Browsing Over 173 Presentations
6IN - Synthetic lethality - EZH2 inhibitor tazemetostat in INI1-negative tumors
- Antoine Italiano (Bordeaux, FR)
- Antoine Italiano (Bordeaux, FR)
7IN - Targeting histone H3K36me3-deficient cancers
- Timothy Humphrey (Oxford, GB)
- Timothy Humphrey (Oxford, GB)
Abstract
Background
SETD2-dependent histone H3 lysine 36 trimethylation (H3K36me3) plays a central role in both maintaining genome stability and in suppressing tumorigenesis, and is frequently depleted in particular cancer types. We find this histone mark plays an important role in promoting homologous recombination (HR) repair of DNA double-strand breaks. Further, H3K36me3 also performs an essential role in facilitating DNA replication following WEE1 kinase inhibition, through promoting efficient deoxyribonucleotide synthesis. Accordingly, H3K36me3-deficient cancers can be specifically targeted using the WEE1 inhibitor, AZD1775, resulting in replicative catastrophe and cell death. The use of AZD1775 to target H3K36me3-deficient cancers is now in clinical trials. Mechanistic insights into the targeting of H3K36me3-deficient cancers with AZD1775 and its implications will be presented.
Legal entity responsible for the study
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
Funding
Medical Research Council; Cancer Research UK; Clarendon Scholarship; Swiss National Science Foundation
Disclosure
The author has declared no conflicts of interest.
8IN - BET domain inhibitors
- Irene Brana Garcia (Barcelona, ES)
- Irene Brana Garcia (Barcelona, ES)
9IN - HDAC inhibitors and check point inhibitors
- René Bartz (Planegg, DE)
- René Bartz (Planegg, DE)
Abstract
Background
Despite successes in the treatment of melanoma patients with checkpoint inhibitors (CI), most patients do not respond to CI alone and a high unmet medical need remains for these patients. One promising approach is to enhance the immunogenicity and alter the tumor microenvironment from a more immune-deserted to an immune-inflamed phenotype by means of combination therapy. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes (e.g. histone deacetylases (HDAC) inhibitors) are particularly promising.
Methods
Tumor bearing animals (CT26 and C38 syngenic models) were treated with 4SC-202, an orally available clinical stage combined HDAC class I/LSD1 inhibitor, or CIs PD-(L)-1 alone as well as in combination. Tumor growth was assessed continuously and after approx. 2 weeks of treatment tumors were excised and analyzed by flow cytometry and gene expression profiling. Additionally, animals not intended for these analyses were further monitored and tumor growth/survival was monitored.
Results
4SC-202 treatment led to an increase of MHC molecules and enhanced expression of inflammatory markers like IFN-γ and various chemokines in tumors. Furthermore, detailed analysis of the tumor revealed that 4SC-202 strongly altered the immune cell composition and particularly the number of cytotoxic T cells (CTL) was markedly increased. Importantly, subsequent combination treatment of 4SC-202 with CIs in syngenic animal models showed a strong synergistic effect resulting in significant longer survival in both models leading to 55% of tumor free animals (C38 model).
Clinical trial identification
ClinicalTrials.gov Identifier:
NCT03278665
Conclusions
NCT03278665
Clinical trial identification
NCT03278665
Legal entity responsible for the study
4SC AG
Disclosure
R. Bartz: I do not conduct activities that would involve a conflict of interest with CME-accreditable training, but that in the past 2 (two) years I have been a paid employee of 4SC AG.
Funding
Has not received any funding
Q&A
Q&A
Q&A
Panel discussion
Q&A
47O - Phase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer
- Mark Pegram (Stanford, US)
- Mark Pegram (Stanford, US)
- Erika Hamilton (Nashville, US)
- Antoinette R. Tan (Charlotte, US)
- Anna M. Storniolo (Indianapolis, US)
- Nairouz Elgeioushi (Gaithersburg, US)
- Shannon Marshall (Gaithersburg, US)
- Shaad Abdullah (Gaithersburg, US)
- Manish Patel (Sarasota, US)
Abstract
Background
MEDI4276 is a HER2-bispecific antibody targeting two different epitopes on HER2, with site-specific conjugation via maleimidocaproyl linker to a potent tubulysin-based microtubule inhibitor. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2+ tumor cells in vitro, including T-DM1 resistant cells.
Methods
This was a phase 1 dose escalation trial in patients with advanced HER2+ breast or gastric cancer that was relapsed or refractory to standard therapy. MEDI4276 was infused intravenously over 60-90 minutes at 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.75, or 0.9 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; secondary endpoints included antitumor activity (RECIST 1.1; ORR, PFS, and OS), pharmacokinetics (PK), and immunogenicity.
Results
As of 13 November 2017, 43 patients (median age 60 years [range: 36-76]; 69.8% female] were enrolled and treated: n = 3 in all groups except 0.4 (n = 6), 0.6 (n = 11), and 0.75 (n = 8) mg/kg. Maximum tolerated dose was exceeded at 0.9 mg/kg; dose-limiting toxicities (DLTs) were grade 3 liver function test (LFT) increases (n = 2; reversible) and grade 3 diarrhea (n = 1). Two other DLTs of grade 3 or 4 LFT increases were reported (0.4 and 0.6 mg/kg). Thirty-eight patients (88%) had drug-related adverse events (AE) of any grade; most common were nausea (58%), fatigue (42%), elevated AST (37%), vomiting (37%), and elevated ALT (35%). Twelve patients (28%) had drug-related AEs of grade 3-4 severity; most common were grade 3 elevated AST (19%) and grade 3 elevated ALT (12%). Drug-related grade 3 peripheral neuropathy was observed in 1 patient (2%) at 0.6 mg/kg and in 2 patients (5%) at 0.75 mg/kg. Four patients (9%) had ≥1 drug-related AE leading to treatment discontinuation. In the as-treated population, there was 1 CR (0.5 mg/kg; breast), 1 PR (0.6 mg/kg; breast), and 12 (28%) patients with SD. MEDI4276 exhibited non-linear PK, rapid clearance and negligible deconjugation.
Conclusions
MEDI4276 has clinical activity, but with increased toxicity at higher doses. Updated results will be presented.
Clinical trial identification
NCT02576548
Legal entity responsible for the study
MedImmune, LLC
Funding
MedImmune
Disclosure
M. Pegram: Consulting work for AstraZeneca, parent company of study sponsor (MedImmune), for non-branded educational sessions, within the past year. A.R. Tan: The author\'s institution has received research funding from MedImmune. A.M. Storniolo: Stock in Gilead, Celgene, Amgen - immediate family member Honoraria from Pfizer – author. N. Elgeioushi, S. Marshall, S. Abdullah: MedImmune employment and stock interests or options in its parent company, AstraZeneca. All other authors have declared no conflicts of interest.
48O - CC-122, a novel cereblon-modulating agent, in combination with obinutuzumab (GA101) in patients with relapsed and refractory (R/R) B-cell non-hodgkin lymphoma (NHL)
- Jean-Marie Michot (Villejuif, FR)
- Jean-Marie Michot (Villejuif, FR)
- Reda Bouabdallah (Marseille, FR)
- Jeanette K. Doorduijn (Rotterdam, NL)
- Umberto Vitolo (Torino, IT)
- Marie José Kersten (Amsterdam, NL)
- Annalisa Chiappella (Torino, IT)
- Pier L. Zinzani (Bologna, IT)
- Michael Pourdehnad (San Francisco, US)
- Zariana Nikolova (Sevilla, ES)
- Vincent Ribrag (Villejuif, FR)
Abstract
Background
Patients (pts) with NHL experiencing early relapse (ER) within two years of initial diagnosis and those double refractory (DR) to both rituximab and chemotherapy have particularly poor outcomes (Casulo et al
Methods
CC-122 was given orally (5/7 d) for 28-d cycles in escalating doses plus a fixed dose of intravenous G 1000 mg on d2, 8, 15 of cycle 1 (c1) and d1 of c2–8. CC–122 active ingredient in capsule formulation (AIC) 1, 2, 3, and 4 mg and CC-122 formulated capsules (F6) 3 and 4 mg were evaluated in separate cohorts. Primary end points included safety and tolerability, NTD, and MTD. Response was assessed using the Cheson 2007 criteria every 2 cycles to c6, every 3 cycles to c12, and every 6 cycles thereafter.
Results
As of September 1, 2017, 44 pts with R/R B-cell NHL were enrolled in the dose-escalation phase. Tumor types included 19 pts with DLBCL, 24 with FL, and 1 with MZL. Median age was 60 y (range, 26–81 y), 29 (66%) were men, and 33 (75%) had stage III/IV disease. Median number of prior anticancer therapies was 3 (range, 1–11), and 18 pts (41%) had 1 prior ASCT; 2 pts had a dose-limiting toxicity (grade 4 neutropenia, n = 1 [CC-122 AIC 3 mg]; grade 5 tumor flare, n = 1 [CC-122 F6 4 mg]). The most common (≥15%) grade 3/4 TEAEs were neutropenia (52%) and thrombocytopenia (25%). ORR/CR rate in the total population was 68%/27% (DLBCL, 47%/11%; FL, 84%/42%). The mDOR was 19.4 mo (95% CI:7.9, NR). Subgroup analysis showed comparable mPFS and DOR for high-risk (ER+DR) and standard-risk FL pts (mPFS, 21.1 mo [2.9, NR] vs 16.2 mo [1.7, 16.2]; DOR, 19.3 mo [1.9, NR] vs NR).
Conclusions
CC-122+G is well-tolerated, with promising response rates and durable remissions in R/R B-cell NHL. Subgroup analysis showed CC-122+G has similar efficacy in the high-risk and standard-risk FL population.
Clinical trial identification
NCT02417285/EUDRACT 2014-003333-26
Legal entity responsible for the study
Celgene Corporation
Funding
Celgene Corporation
Disclosure
J.K. Doorduijn: Received honoraria from Roche and Celgene. U. Vitolo: Received honoraria from Roche, Celgene, Janssen, Takeda, Mundipharma, Gilead and is an advisory member of Roche, Celgene and Janssen. M.J. Kersten: Research funding from Celgene, Roche and Millennium/Takeda and honoraria from Celgene, Roche, Millennium/Takeda, Novartis, Kite Pharma, Gilead. A. Chiappella: Speakers bureau from Amgen, Celgene, Janssen, Nanostring, Pfizer, Roche, and Teva. P.L. Zinzani: Advisory board member for Roche, Celgene, Gilead, J&J, BMS, Karyopharma, Takeda, Bayer, Verastem, Merck and Servier. M. Pourdehnad: Employee of and stock ownership from Celgene Corporation. Z. Nikolova: Employee of and stock ownership from Celgene International Sarl. V. Ribrag: Research funding from ArgenX and honoraria from Roche, Servier, BMS, MSD, Infinity, Gilead, Nanostring, and Epizyme. All other authors have declared no conflicts of interest.
49O - Downregulation of USP28 confers poorer overall survival to melanoma patients and causes resistance to RAF inhibitors
- Azad Saei (Singapore, SG)
- Azad Saei (Singapore, SG)
- Marta Palafox (Barcelona, ES)
- Touati Benoukraf (Singapore, SG)
- Nishi Kumari (Singapore, SG)
- Prassana Iyengar (Singapore, SG)
- Zul Fazreen Bin Adam Isa (Singapore, SG)
- Henry Yang (Singapore, SG)
- Wai Leong Tam (Singapore, SG)
- Violeta Serra (Barcelona, ES)
- Pieter Eichhorn (Singapore, SG)
Abstract
Background
The mutation in BRAF kinase at V600 has been frequently reported in nearly 50% of melanoma patients resulting in the hyper-activation of MAPK pathway. As such, various inhibitors which target mutant BRAF have been developed including vemurafenib and dabrafenib both of which have demonstrated significant clinical outcomes. Nevertheless, both primary and acquired resistance reduce the overall response of patients to the therapy. So, the search of efficient biomarkers to stratify melanoma patients has become an imperative subject of research to enhance the efficacy of RAF inhibitor treatments and to decrease the rate of side effects due to the therapy. The mechanism of ubiquitination in controlling various functions such as stabilization of a protein cannot be neglected. A number of ubiquitin regulatory enzymes have been already shown to act on and regulate various component of MAPK pathway.
Methods
In order to investigate the role of deubiquitinating enzymes (DUBs) in MAPK signaling, we performed a RNAi screen using a shRNA library targeting all known human DUBs and phosphorylated ERK level was assessed by western blotting. Biochemical analysis of significant hits and their potential role in response of melanoma patients to RAF inhibitors were investigated.
Results
We identified 9 DUBs which significantly regulate MAPK pathway activity including USP28. Interestingly, USP28 has been reported to be mutated in 10% of melanoma patients. Our analysis demonstrated that the loss of USP28 functionality confers poorer overall survival to melanoma patients. The correlation analysis of expression of USP28 in BRAF600E mutated melanoma patients confirmed the tumor suppressor role of USP28 in melanoma. Our results revealed that cells depleted for USP28 show BRAF stabilization resulting in high MAPK activity. Moreover, tissue microarray analysis of 98 melanoma patients showed the inverse correlation of USP28 and BRAF protein expression. Critically we demonstrated that stabilization of BRAF due to the loss of USP28 results in vemurafenib resistance in melanoma.
Conclusions
Overall, our results demonstrate that the loss of USP28 could be used as a novel and promising biomarker for resistance to RAF inhibitors in melanoma patients.
Legal entity responsible for the study
National University of Singapore
Funding
National University of Singapore
Disclosure
All authors have declared no conflicts of interest.