Abstract: Background: Receptor tyrosine kinase (RTK) activation is the starting point of intracellular signaling cascades that control cellular process such as proliferation, differentiation, migration and survival and aberrant RTK activation may promote cancer initiation and progression. The purpose of this study was to determine the frequency and the influence of major RTKs including EGFR, HER-2, c-MET, and FGFR-2 expression on the outcomes of gastric cancer patients. Methods: Between January 2000 and December 2004, 122 patients with advanced gastric cancer in our institute were selected. All patients underwent gastrectomy and D2 lymph node dissection with a curative aim and pathologically confirmed N3 stage without distant metastasis. Formalin-fixed paraffin-embedded (FFPE) tissue specimens were examined for the expression of EGFR, HER-2, c-MET, FGFR-2 by immunohistochemistry (IHC). The score for expression was assessed by the independent pathologist with weighted histoscore method. We defined positive result as the expression of 3+ in IHC for each RTK. Results: Among 4 RTKs, c-MET expression showed highest frequency as 31 patients (25.4%) followed by FGFR-2 (13; 11.2%), HER-2 (10; 8.5%) and EGFR (6; 5.0%). The majority of samples (58.2%) were negative (wild type) for all four markers. Fourteen patients (11.5%) showed co-expression for these RTKs; one patient was quadruple positive, and the others showed double positivity for c-MET and one of 3 other markers. There were no significant correlations between each biomarker and clinic-pathologic parameters such as patient's gender, differentiation, T stage, lymphovascular invasion, Lauren classification or the number of LN metastasis. With the follow-up period of 21.5 months (0.5–115.7), median overall survival of all patients was 20.9 months (95% CI, 15.2–26.6) and median disease-free survival (DFS) was 17.1 months (95% CI, 9.4–24.8). Based on the status of each receptor, survival outcome was only associated with c-MET over-expression; median DFS of 10.8 months in c-MET positive patients and 22.0 months in c-MET negative patients (p=0.04). Median DFS in patients with co-expression of RTKs showed poorer trend than single marker positive group and wild type group (10.8m, 15.7m, and 19.4m, respectively; p=0.27). Conclusion: We evaluated the expression pattern with four major RTKs in relatively homogenous subgroup of gastric cancer patients with pathologic N3. c-MET over-expression could be a prognostic biomarker for DFS in these patients, suggesting the significant role of c-met in gastric cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B34.

Abstract: The ADAMs (a disintegrin and metalloproteinase) comprise a family of multidomain transmembrane and secreted proteins. Accumulating evidence associates an increased expression of individual ADAM family members with various types of cancer including prostate, breast, skin and lung cancers. However, little is known about its role in gastric cancer. Herein, we investigated the expression of ADAM-9 in gastric cancer, and its implication as a potential therapeutic target for anti-metastaasis therapy. First, we evaluated the expression of ADAM-9 on protein by immunoblotting and transcript level in 24 gastric cancer cell lines by RT-PCR. ADAM-9 protease activity was also measured using ADAM-9 fluorogenic substrate (R & D systems, Minneapolis, MN, USA). We then conducted invasion assay using transwell coated with matrigel in the presence or absence of ADAM-9-specific inhibiting antibody (kindly supplied from Raven Biotechnologies, Inc., South San Francisco, CA). The mRNA expression of ADAM-9 was observed in all the gastric cancer cell lines while the protein expressions of pro- and active-form and protease activities were variable. We selected the cell lines of high baseline ADAM-9 expression (SNU-638, MKN-28 and AGS) and of low baseline expression (SNU-216, MKN-1 and HS-746T) to continue further experiment. Baseline level of ADAM-9 is little correlated with invasion activity though matrigel. Treatment of anti-ADAM-9 antibody does not influence the cytotoxicity. However, it reduced its protease activity and invasiveness, which was dependent on baseline ADAM-9 activity. Actually, protease activity reduced 64.5±0.3% when the specific antibody to ADAM-9 was treated to high expressed cell lines, but 9.6±0.4% were decreased in low expressed cell lines at the 20ug/ml of the antibody. Anti-ADAM-9 antibody inhibited the invasion activity dose dependently, and its effect was more prominent in high ADAM-9-expressing cell lines (67.7±1.9% vs 5.9±4.3% at the 20 ug/ml antibody). Anti-ADAM-9 treatment did not influence on the cell-matrix adhesion, which implies this anti-invasive effect is through its inhibition of protease function. In the hypoxic condition (1% oxygen), invasion was increased along with elevation of both active form of ADAM-9 and its protease activity, suggesting that increased ADAM-9 could have a role of enhancing invasiveness of gastric cancer. To conclude, we presented that ADAM-9 has a role in invasiveness of gastric cancer and would be one of the putative targets for anti-metastasis therapy. This work was supported by the Brain Korea 21 Project for Medical Science, Yonsei University. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 525.

Abstract: Background: TSU-68 is a novel oral multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. Since TSU-68 inhibit angiogenesis pathway which is important to tumor growth and metastasis in human colorectal cancer, we conducted a phase I study to evaluate the safety, tolerability and PK of TSU-68 plus S-1 and oxaliplatin (SOX) in patients with metastatic colorectal cancer (mCRC) treated with prior chemotherapy. Methods and Materials: ECOG PS 0 or 1 patients with mCRC were treated with TSU-68 400 mg/day (Level 1) or 800 mg/day (Level 2) on Days 1–21, S-1 70 mg/m2 on Days 1–14 with one week rest and oxaliplatin 130 mg/m2 IV on Day 1 repeated every 3 week. The dose escalation of TSU-68 was not done more than Level 2 based on the results of phase I studies of TSU-68 alone in Japan. Results: Eleven patients were enrolled in the study. Of 11 patients, 2 patients were excluded from DLT assessment because both patients withdrew the written informed consent (IC) without a DLT during cycle 1. Of 9 evaluable patients, initial 3 patients in Level 1 experienced no DLT. Of 3 patients in Level 2, two patients experienced a DLT (one patient: grade 3 hiccup and grade 3 rash, another one: grade 2 neutropenia which prevented the initiation of the next cycle within 14 days). According to the protocol, additional 3 evaluable patients were enrolled in Level 1, and experienced no DLT. The MTD and RD of TSU-68 in combination with SOX was 400mg. Common adverse drug reactions (ADRs) in cycle 1 included peripheral sensory neuropathy (91%), nausea (82%), anorexia (82%), fatigue (46%), vomiting (36%) and diarrhoea (36%). No patient exhibited grade 4 ADR and treatment related death. Partial response was observed in 2 patients treated with prior chemotherapy. Median PFS was 218 days. TSU-68 plasma concentrations, Cmax and AUC0-t in Level 1 were higher than those in Level 2. There was no appreciable effect of administered TSU-68 on the PK of S-1 components (FT, CDHP and Oxo) and oxaliplatin-derived platinum. Conclusions: Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 400mg. A multi-institutional phase II study of TSU-68 at 400mg/day in combination with SOX is planned. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B8.

Abstract: Introduction: Non-Hodgkin lymphoma (NHL) constitutes ~40% of hematologic malignancies and, in 2020, resulted in 19,940 deaths in the USA. The most common NHL subtypes are diffuse large B-cell lymphoma (DLBCL), including primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma (FL). Although a majority of patients respond to standard-of-care therapy, many patients with NHL eventually relapse, highlighting the need for additional treatments. Real-world data regarding the safety and efficacy of emerging therapies in the relapsed/refractory (R/R) population, and the association between treatment patterns and patient outcomes, are limited. These data could provide unique insights to clinical and health-related quality of life (HRQoL) outcomes in patients with DLBCL, FL, or PMBCL treated with emerging therapies, especially novel options such as chimeric antigen receptor (CAR) T cell therapies. Methods: The Connect ® Lymphoma Disease Registry (NCT04982471) is a US-based, multicenter, prospective observational cohort study of patients with R/R NHL (DLBCL, FL, and PMBCL). Approximately 2100 patients ≥ 18 years of age from ~200 community oncology (~80%) or academic (~20%) sites will be enrolled over a ~3-year period. Patients with histologically confirmed NHL subtypes will be enrolled into 1 of 4 cohorts: first R/R DLBCL, second R/R DLBCL, first R/R FL, or first R/R PMBCL (Figure). Patients will be required to have begun second- (first R/R) or third- (second R/R) line systemic treatment within 60 days prior to enrollment. Patients receiving treatment for any active malignancy other than DLBCL, FL, or PMBCL at the time of enrollment, or who are diagnosed with any other malignancy in the 6 months prior to enrollment, will be excluded. All treatment and management decisions will be determined by the practicing clinicians. Patients may undergo hematopoietic stem cell transplantation, CAR T cell therapy, or other treatments at other sites while participating in this study. Patients will be followed from enrollment for up to 5 years or until death, withdrawal of consent, loss to follow-up, or study termination, whichever occurs first. Data collection will occur at enrollment (baseline) and then every ~3 months. The main objectives of the Connect ® Registry are to describe patient characteristics, practice patterns, and factors associated with treatment choice, sequencing, and effectiveness in NHL subtypes. Secondary objectives include describing treatment regimen safety, patient-reported outcomes (PROs) including HRQoL, and healthcare resource utilization outcomes. Exploratory objectives include tumor and blood biomarker evaluation and understanding the availability of social support and its impact on long-term treatment decision-making. Case report forms will be used to collect clinical and treatment data, including baseline demographics, clinical characteristics, treatment details and response, and socioeconomic factors. Outcome measures for efficacy will be progression-free survival, event-free survival, objective response rate, time to next treatment, and overall survival. The availability of social support will be assessed via a specific questionnaire administered at baseline. General (EQ-5D-5L) and disease-specific (FACT-Lym) questionnaires will also be administered. Patients may also optionally agree to release tumor biopsies and blood samples for biomarker analysis. Clinicians will be required to report serious adverse events (AEs), secondary primary malignancies, and confirmed COVID-19 infections within 24 hours. Non-serious AEs of interest include grade 1-3 cytokine release syndrome, grade 1-3 neurotoxicity, grade 3 colitis, grade 3 arrhythmia, grade 3 hemorrhage. Other AEs of interest to be collected include grade 3 hypogammaglobulinemia, prolonged grade 3 cytopenia, and grade 3 infections. Data collected in the Connect ® Registry will increase understanding of the association between emerging therapies and patient outcomes for R/R DLBCL, FL, and PMBCL. Study support: Bristol Myers Squibb Figure 1 Figure 1. Disclosures Flowers: Amgen: Research Funding; Janssen: Research Funding; Biopharma: Consultancy; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Nektar: Research Funding; Karyopharm: Consultancy; Iovance: Research Funding; Allogene: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; BeiGene: Consultancy; Kite: Research Funding; EMD: Research Funding; Genentech/Roche: Consultancy, Research Funding; Morphosys: Research Funding; Adaptimmune: Research Funding; Novartis: Research Funding; Epizyme, Inc.: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Acerta: Research Funding; 4D: Research Funding; Denovo: Consultancy; Celgene: Consultancy, Research Funding; Guardant: Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; SeaGen: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Takeda: Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding. Andorsky: Celgene/Bristol Myers Squibb: Research Funding; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AstraZeneca: Other: served on steering committees; Epizyme: Research Funding; AbbVie: Research Funding. Burke: SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; Beigene: Consultancy, Speakers Bureau; Kymera: Consultancy. Cerhan: Genentech: Research Funding; NanoString: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration. Grinblatt: Astellas Pharma, Inc.: Consultancy; Bristol Myers Squibb: Consultancy; Astra Zeneca: Consultancy; AbbVie: Consultancy. Toomey: Bristol Myers Squibb: Consultancy. Zelenetz: Gilead: Honoraria, Research Funding; Verastem: Honoraria; Novartis: Honoraria; MEI Pharma: Honoraria, Research Funding; SecuraBio: Honoraria; Abbvie: Honoraria, Research Funding; MorphoSys: Honoraria; Pharmacyclics: Honoraria; AstraZeneca: Honoraria; LFR: Other; Genentech/Roche: Honoraria, Research Funding; NCCN: Other; MethylGene: Research Funding; Beigene: Honoraria, Other, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Amgen: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Sullivan: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Flick: Bristol Myers Squibb: Current Employment. Kiselev: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kaplan: Bristol Myers Squibb: Current Employment. Ahn: Bristol Myers Squibb: Current Employment.