays an important role in normal physiology such as myogenesis muscle regeneration and bile acid synthesis Activating mutations in the kinase domain of FGFR4 have been shown to mediate cancer development, for example, breast cancer, hepatocellular carcinoma (HCC) or rhabdomyosarcoma. Rogaratinib is a potent inhibitor of all FGFR subtypes with low nanomolar binding kinetics towards the four kinase domains. We explored the effect of rogaratinib on cell lines with high expression levels of FGFR4 mRNA, such as breast cancer cell line MDA-MB453 and rhabdomyosarcoma cell line SH30. We could show that the proliferation of these cell lines is potently inhibited by rogaratinib and accompanied with induction of apoptosis. The Mode-of-action analysis of rogaratinib activity in these cell lines showed inhibition of FGFR4-phosphorylation and downstream signaling at clinical relevant doses. The in vitro efficacy of rogaratinib in FGFR4 dependent cell lines was further observed as in vivo efficacy in xenograft models of rhabdomyosarcoma and HCC. Elevation of FGFR4 expression has been associated with resistance development in several cancer types such as breast cancer. In line with the observed anti-tumor efficacy of rogartinib in vitro and in vivo in breast cancer, sarcoma and HCC models, RNA in situ hybridization by RNAscope, revealed high FGFR4 mRNA expression in TMA's from these tumor types..) The combination of rogaratinib with standard-of-care provides further options for addressing resistance mechanisms mediated by elevated FGFR4 expression. In addition we have profiled a number of patient derived HCC xenograft models revealing the high efficacy of rogaratinib in models with elevated FGFR expression including FGFR4. Citation Format: Oliver Politz, Sylvia Gruenewald, Alexander Walter, Franziska Siegel, Arne Scholz, Sebastian Bender, Christoph Kneip, Peter Ellinghaus. Rogaratinib, a small molecule pan-FGFR inhibitor potently inhibits FGFR4-phosphorylation and exerts anti-tumor efficacy in vivo and in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4779.

FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis and lung cancer.

The aim of this study was to investigate the expression of FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) as well as their clinical significance. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were used to detect FGF2 and FGFR2 expression in LC and adjacent normal tissues of LC patients and lavage fluid of idiopathic pulmonary fibers patients and normal controls (confirmed by bronchoalveolar lavage examination). The expression levels of FGF2 mRNA and protein in the non-small cell LC tissues were significantly higher than those in the adjacent normal tissues (P<0.001). The expression level of FGF2 protein in lavage fluid of patients with IPF was higher than that of the control group (P<0.001). The expression level of FGFR2 mRNA in the non-small cell LC tissues was significantly higher than that in the adjacent normal tissues (P<0.001). The expression level of FGFR2 protein in the non-small cell LC tissues was higher than that in the adjacent normal lung tissues (P<0.001). The expression levels of FGF2 mRNA and FGFR2 mRNA in cancer tissues were not significantly correlated with age, sex and history of smoking (P>0.05), but were significantly correlated with lymph node metastasis, tumor differentiation and TNM staging. FGF2 and FGFR2 proteins were highly expressed in cancer tissues of LC patients and lavage fluid of patients with IPF. The expression of FGF2 mRNA and FGFR2 mRNA was correlated with lymph node metastasis and TNM stage. The high expression levels of FGF2 mRNA and FGFR2 mRNA were associated with tumor metastasis and poor prognosis of LC patients.

Preselection of lung cancer cases using FGFR1 mRNA and gene copy number for treatment with ponatinib.

12095Background: NSCLC and SCLC cell line data suggested high FGFR1 mRNA levels and FGFR1 amplification (FGFR1-AMP) could predict sensitivity to FGFR TKIs. Overlap with KRAS mutations did not precl...

Rogaratinib in patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression and effects of mutations in the FGFR signaling pathway.

4513Background: Activation of FGFR signaling is involved in a variety of malignancies including advanced urothelial cancer (UC). Rogaratinib is an oral pan-FGFR kinase inhibitor. We report here the...

FGF8 and FGFR3 are up-regulated in hypertrophic chondrocytes: Association with chondrocyte death in deep zone of Kashin-Beck disease

ObjectiveThe aim of this study was to investigate FGF8 and FGFR3 expression in clinical samples of Kashin–Beck disease (KBD), an endemic osteochondropathy found in China, as well as in pre-clinical models of this disease. MethodCartilage was collected from the hand phalanges of five patients with KBD and from five healthy children. Sprague-Dawley rats were administered a selenium-deficient diet for four weeks prior to exposure to the T-2 toxin. ATDC5 cells were differentiated into hypertrophic chondrocytes for twenty-one days, and then treated with 3-morpholinosydnonimine (SIN-1) (0, 1, 3, or 5 mM) for 24 h. FGF8 and FGFR3 were visualized using immunohistochemistry; protein levels were assessed by western blotting, and mRNA levels were determined by real-time RT-PCR. ResultsIncreased staining of FGF8 and FGFR3 was observed in the cartilage of children with KBD compared to normal children. Both increased FGF8 and FGFR3 staining, as well as protein levels, were also observed in the cartilage of rats fed normal or Se-deficient diets plus T-2 toxin exposure, compared to those in rats fed with normal or Se-deficient diets alone. SIN-1 treatment of hypertrophic chondrocytes (ATCD5 cells) increased FGF8 and FGFR3 protein and mRNA levels in a dose-dependent manner. ConclusionOur data indicate that SIN-1 induces FGF8 and FGFR3 overexpression and this is involved in the abnormal terminal differentiation and degradation of the ECM in cartilage. FGF8 and FGFR3 may therefore play an important role in the onset of deep zone necrosis and pathogenesis in KBD in adolescent children.

Sex differences in the development of hepatic steatosis in cafeteria diet-induced obesity in young mice

The present study was planned to improve our understanding about sex differences in the development of hepatic steatosis in cafeteria diet-induced obesity in young mice. Female (FCaf) and male (MCaf) mice fed a cafeteria diet had similar body weight gain and adiposity index, but FCaf had a more extensive steatosis than MCaf. FCaf livers exhibited a higher non-alcoholic fatty liver disease activity score, elevated lipid percentage area (+34%) in Sudan III staining and increased TG content (+25%) compared to MCaf. Steatosis in FCaf was not correlated with changes in the transcript levels of lipid metabolism-related genes, but a reduced VLDL release rate was observed. Signs of oxidative stress were found in FCaf livers, as elevated malondialdehyde content (+110%), reduced catalase activity (−36%) and increased Nrf2 and Hif1a mRNA expression compared to MCaf. Interestingly, fibroblast growth factor 21 (Fgf21) mRNA expression was found to be exclusively induced in MCaf, which also exhibited higher FGF21 serum levels (+416%) and hepatic protein abundance (+163%) than FCaf. Moreover, cafeteria diet increased Fgfr1, Fsp27 and Ucp1 mRNA expression in brown adipose tissue of males (MCaf), but not females (FCaf). FGF21 hepatic production by male mice seems to be part of a complex network of responses to the nutritional stress of the cafeteria diet, probably related to the unfolded protein response activation. Although aimed at the restoration of hepatic metabolic homeostasis, the branch involving Fgf21 upregulation seems to be impaired in females, rendering them incapable of reducing the hepatic lipid content and cellular oxidative stress.

Relationship between FGF23/FGFR4 expression in atrial tissue and atrial fibrosis in patients with atrial fibrillation

Objective: To observe the expression of fibroblast growth factor 23 (FGF23) and FGFR4 in patients with atrial fibrillation (AF) and its relationship with atrial fibrosis. Methods: Fifty-one patients with rheumatic heart disease undergoing cardiac surgery at the Second Affiliated Hospital of Nanchang University from October 2016 to April 2017 were divided into two groups according to whether they were complicated with atrial fibrillation: 39 patients with persistent AF(AF group), and 12 patients with sinus rhythm (SR group). The right atrial appendage was cut out during cardiac surgery. The expression of FGF23 and FGFR4 mRNA was detected by quantitative real-time PCR. The expression of FGFR4 protein was detected by Western blot. Atrial structure was evaluated by echocardiography. Masson staining was used to evaluate the degree of atrial fibrosis. The expression of FGF23 and FGFR4 was compared between the two groups.Additionally, the relationship between FGF23 and FGFR4 expression and atrial fibrosis was evaluated. Results: AF group had significantly higher right and left atrial diameter than SR group((40.1±1.6 )mm vs (34.1±1.5)mm, (52.4±2.9)mm vs (41.3±2.4)mm, all P<0.05) . There were no statistically significant differences in age, gender, ejection fraction between the two groups. The expression of FGF23 and FGFR4 mRNA in AF group were significantly higher than those in SR group (1.93±0.32 vs 0.93±0.14, 1.89±0.17 vs 0.91±0.11, both P<0.05). Compared with the SR group, the protein expression of FGFR4 in the AF group was significantly higher(1.76±0.21 vs 0.84±0.12). In AF group, there was no correlation between FGF23 mRNA and atrial diameter (r=0.274 (left atrial), r=0.238 (right atrium), both P>0.05). Meanwhile, FGFR4 mRNA and protein expression had no correlation with atrial diameter either. There was positive correlation between FGF23 mRNA and atrial collagen volume fraction in AF group (r=0.42, P<0.05). The expression of FGFR4 mRNA and protein were positively correlated with the atrial collagen volume fraction (r=0.573, r=0.478, all P<0.05). Conclusion: The expression of FGF23 and FGFR4 in atrial fibrillation patients is increased, which is positively correlated with atrial fibrosis, suggesting that FGF23/FGFR4 pathway may play an important role in atrial fibrillation by promoting atrial fibrosis.

Overexpression of miR-133 decrease primary endothelial cells proliferation and migration via FGFR1 targeting

Angiogenesis is one of the essential hallmarks of cancer that is controlled by the balance between positive and negative regulators. FGFR1 signaling is crucial for the execution of bFGF-induced proliferation, migration, and tube formation of endothelial cells (ECs) and onset of angiogenesis on tumors. The purpose of this study is to identify whether or not miR-133 regulates FGFR1 expression and accordingly hypothesize if it plays a crucial role in modulating bFGF/FGFR1 activity in ECs and blocking tumor angiogenesis through targeting FGFR1. The influences of miR-133 overexpression on bFGF stimulated endothelial cells were assessed by cell growth curve, MTT assaying, tube formation, and migration assays. Forced expression of miR-133 caused significant reductions in bFGF-induced proliferation and migratory ability of ECs. MiR-133 Expression was negatively correlated with both mRNA and protein levels of FGFR1 in the transfected ECs isolated from peripheral blood. Moreover, overexpression of miR-133 drastically reduced the rate of cell division and disturbed capillary network formation of transfected ECs. These findings suggest that miR-133 plays an important function in bFGF-induced angiogenesis processes in ECs and provides a rationale for new therapeutic approaches to suppress tumor angiogenesis and cancer.

Rogaratinib treatment of patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression.

494 Background: Activation of FGFR signaling is involved in a variety of malignancies including advanced urothelial cancer (UC). Rogaratinib is an oral pan-FGFR kinase inhibitor. We report here the results from a phase I expansion cohort in UC patients prescreened for FGFR1-3 mRNA expression levels and activating mutations. (NCT01976741) Methods: Patients with advanced urothelial carcinomas were selected based on high FGFR1-3 mRNA expression in biopsy specimens. Selected patients were treated with rogaratinib 800mg twice daily until tumour progression, untolerable toxicity, or withdrawal. Tumor response was assessed by RECIST, v1.1. Adverse events were reported using CTCAE v4.03 criteria. Results: A total of 219 UC patients were prescreened for FGFR1-3 mRNA expression levels and FGFR3 activating mutations, with 99 samples (45%) found to be FGFR-positive. Of those, 87% of samples were positive for FGFR3 mRNA, 5% for FGFR1 mRNA and 8% were double FGFR mRNA-positive (FGFR1/2, 1/3 or 2/3). Frequency of FGFR3 activating mutations in UC samples was 7%, all of which also had high FGFR3 mRNA. Fifty two patients (median prior line of treatment 2) started treatment and 51 were evaluable for response. Rogaratinib was generally well tolerated and AEs manageable with dose modification. The most common AEs were diarrhea (49%) and hyperphosphatemia (49%). Objective response rate (ORR) was 24% (12/51; all PRs) and disease control rate (DCR) was 73% (37/51). Eleven of 12 pts with a PR were positive for FGFR3 mRNA, 5 of whom also had FGFR3 mutations, and one patient was positive for FGFR1 mRNA. Ten FGFR-positive UC patients had prior immuno-oncology (I/O) treatment, 9 of whom had progressive disease as best response. For these 10 patients the ORR was 30% and the DCR 80%. Conclusions: Selection of pts for treatment with rogaratinib based on FGFR mRNA expression levels was feasible and identified drug-sensitive patients with and without underlying DNA alterations. Rogaratinib had a favorable safety profile and showed promising anti-tumor activity in UC patients. Responses and disease stabilization were observed with rogoratinib in UC pts refractory to prior I/O treatment. Clinical trial information: NCT01976741.

Fibroblast growth factor receptor 1 and 3 expression is associated with regulatory PI3K/AKT kinase activity, as well as invasion and prognosis, in human laryngeal cancer.

Aberrant fibroblast growth factor receptor (FGFR) expression is thought to contribute to the development of many types of cancer. As yet, however, their impact on the course and prognosis of head and neck cancer remains to be determined. Here, we aimed to investigate the effects of expression of the FGFR family members FGFR1 and FGFR3, as well as their downstream PI3K/AKT signal-regulated kinases, on the aggressiveness and prognosis of laryngeal cancer. In total 137 surgically removed squamous cell laryngeal cancer (SCLC) and 100 matched non-cancerous laryngeal mucosa (NCLM) samples were assessed for mRNA expression using quantitative real-time PCR. The corresponding proteins were analyzed by Western blotting. SLUG expression was assessed by immunohistochemistry. The expression data were subsequently related to tumor front grading (TFG), local/nodal recurrences, prognosis and overall survival. The FGFR1, FGFR3 and PI3K/AKT kinase mRNA and protein levels were found to be significantly higher in the SCLC than the NCLM samples (p < 0.05). A high FGFR1 mRNA/protein expression level was found to be associated with an increased invasion rate, according to TFG scale and SLUG level, a high local/nodal recurrence rate and a poor prognosis (p < 0.05). Similarly, we found that a high FGFR3 mRNA/protein expression level was associated with a shorter survival time (p < 0.05). In addition, we found that high PI3K/AKT kinase mRNA/protein levels were associated with a high TFG (p < 0.05). We also found that FGFR1/3 mRNA and FGFR1 protein levels were inversely associated with overall survival (log-rank test: FGFR1 mRNA p = 0.03, FGFR3 mRNA p = 0.04, FGFR1 protein p = 0.03). Subsequent multivariate analyses revealed that high FGFR3 mRNA expression may serve as an independent poor prognostic factor (HR 2.32, 95% CI 1.03-6.59; p = 0.04). We also found that the p-PI3K regulatory kinase protein level was significantly associated with survival in the cohort studied (HR 1.78, 95% CI 0.64-8.53; p = 0.03). From our data we conclude that FGFR1 and FGFR3, as well as its downstream regulatory PI3K/AKT kinases, may serve as potential biomarkers for the invasiveness and prognosis of laryngeal cancer. The expression of FGFR1/3-PI3K/AKT regulatory pathway members may be instrumental for the identification of patients at risk for an unfavorable clinical outcome.

Abstract A099: Safety, tolerability, pharmacokinetics, and efficacy of pan-fibroblast growth factor receptor inhibitor rogaratinib in Japanese patients with refractory, locally advanced metastatic solid tumors selected with a novel, mRNA-based patient selection strategy

Abstract Background: Fibroblast growth factor receptor (FGFR)-mediated pathways are considered to be promising anticancer therapy targets. There are several types of genetic evidence that support an oncogenic function of FGFRs: identification of gene amplifications, activating mutations, chromosomal translocations, and aberrant splicing at the post-transcriptional level. Since FGFR expression is regulated not only by genetic but also by epigenetic mechanisms, examination of tumor FGFR mRNA levels may identify cancer patients likely to benefit from rogaratinib (BAY 1163877), an oral, potent small-molecule pan-FGFR inhibitor. We conducted a phase I study of rogaratinib in Japanese subjects with refractory, locally advanced or metastatic solid tumors selected by elevated tumor FGFR1-3 mRNA expression to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy (NCT02592785). Methods: Japanese subjects were enrolled at 600 mg BID (Cohort1) or 800 mg BID as the recommended phase 2 dose (Cohort 2) on a continuous 21-day cycle based on high FGFR1-3 mRNA expression. Archival or newly obtained formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples were analyzed for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope®; Advanced Cell Diagnostics, Inc., Newark, CA) and Nanostring® assay (NanoString Technologies, Inc., Seattle, WA). Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: In the prescreening phase of this study, 62 FFPE samples from cancer patients with several tumor types were assessed for FGFR1-3 tumor mRNA expression levels and the valid prescreening results were obtained from 48 samples. Among them, 16 samples (16/48, 33%) were found to overexpress FGFR mRNA. Overall, 9 FGFR mRNA-positive patients were enrolled and treated with rogaratinib, 3 in Cohort 1 and 6 in Cohort 2. All subjects had experienced more than one adverse event (AE). Most of them were Grade 1 or 2. No DLT, no SAE, no Grade 4 or 5 AEs were reported. Two G3 drug-related AEs were hyponatremia and increased ALT. The most common treatment related AE was hyperphosphatemia with Grade 1 or 2 and all cases were controllable with anti-hyperphosphatemia treatment. PK exposure in Japanese subjects was comparable to Western subjects. Eight patients could be advanced to at least one tumor response assessment by CT imaging. As a result, 1 patient with epipharynx cancer achieved a partial response (PR) while 5 patients had stable disease (SD) as best response in target lesions, including three SD patients with tumor shrinkage compared to baseline CT imaging. Conclusions: Rogaratinib showed a good tolerability with a confirmed PR and a disease control rate (DCR) of 56% (5/9). We concluded that 800 mg BID is safe and well tolerable to Japanese patients confirming the global recommended dose. The high prevalence of FGFR mRNA overexpression in tumors as well as the clinical response of FGFR-positive tumors support an mRNA-based patient selection for FGFR inhibitor treatment of cancer. Citation Format: Makoto Tahara, Shunji Takahashi, Matthias Ocker, Stuart Ince, Hendrik Nogai, Changliang Zhang, Fumiyoshi Sei, Peter Ellinghaus. Safety, tolerability, pharmacokinetics, and efficacy of pan-fibroblast growth factor receptor inhibitor rogaratinib in Japanese patients with refractory, locally advanced metastatic solid tumors selected with a novel, mRNA-based patient selection strategy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A099.

FGFR1 signaling potentiates tumor growth and predicts poor prognosis in esophageal squamous cell carcinoma patients

ABSTRACTFibroblast growth factor receptor-1 (FGFR1) over-expression was broadly found in squamous cancer, where it induced cellular proliferation, differentiation, and metastasis by activating various signaling pathway. However, the role of FGFR1 gene expression in predicting prognosis of Esophageal Squamous Cell Carcinoma (ESCC) and its regulatory function in the progression of ESCC are not well understood. Therefore, we performed an analysis of FGFR1 mRNA expression by quantitative RT-PCR in tumor tissue of 145 patients with ESCC. The relationships between FGFR1 gene expression and clinicopathological parameters, also the prognosis were further examined. Results suggested that higher FGFR1 gene expression predicted worse overall survival (HR = 1.502, 95%[CI] = 1.005–2.246, P = 0.045). Disease-free survival tends to be shorter in patients with higher FGFR1 expression but without statistical significance (HR = 1.398, 95%[CI] = 0.942–2.074, P = 0.096). FGFR1 was up regulated in multiple ESCC cell lines. Subsequent in vitro experiments demonstrated that anti-FGFR1 treatment by PD173074 inhibited TE-1 and EC9706 cell viability along with the attenuation of MEK-ERK signaling pathway. In vivo, PD173074 administration also had shown potent ESCC growth arresting effect. Overall, our study suggested that FGFR1 gene expression could be an independent prognosis predictive factor in patients with ESCC. Anti-FGFR1 inhibited ESCC growth and could be a potential strategy in ESCC targeted therapy.

Blocked expression of key genes of the angiogenic pathway in JSRV-induced pulmonary adenocarcinomas

JSRV (Jaagsiekte Sheep Retrovirus) is a retrovirus inducing a transmissible lung adenocarcinoma in sheep and goats with predominantly lepidic and papillary lesions. This naturally occurring lung cancer in large animals shares many features with human pneumonic-type lung adenocarcinomas with predominant lepidic growth. The metastatic spread is rare in both human and animal cancers. This unique feature prompted us to decipher the angiogenesis pathway in these cancers. We focused on the levels of mRNA and proteins of genes implicated in the extension of JSRV-induced lung adenocarcinomas by studying their expression in lung cancers (n = 10) and normal lungs (n = 10) and in primary epithelial alveolar type II cells derived from cancers (n = 10) or normal lungs (n = 6). In parallel, we evaluated the levels of expression of key genes in lung tissues collected from lepidic (n = 13) or papillary (n = 5) human adenocarcinomas and, when available, adjacent normal lungs (n = 11). We measured the expression of the same key genes implicated in angiogenesis, lymphangiogenesis and degradation of the extracellular matrix. In ovine adenocarcinomas, VEGFR2 and VEGFD mRNA were downregulated in cancers; MMP9, TIMP1 and FGFR2 mRNA were overexpressed as compared to normal lungs. Importantly, VEGFA and VEGFR2 proteins were not expressed in JSRV-induced cancers. In human lepidic adenocarcinomas, VEGFA and VEGFR2 mRNA were weakly expressed and no VEGFR2 protein was detectable. Downregulation of key angiogenic players may contribute to the control of extra thoracic invasion of cancer cells in human and ovine pneumonic-type adenocarcinoma with predominant lepidic growth.

P2.02-011 Clinical and Molecular Features of Lung Cancers with Increased FGFR1 mRNA and/or Gene Copy Number

P2.02-011 Clinical and Molecular Features of Lung Cancers with Increased FGFR1 mRNA and/or Gene Copy Number