Browsing Over 131 Presentations
45P - Antimetastatic activity of apigenin in human breast carcinoma cells by regulation of different MMPs gene expression (ID 239)
- Shweta Rajoriya (Jabalpur, India)
- Shweta Rajoriya (Jabalpur, India)
Abstract
Background
Matrix metalloproteinases are family of zinc dependent endoproteinases degrade the extracellular matrix, have been identified as poor prognosis markers and therapeutic targets for breast cancer patients. Effect of apigenin was observed on mRNA expression on different MMPs in MDA MB- 231 breast cancer cells including its effect on cancer cell migration and invasion.
Methods
MDA MB- 231 cells were cultured with different concentrations (0, 10, 20 and 40 μM) of apigenin for 48 hrs. mRNA expressions of MMP-1, MMP-3, MMP-7, MMP-9 amd MMP- 11 were analyzed by real time PCR. For cell migration wound healing assay was done at 0, 6, 24, and 48 h periods. To asses the cell invasion MDA MB-231 cancer cells were seeded on collagen based matrigel chamber and treated with 10, 20 and 40μM apigenin, whereas untreated cells considered as control. After 48hrs cells invaded through matrigel quantified by colorimetric method.
Results
Our results showed that MMP-1 and MMP-11 were significantly downregulated upto 0.36 folds and 0.55 folds respectively at 40 μM apigenin treatment in MDA MB-231 cells in comparision to cells without drug. In comparision to untreated cancer cells the MMP-3 gene expressions were 0.46, 0.27 and 0.12 fold in 10μM, 20μM and 40μM apigenin treated MDA MB-231 cells. The apigenin significantly decreased MMP-7 gene expression level upto 0.34 fold and 0.05 fold at 20 μM and 40 μM concentrations in MDA MB-231 cells. Apigenin significantly downregulated MMP-9 mRNA expression level in dose dependent manner in MDA MB-231 cancer cells as compared to untreated cells. Wound healing assay results exhibited that apigenin significantly reduce the migration of cancer cells. In cells treated with 20μM and 40μM apigenin 16.64% and 25.81% of the wound remains unresolved after 48 hrs. The cell invasion assay showed that apigenin significantly inhibited the migration of cells, 40 μM of apigenin showed only 73.52% invasion, as compared to the untreated cells.
Conclusions
In conclusion, apigenin reduced the mRNA expressions of MMP-1, MMP-3, MMP-7, MMP-9 and MMP-11 in MDA-MB-231 cells. Apigenin also inhibited the invasion and cell migration. Therefore, we suggest that apigenin may be used as a candidate drug for the inhibition of metastasis of human breast cancer.
Editorial acknowledgement
This is the part of my Ph. D. degree, done at Animal Biochemistry Division, ICAR- Indian Veterinary Reasech Institute, Izatnagar, Bareilly, U.P., India
Legal entity responsible for the study
Dr. Shweta Rajoriya.
Funding
ICAR-Indian Veterinary Research Institute, Bareilly, U.P., India (Indtitutional Funding).
Disclosure
The author has declared no conflicts of interest.
TAT 2021 Honorary award keynote lecture: Academic drug discovery - Is partnership with industry a marriage made in heaven? (ID 318)
- Ruth Plummer (Newcastle-upon-Tyne, Tyne and Wear, United Kingdom)
- Ruth Plummer (Newcastle-upon-Tyne, Tyne and Wear, United Kingdom)
PSMA targeted CAR-T therapy (ID 11)
- Bruce Levine (Philadelphia, PA, United States of America)
- Bruce Levine (Philadelphia, PA, United States of America)
Live Q&A and discussion (ID 58)
- Martin E. Gutierrez (Hackensack, NJ, United States of America)
- Martin E. Gutierrez (Hackensack, NJ, United States of America)
- Anthony W. Tolcher (San Antonio, TX, United States of America)
- Daniel S. S. Chen (Mountain View, CA, United States of America)
- Michael T. Stumpp (Schlieren, Switzerland)
- Pablo Umana (Schlieren, Zurich, Switzerland)
32O - First-in-human (FIH) study of SCC244, a novel potent and highly selective c- MET inhibitor, in patients (pts) with advanced non-small cell lung cancer (NSCLC) (ID 225)
- Huajun Chen (Guangzhou, China)
- Huajun Chen (Guangzhou, China)
- Jin-ji Yang (Guangzhou, China)
- Jian-ying Zhou (Hangzhou, China)
- Jun Zhao (Beijing, China)
- Yu-ping Sun (Jinan, China)
- Qing Wen (Jinan, China)
- Qing Zhou (Guangzhou, China)
- Zhen Zhang (Guangzhou, China)
- Hai-yan Tu (Guangzhou, China)
- Jian-ya Zhou (Hangzhou, China)
- Pei Zhang (Hangzhou, China)
- Xi Chen (Hangzhou, China)
- Han-xiao Chen (Beijing, China)
- Qi Dang (Jinan, China)
- Ming-hui Sun (Shanghai, China)
- Yue Li (Shanghai, China)
- Yi-long Wu (Guangzhou, China)
Abstract
Background
SCC244 is a novel potent and highly selective c-MET inhibitor, which displayed high antitumor activity and desirable pharmacokinetic (PK) profile in preclinical models. This first-in-human phase I study was designed to evaluate the safety, PK, and preliminary efficacy of SCC244. Here, we reported the results from phase Ia part of the study.
Methods
Escalating doses of SCC244 (from 100 mg to 400 mg), using a conventional 3+3 escalation scheme, were administered orally once daily in advanced NSCLC pts regardless of c-MET status.
Results
At the data cut-off date of Aug 21, 2020, a total of 19 pts were enrolled to 4 dose levels (3 at 100 mg, 3 at 200 mg, 7 at 300 mg, and 6 at 400 mg). The most common (≥ 20%) any grade treatment-related adverse events included oedema peripheral (36.8%）, decreased appetite (36.8%), headache (31.6%), dizziness (31.6%), vomiting (31.6%), nausea (31.6%), bilirubin conjugated increased (26.3%) and asthenia (26.3%). Only one pt at 400 mg (1 of 6 pts) had experienced dose-limiting toxicity: grade 3 vomiting. The maximum tolerated dose was not reached. 300 mg QD was selected as recommended phase II dose (RP2D) for further study. The Cmax was reached in approximately 2 to 3 hours; SCC244 exposure (AUC0-24h and Cmax) increased approximately in a dose-proportional manner; the mean (range) of T1/2 was 34.8 (12.4-64.1) hours; the mean (range) of Rac (AUC) was 3.4 (1.5-5.9), Rac (Cmax) was 3 (1.2-5.4). In total of 17 evaluable pts, two pts achieved confirmed partial response (PR) per RECIST 1.1. One pt at 300 mg achieved confirmed PR with a duration of response (DOR) of 7.3 months. Exploratory analysis showed that this pt carried c-MET ex14 skipping mutation. Another pt at 200mg, who had disease progression after the fourth lines of anti-EGFR therapy, achieved confirmed PR with a DOR of 11.1 months, and was found to be c-MET IHC 3+.
Conclusions
This first-in-human study of the c-MET selective inhibitor SCC244 demonstrated a tolerable and manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. The long T1/2 supports once daily dosing. Studies with SCC44 in patients with METex14 skipping mutation in NSCLC are ongoing to further explore the safety and efficacy in larger populations.
Clinical trial identification
NCT03466268.
Legal entity responsible for the study
Haihe Biopharma Co., Ltd.
Funding
Haihe Biopharma Co., Ltd.
Disclosure
M-H. Sun, Y. Li: Full/Part-time employment: Haihe Biopharma Co., Ltd. All other authors have declared no conflicts of interest.
38MO - IND.236: A Canadian Cancer Trial Group (CCTG) phase Ib trial of combined CFI-402257 and weekly paclitaxel (Px) in patients with HER2-negative (HER2-) advanced breast cancer (BC) (ID 301)
- Mihaela Mates (Kingston, ON, Canada)
- Mihaela Mates (Kingston, ON, Canada)
- Philippe Bedard (Toronto, Ontario, Canada)
- John Hilton (Ottawa, MA, Canada)
- Karen A. Gelmon (Vancouver, British Columbia, Canada)
- Amirrtha Srikanthan (Ottawa, Canada)
- Arif Awan (Ottawa, Canada)
- Xinni Song (Ottawa, Canada)
- Caroline Lohrisch (Vancouver, Canada)
- Andrew Robinson (Kingston, ON, Canada)
- Dongsheng Tu (Kingston, ON, Canada)
- Linda Hagerman (Kingston, ON, Canada)
- Siwei Zhang (Kingston, ON, Canada)
- Nancy Drummond-Ivars (Ottawa, Canada)
- Irene Li (Toronto, ON, Canada)
- Laleh Rastgou (Vancouver, Canada)
- Jackie Edwards (Kingston, ON, Canada)
- Mark Bray (Toronto, ON, Canada)
- Moira Rushton (Kingston, Canada)
- Pierre-Olivier Gaudreau (Kingston, Canada)
Abstract
Background
CFI-402257 (CFI) is a selective oral inhibitor of TTK protein kinase, a critical regulator of the mitotic spindle assembly checkpoint, is overexpressed in BC and enhances activity of Px in BC xenografts.
Methods
Define recommended phase II dose (RP2D) of CFI in combination with weekly Px using 3+3 escalation. Patients with HER2- advanced BC with adequate organ function, PS=0-1, previously treated with 1 or more non-taxane chemotherapy, were eligible. CFI was given on a 2-day on, 5-day off schedule with Px 80mg/m2 on day 1, 8, 15 every 28 days. Starting dose, based on the CFI phase I study, was 84mg PO. Five dose levels (DL) were planned: 84, 112, 168, 210 and 252mg.
Results
29 patients received a total of 169 cycles. Median age was 58 years; 90% ER+/HER2-; 45% PS=1; 21% 3 or more prior chemotherapy regimens (76% received CDK4/6 inhibitors). Grade (G) 3 or more ANC was reported in 66%, G4 in 39%, and 2 patients had infection (febrile neutropenia and skin). Five patients met criteria for dose limiting toxicity (DL3=2; DL4=2; DL5=1): all were G4 ANC. ANC appeared dose dependent and G4 ANC was only reported in DL3, 4 and 5. Increased age was also associated with higher likelihood of G4 ANC (median age of patients with G4 ANC 68 years vs. 51 years; p=0.0025). Adverse events related to CFI and or Px G2 or more included: alopecia (3%), fatigue (10%) and nausea (3%). Partial response was reported for 3 patients.
Conclusions
CFI plus Px has a manageable toxicity profile, with anticancer activity in this heavily pretreated population. Expansion at DL3 (168mg) is ongoing; updated safety/efficacy data will be presented at the meeting.
Clinical trial identification
CCTG IND.236; NCT03568422.
Legal entity responsible for the study
Queen's University.
Funding
CCTG is supported by the Canadian Cancer Society (704970). This study was supported by a SU2C Canada - Canadian Cancer Society Breast Cancer Dream Team Research Funding (SU2C-AACR-DT-18-15) and OICR, funding provided by the Government of Ontario.
Disclosure
M. Mates: Honoraria (self), Advisory/Consultancy: Seagen; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: GenomicHealth; Honoraria (self), Advisory/Consultancy: BMS. P. Bedard: Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Servier; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): SignalChem; Research grant/Funding (institution): PTC Therapeutics; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Mersana; Research grant/Funding (institution): Immunomedics. J. Hilton: Advisory/Consultancy, DSBM: BMS; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Merck; Research grant/Funding (institution): GSK. K.A. Gelmon: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy: Oncotheryon; Advisory/Consultancy: NanoString; Advisory/Consultancy: Merck; Advisory/Consultancy: Mylan; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Genomic Health; Advisory/Consultancy, Research grant/Funding (self): BMS; Research grant/Funding (self): Expert Testimony; Research grant/Funding (self): Genentech. A. Awan: Advisory/Consultancy: Eli Lily; Advisory/Consultancy: Exact Sciences; Advisory/Consultancy: Exactis; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Honoraria (self): Apotex; Honoraria (self), Travel/Accommodation/Expenses: Roche. X. Song: Advisory/Consultancy, attended advisory board meetings: Novartis; Advisory/Consultancy, attended advisory board meetings: Merck; Advisory/Consultancy, attended advisory board meetings: Pfizer. C. Lohrisch: Advisory/Consultancy: AstraZeneca. M. Bray: Full/Part-time employment, CSO: Treadwell Therapeutics. All other authors have declared no conflicts of interest.
Immunotherapy (ID 361)
T-cell agonists (ID 5)
- Samir Khleif (Washington, WA, United States of America)
- Samir Khleif (Washington, WA, United States of America)
Live Q&A and discussion (ID 52)
- Susan Bates (New York, NY, United States of America)
- Susan Bates (New York, NY, United States of America)
- Josep Tabernero (Barcelona, Spain)
- Udai Banerji (Sutton, Surrey, United Kingdom)
- Mariano Barbacid (Madrid, Spain)
- Sophie Postel-Vinay (Villejuif, France)
1P - Is 177Lu-PSMA an effective treatment modality for mCRPC patients with visceral metastasis? (ID 219)
- Manoj Gupta (New Delhi, India)
- Manoj Gupta (New Delhi, India)
- Partha S. Choudhury (New Delhi, India)
- Amitabh Singh (New Delhi, India)
- Sudhir Rawal (New Delhi, India)
Abstract
Background
Metastatic castration-resistant prostate cancer (mCRPC) is the most challenging stage in prostate cancer. Patient with visceral metastasis have the poorest outcome amoung them. In this retrospective study, we analyzed the clinical outcome of lutetium-177 prostate-specific membrane antigen (177Lu-PSMA) in mCRPC patients with visceral metastasis.
Methods
Ten patients of mCRPC with visceral metastasis were enrolled for one cycle of 177Lu-PSMA therapy. Number of efficacy and safety parameters, e.g., prostate-specific antigen (PSA), visual analog scale (VAS) and analgesic quantification scale (AQS), hemoglobin (Hb), total leukocytes counts (TLC), platelets, creatinine, & total bilirubin, were assessed and compared with Wilcoxon signed-rank test. The progression-free survival (PFS) curve was computed by the Kaplan-Meier method. The receiver operating characteristic curve (ROC) was also plotted for 177Lu-PSMA dose. P≤0.05 was considered significant.
Results
Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of 177Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen.
Conclusions
Lutetium-177-PSMA was a reasonable palliative treatment option with limited toxicity for these end-stage mCRPC patients with visceral metastasis with adequate PSA stabilization.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
16P - How to translate what we learned from Gaucher’s disease into new treatments for brain tumours (ID 285)
- Claudia Paret (Mainz, Germany)
- Claudia Paret (Mainz, Germany)
- Roger Sandhoff (Heidelberg, Germany)
- Khlaifa El Malki (Mainz, Germany)
- Katrin Frauenknecht (Mainz, Germany)
- Arthur Wingerter (Magonza (Germania), Germany)
- Nadine Vewinger (Mainz, Germany)
- Nadine Lehmann (Magonza (Germania), Germany)
- Jörg Faber (Magonza (Germania), Germany)
Abstract
Background
Gaucher's disease is characterized by intralysosomal storage of glucosylceramide due to a genetic deficiency of the enzyme glucosylceramidase. Gaucher’s disease can be treated using eliglustat and miglustat, two inhibitors of the glucosylceramide synthase (GSL). The conversion of ceramide to glucosylceramide is one of the first steps in the synthesis of glycosphingolipids which can be therefore inhibited by eliglustat and miglustat. Glycosphingolipids play a major role in brain development and have been involved in the pathology of brain tumors. Here we analyzed the glycosphingolipids composition and the effect of eliglustat in diffuse midline glioma (DMG), one of the deadliest cancers in the pediatric population.
Methods
We established and characterized primary cells from two pediatric DMG patients. Glycosphingolipids were analyzed by thin layer chromatography, liquid chromatography-coupled tandem mass spectrometry and flow cytometry. The effect of eliglustat on the cell proliferation was examined.
Results
Immunohistochemistry analysis of DMG primary cells of both patients revealed glial origin (GFAP), high proliferative activity (Ki67) as well as the presence of H3 K27M mutant protein. The ganglioside GD2 was highly expressed. Neutral glycosphingolipids with 1 to 4 monosaccharides were also present in high concentration. Eliglustat completely abrogated the proliferation of the primary cells. Based on this promising data, treatment with miglustat of one patient has been started.
Conclusions
We show for the first time that inhibition of GSL effectively affects the survival of H3K27M-mutant DMG. Eliglusat and miglustat are released for the treatment of pediatric patients with Gaucher's disease and miglustat accumulates in the brain. Thus, targeting the glycosphingolipids metabolism with miglustat may accelerate the development of new therapies for brain tumors.
Legal entity responsible for the study
The authors.
Funding
Kinderkrebshilfe Mainz.
Disclosure
All authors have declared no conflicts of interest.
Q&A (ID 350)
- Giuseppe Curigliano (Milan, Italy)
- Giuseppe Curigliano (Milan, Italy)
- Matthias Peipp (Kiel, Germany)