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- | Journal, IO Biomarker: MicroRNA-30a-3p inhibits the progression of lung cancer via the PI3K/AKT by targeting DNA methyltransferase 3a. (Pubmed Central) - Nov 7, 2019
Furthermore, we observed the opposite phenomenon in A549 cells transfected with both miR-30a-3p and DNMT3a vector. Our data show that miR-30a-3p suppressed the progression of lung cancer via regulating p38 MAPK pathway by targeting DNMT3A in A549 cells, indicating that miR-30a-3p might be a novel potential therapeutic strategy in the treatment of lung cancer.
- | Journal, IO Biomarker: Apiosporamide, A 4-hydroxy-2-pyridone Alkaloid, Induces Apoptosis Via PI3K/Akt Signaling Pathway In Osteosarcoma Cells. (Pubmed Central) - Nov 7, 2019
In addition, apiosporamide also attenuated PI3K/Akt signaling pathway. Apiosporamide effectively suppressed MG63 cells proliferation by inducing apoptosis through PI3K/Akt and caspase-associated apoptotic pathway.
- || Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors https://t.co/FabRJ8tTZF (Twitter) - Nov 7, 2019
- Complement C3a Not C4a Activates Osteoclasts By Regulating the PI3K/PDK1/SGK3 Pathway in Patients with Multiple Myeloma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_6163;
There was no difference among the osteoclasts area, relative expression of osteoclasts related genes and absorption area of osteoclast resorption pit between C4a (1μg/ml and 10μg/ml) group and control group (0μg/ml) . RNA-Seq was performed on total RNA of osteoclasts induced by C3a in 1μg/ml group and 0μg/ml group of 4 patients with NDMM .
- dexamethasone / Generic mfg., Darzalex IV (daratumumab) / J&J, doxorubicin hydrochloride / Generic mfg.
Combined Inhibition of HDAC and AKT As a Strategy to Overcome Multi-Drug Resistance in Patients with Multiple Myeloma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_6071;
Lenalidomide (Len) selectively binds to cereblon (CRBN), which mediates recruitment of specific substrates like IKZF1 to E3 ubiquitin ligase and subsequent degradation, resulting in downregulation of IRF-4 and c-Myc...We observed that ADCC activity of both daratumumab and elotuzumab against MM cells was enhanced in the presence of HDAC inhibitors, which was compatible with our previous data that HDAC inhibitors upregulated MICA mRNA expression via inhibition of IKZF1 (ASH2018 abstract #4435)...Afuresertib, an AKT inhibitor, suppressed GSK-3 phosphorylation (p-GSK-3) with or without ACY-1215, an HDAC inhibitor, leading to a substantial decrease of c-Myc (Figure 2)...Bortezomib, doxorubicin, and dexamethasone resistant MM cell lines were also sensitive to CUDC-907...Furthermore, CUDC-907 was effective on primary MM cells which were resistant to bortezomib and Len (Figure 5). Thus, dual inhibition of HDAC and AKT with or without monoclonal antibodies is a promising therapeutic approach to multi-drug resistant MM.
- Arzerra (ofatumumab) / Novartis, Genmab, Copiktra (duvelisib) / Verastem
Cytogenetic and Molecular Marker Associations to Outcomes with Duvelisib and Ofatumumab Treatment in Patients with Relapsed or Refractory CLL/SLL in the DUO Trial (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_6057;
Introduction In chronic lymphocytic leukemia (CLL), prognostic factors, such as genetic alterations and lines of treatment, have been well studied with chemoimmunotherapy and are advancing with ibrutinib, venetoclax, and PI3K inhibitors...An increased risk of autoimmune AEs in M-IGHV patients was previously reported with idelalisib given frontline (Lampson et al...Patients with M-IGHV had a higher rate of discontinuation due to immune-related AEs in the second-line setting . As such, the use of prognostic markers continues to have value in selection of therapy for patients with CLL/SLL treated with novel agents, including in ongoing clinical studies with DUV.
- Identification of Genotype-Specific Therapeutic Vulnerabilities By Comparative Dynamic BH3 Profiling Analysis of Human and Murine CLL (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_6025;
Altogether, these results suggest that both MDR and Sf3b1mut/Atmdel mouse lines are valuable tools for predicting therapeutic sensitivities of genetically matched primary CLLs . We are currently extending this approach to the testing of additional drugs, and to the validation of the most relevant compounds in larger cohorts of primary CLLs.
- azacitidine / Generic mfg.
The Inspire Study in Higher-Risk Myelodysplastic Syndrome (HR-MDS): A Novel Phase 3 Study Adaptive Design for Hematological Malignancies in Adults (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5992;
P3
The Adaptive Design used real time data from the IA to modify sample size and mitigate the risk of underpowering without undermining its validity and integrity, while preserving type-1 error. The study design used in INSPIRE may be advantageous for other novel agents in rare hematological diseases during the transition from phase 2 to phase 3 studies.
- azacitidine / Generic mfg., Estybon (rigosertib) / Onconova, SymBio, Knight Therap, azacitidine/rigosertib / Onconova, Knight Therap
The Sequenced Combination of Rigosertib and Azacitidine Has Modulatory Effects on CXCL8, RIG-I like Receptor (RLR) and Wnt/β-Catenin Signaling and Downstream Hematopoiesis Pathways in an in Vitro Model of the Myelodysplastic Syndrome (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5973;
Involvement of CXCL8 (RLR responsive gene) and activation of wnt signaling genes suggests their linkage to hematopoiesis. Further studies are underway to determine the effects of these signaling pathways on improving hematopoiesis both in vitro and in vivo in the HMA clinical resistance setting to identify potential therapeutic targets to reverse bone marrow failure in pts with HMA resistance.
- Venclexta (venetoclax) / Roche, AbbVie, fimepinostat (CUDC-907) / Curis, Rituxan (rituximab) / Roche, Biogen
A Multi-Center Dose-Finding Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Fimepinostat (CUDC-907) in Combination with Venetoclax in Patients with Relapsed/Refractory (R/R) Lymphoma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5840;
P1/2
A Pooled Analysis of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients Treated with the Dual PI3K and HDAC Inhibitor Fimepinostat (CUDC-907), Including Patients with MYC-Altered Disease . Blood,132(Suppl 1), 4184.
- KA2237 / Karus, Rituxan (rituximab) / Roche, Biogen
Results of a First in Human, Dose Ascending, Phase I Study Examining the Safety and Tolerability of KA2237, an Oral PI3K p110β/δ Inhibitor in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5835;
P1
The recommended phase II dose is 200mg daily . The findings of this study support the further evaluation of KA2237.
- Opdivo (nivolumab) / Ono Pharma, BMS, Aliqopa (copanlisib) / Bayer
Copanlisib in Combination with Nivolumab in Subjects with Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Primary Mediastinal Large B-Cell Lymphoma: A Phase 2 Study (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5826;
P2
A phase 1b trial in heavily pre-treated relapsed/refractory (RR) PMBCL using pembrolizumab (a PD-1 blocker) showed that it was safe and active with an ORR of 41%...Copanlisib, a pan-PI3K inhibitor, with particularly potent PI3K-α/PI3K-δ inhibition, showed activity in both indolent and aggressive NHL, with a safer toxicity profile than the FDA-approved agent idelalisib...This study is conducted through NCI-CTEP (NCI Protocol #10193; NCT03484819) and is funded by Bayer . The study is to open in fall of 2019 at 11 ECTCN sites, and is available to interested sites to join in.
- Venclexta (venetoclax) / Roche, AbbVie, Imbruvica (ibrutinib) / AbbVie, J&J
Targeting PI3K and PLK1 to Overcome Ibrutinib-Venetoclax Resistance in Mantle Cell Lymphoma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5797;
Our data demonstrated that pan-PI3K inhibitor copanlisib and PLK1 inhibitor volasertib are potent agents in targeting MCL cells in vitro and in vivo, and they have great potential to overcome ibrutinib and venetoclax resistance in MCL. When combined, copanlisib and volasertib have even greater potential to overcome ibrutinib and venetoclax resistance in MCL.
- Keytruda (pembrolizumab) / Merck (MSD), Aliqopa (copanlisib) / Bayer
Pembrolizumab and Copanlisib for the Treatment of Relapsed or Refractory Mature T-Cell Lymphomas (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5765;
P1/2
The probability of early stopping under the null is 80% . Correlative studies include changes in in composition, activation, and function of peripheral blood T-, NK-, and myeloid cells by flow cytometry, RNA sequencing of tumor tissue to identify a gene expression signature that may correlate with response, as well as non-invasive disease monitoring using T-cell receptor high throughput sequencing of circulating tumor DNA.
- Aliqopa (copanlisib) / Bayer
Copanlisib, a PI3K Inhibitor, Demonstrates a Favorable Long-Term Safety Profile in a Pooled Analysis of Patients with Hematologic Malignancies (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5742;
P2
Transient, manageable hyperglycemia and hypertension were among the most common TEAEs; no new unexpected safety issues were identified . These results support the known safety profile and approved indication of copanlisib.
- Rituxan (rituximab) / Roche, Biogen
Comparative Outcomes of Relapsed Follicular Lymphoma Patients Treated with Novel Agents: A Multi-Center Analysis (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5715;
With the caveat of retrospective comparison, lenalidomide + mAb (i.e . R2) appears superior to PI3Ki as first novel agent in the relapsed setting with the recognition that a high proportion of patients discontinued PI3Ki due to toxicity .
- CYAD-02 / Celyad
Next Generation NKG2D-based CAR T-cells (CYAD-02): Co-expression of a Single shRNA Targeting MICA and MICB Improves Cell Persistence and Anti-Tumor Efficacy in vivo (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5661;
Conclusions By using a single vector encoding the NKG2D-based CAR next to a shRNA targeting MICA and MICB and combined with improved cell culture methods, CYAD-02, the next-generation of NKG2D-based CAR T-cells, demonstrated enhanced in vivo persistence and anti-tumor activity. Following FDA acceptance of the IND application, a Phase 1 dose-escalation trial evaluating the safety and clinical activity of CYAD-02 for the treatment of r/r AML and MDS is scheduled to start in early 2020.
- Therapeutic Stratification of PTEN-MYC Axis Appears to be Promising for Molecular Targeted Therapies in Refractory and Relapsed T-Cell Acute Lymphoblastic Leukemia (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5611;
A second drug combination that showed synergy in PTENm was observed with copanlisib and alisertib, an Aurora kinase-A (AURKA) inhibitor, expecting changes in cell cycle and reduced MYC stability...Contrary to PTENm, in PTENwt cell lines, PI3K inhibition alone showed no cytotoxic effect, but synergy was detected in combination with the MEK inhibitor cobimetinib...Based on these findings, PTEN-MYC axis seems suitable as a potential stratification marker for future therapy options in refractory and relapsed T-ALL . In the next step, promising drug combinations will be tested in a patient derived xenograft mouse model to validate these findings.
- Targeting Unique Synthetic Lethal Interactions between PI3K and MYC in B-ALL (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5509;
As a result of the unique metabolic gatekeeper activity of B-cell-specific PAX5 and IKZF1-function, B-cells survive under conditions of chronic energy deprivation, which makes them particularly susceptible to acute fluctuation of energy expenditure, e.g . by activation of PI3K upon deletion of PTEN .
- Rituxan (rituximab) / Roche, Biogen
Incidence of Serious Adverse Events, Pneumonitis, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Phosphatidylinositol 3-Kinase (PI3K) Inhibitors (Valencia A (W415A), Level 4 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5098;
Moreover, patients on PI3K inhibitors experienced 5.68% higher incidence of treatment-related deaths with RR of 1.87, compared to control arm. Since treatment-related serious toxicities and deaths are higher amongst patients treated with these agents, extra caution should be observed and recommended with their use.
- BAY 1082439 / Bayer, pictilisib (GDC-0941) / Roche
Loss of Dnmt3a Dysregulates Hematopoietic Homeostasis and Myeloid Skewing Via the PI3Kinase Pathway: PI3Kα/β Inhibition Corrects Extramedullary Hematopoiesis and Myeloid Skewing Due to Loss of Dnmt3a (Valencia D (W415D), Level 4 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5004;
These results demonstrate that Dnmt3a ablation induces liver specific expansion of hematopoietic cells, and extramedullary hematopoiesis in spleen via aberrant activation of PI3Kinase signaling in HSCPs . Consistent with this notion, PI3K inhibitor treatment of malignant Dnmt3a-/- bearing mice showed significantly improved overall survival compared to controls.
- Opdivo (nivolumab) / Ono Pharma, BMS
PD-1 Is Expressed at Low Levels on All Peripheral Blood Natural Killer Cells but Is a Significant Suppressor of NK Function Against PD-1 Ligand Expressing Tumor Targets (W414AB, Level 4 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4851;
These data indicate that PD-1 is present on human NK cells and PD-1 ligation negatively regulates NK function against PD-L1 expressing tumor targets . The observation that functional PD-1 is expressed on NK cells under resting conditions strongly suggests that the use of a PD-1 antagonist, in combination with NK cell therapy, should be clinically effective for treatment of cancer.
- Lynparza (olaparib) / Merck (MSD), AstraZeneca
PARP Inhibition Sensitize BCR-ABL1 Positive Cel (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4572;
Mouse HCS was infected with BCR-ABL1 expressing retrovirus and transplanted lethally Olaparib or vehicle was administrated intraperitoneal injection one day after transplantation . BCR-ABL1 mediated leukemic death was observed 1 month after transplantation in sham-treated mouse, whereas, Olaparib treated mouse did not develop BCR-ABL1 mediated leukemia .
- Rituxan (rituximab) / Roche, Biogen
Allogeneic Stem Cell Transplantation (alloHSCT) for Chronic Lymphocytic Leukemia (CLL) in the Era of Novel Agents (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4524;
As many pts treated with ibr and/or ven will progress or be intolerant, alloHSCT should be included in treatment algorithms for appropriate candidates . These data suggest that exposure to 1 vs .
- Rituxan (rituximab) / Roche, Biogen
Comparison of Overall Survival in High Risk Patients with Minimal Residual Disease after First-Line Treatment across Three Generations of Phase 3 Trials of the German CLL Study Group (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4232;
(Figure 1b) This analysis demonstrated an improvement for overall survival in patients with high risk CLL included in the CLLM1 study as compared to pts in the CLL8 and CLL10 trials of the GCLLSG. So far, the results suggest that progress in maintenance therapy or subsequent use of novel agents (BTK or PI3K inhibitors) may improve the outcome of high-risk CLL patients initially treated with chemoimmunotherapy.
- Jakafi oral (ruxolitinib) / Novartis, Incyte
Patient Derived Xenografts (PDX) Recapitulate Ruxolitinib Clinical Trial Responses and Identify a Novel Combination Therapy for Chronic Myelomonocytic Leukemia (CMML) (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4173;
To our knowledge, this is the first report of PDX models recapitulating clinical trial responses in leukemia . A cohort of 6 additional patient samples are currently being assessed to validate these results.
- Venclexta (venetoclax) / Roche, AbbVie, Copiktra (duvelisib) / Verastem
The Dual PI3K-δ/γ Inhibitor Duvelisib in Combination with the Bcl-2 Inhibitor Venetoclax Shows Promising Responses in Richter Syndrome-PDX Models (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4044;
In conclusion, DUV and VEN treatment combination, simultaneously inhibiting PI3K-δ/γ and Bcl-2, induced RS tumor regression, offering a promising treatment combination, at least for RS patients expressing high levels of PI3K gamma and delta subunits and Bcl-2 . These results pave the way for clinical testing of duvelisib and venetoclax combination for patients with RS.
- tenalisib (RP6530) / Rhizen
Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4012;
P1, P1/2
Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL . Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population.
- Aliqopa (copanlisib) / Bayer
PI3Kα/δ Inhibitor, Copanlisib, Inhibits Acute Lymphoblastic Leukemia Cell Growth, Increases Survival and Inhibits CNS Disease Progression in Leukemic Mice (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3935;
We demonstrate that copanlisib inhibits ALL proliferation through induction of cell cycle arrest and decreases ALL invasion by blocking integrin-mediated cell migration. We also show that copanlisib treatment after chemotherapy can enhance ALL cell kill by blunting cytarabine-induced anti-apoptotic signaling responses.
- uproleselan sodium (GMI-1271) / Glycomimetics, cytarabine / Generic mfg.
Blocking Vascular Niche E-Selectin Dampens AML Stem Cell Regeneration/Survival Potential In Vivo By Inhibiting MAPK/ERK and PI3K/AKT Signalling Pathways (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3832;
Thus contact with vascular E-selectin induces a range of survival/regenerative signaling pathways within BM AML blasts that would be highly advantageous for the blast in times of stress. In summary we show, (1) vascular niche E-selectin blockade by GMI-1271 dampens malignant AML reconstitution/survival potential in vivo when administered as sole agent alone, (2) That E-selectin blockade mediates these effects via dampening a range of intracellular survival/regeneration signalling pathways in the malignant cell, and finally (3) these data suggest E-selectin blockade may synergise with other specific pathway inhibitors to improve treatment outcomes - but only for malignant cells that are appropriately glycosylated to interact with E-selectin.
- sirolimus / Generic mfg.
Class I PI3K Is Required for HSC Differentiation (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3623;
Furthermore, rapamycin treatment impairs serial replating of TKO bone marrow cells. In conclusion, we found that inactivation of all Class 1A PI3 kinases leads to impaired HSC differentiation, likely due to a defect in autophagy induction in response to growth factor deprivation.
- Venclexta (venetoclax) / Roche, AbbVie
Efficacy of Therapies Following Venetoclax Discontinuation in CLL: Focus on B-Cell Receptor Signal Transduction Inhibitors and Cellular Therapies (Hall D, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3332;
For BTKi naïve pts, selection of a covalently binding BTKi results in high ORR and durable remissions . PFS-2 data provide reassurance for using VEN prior to IBR .
- Venclexta (venetoclax) / Roche, AbbVie, Rituxan (rituximab) / Roche, Biogen
Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) (Hall E1, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3101;
24-month post-treatment cessation PFS was 68.0% in pts completing 2 years of Ven, and pts who attained PB uMRD showed particularly durable responses. These follow-up data provide further support for the application of time-limited VenR in R/R CLL.
- Gazyva (obinutuzumab) / Biogen, Roche, Zydelig (idelalisib) / Gilead
Open Label Non-Randomized Phase II Study Exploring «Chemo-Free » Treatment Association with Idelalisib + Obinutuzumab in Patients with Relapsed/Refractory (R/R) Waldenstrom’s Macroglobulinemia (MW), a Filo Trial: Results of the Intermediary Analysis of the Induction Phase (Tangerine 3 (WF3-4), Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3090;
P2
Median PFS was 25 months . Most of grade ≥ 3 AE or SAE are hepatotoxicity, diarrhea and neutropenia as expected with idelalisib.
- Tyrosine Kinase Inhibitors (TKIs) Targeting Syk and BTK Signaling Differentially Affect PI3K Signalosome Organization and Platelet Function (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2930;
Moreover, our findings suggest that in addition inhibiting protein kinase activities, the discrepant effects of some TKIs may be attributed to, in part, altered protein relations around BTK, PLCγ2 and other components of the PI3K signalosome in activating platelets . Ongoing studies aim to specify protein:protein interactions affected by reversible as well as irreversible TKIs; to examine patient samples for evidence of PI3K mislocalization – especially in cases of BTK inhibitor-associated bleeding; and, to determine if PI3K signalosome disorganization has roles in other physiological, therapeutic and toxic effects of TKIs.
- bortezomib / J&J, Generic mfg.
Inhibition of Heme Oxygenase-1 Attenuates Bortezomib Resistance in Multiple Myeloma Via Down-Regulating Gas6 Production (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2624;
Conclusion These results demonstrate that inhibition of HO-1 attenuates bortezomib resistance in MM via down-regulating Gas6 production. Targeting these pathological interactions holds promise for improve MM treatment.
- Venclexta (venetoclax) / Roche, AbbVie, Copiktra (duvelisib) / Verastem
A Phase I Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL / SLL (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2605;
Although high rates of neutropenia were observed, infections were infrequent . Early efficacy data for this 1-year time-limited, all oral regimen are promising, with CRs and uMRD already observed despite short follow-up .
- Arzerra (ofatumumab) / Novartis, Genmab, Zydelig (idelalisib) / Gilead, Copiktra (duvelisib) / Verastem
Imbalance in T Cell Subsets Triggers the Autoimmune Toxicity of PI3K Inhibitors in CLL (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2586;
We hypothesize that an imbalance of Tregs and Th17 T cells is contributing to irAEs in some idelalisib treated patients . Preliminary data with duvelisib suggest alternative mechanisms which we are still analyzing, along with performing cytokine analysis and immunohistochemistry on patient biopsies to further validate these findings.
- Aliqopa (copanlisib) / Bayer, Imbruvica (ibrutinib) / AbbVie, J&J
Phase Ib of Copanlisib in Combination with Ibrutinib in Recurrent/Refractory Primary CNS Lymphoma (PCNSL) (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2431;
Treatment with copanlisib and ibrutinib in patients with PCNSL has manageable adverse events after initiation of mandatory PCP prophylaxis. Clinical response was seen in 67% of patients.
- Farydak (panobinostat) / Novartis, Aliqopa (copanlisib) / Bayer
Development of a Pathway-Directed Drug Screen Platform for Cutaneous T Cell Lymphoma Using Patient-Derived Xenograft Models (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2410;
Additional studies showed synergistic combination of PI3K-δ inhibitors with histone deacetylase (HDAC) inhibitors . The particularly potent combination of copanlisib and panobinostat is proposed for further clinical development.
- Xenical (orlistat) / Roche, GSK, buparlisib (BKM120) / Novartis, Adlai Nortye, cerulenin / Fermentek
Identification of FASN-Dependent Onco-Metabolic Regulation of the Pentose Phosphate Pathway (PPP) and Nucleotide Metabolism in Non-Hodgkin Lymphoma (NHL) (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2405;
In addition, co-targeting FASN and PI3K induced synergistic cell death . Altogether, blocking FASN and the dependent onco-metabolic functions represent highly novel targets for therapeutic strategies in NHL.
- Aliqopa (copanlisib) / Bayer, Rituxan (rituximab) / Roche, Biogen
Long-Term Efficacy and Safety of Copanlisib in Multiply Relapsed or Refractory Patients with Marginal Zone Lymphoma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2361;
P2
Responses were durable, with a median DoR of 17.4 mo and PFS of 24.1 mo, exceeding previous benchmarks . Phase III studies are underway to confirm the efficacy and safety of copanlisib in combination with other therapies in pts with indolent lymphoma, including MZL.
- Zydelig (idelalisib) / Gilead, Rituxan (rituximab) / Roche, Biogen
Somatic Mutation Profile Analyzed By Next-Generation Sequencing in Relapsed/Refractory Follicular Lymphoma Treated with Idelalisib (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2331;
Conclusion The m7FLIPI at diagnosis identifies patients with higher risk of treatment failure in patients with R/R FL treated with idelalisib . Patients with idelalisib refractory disease have more frequently mutations of EP300, B2M, FBXW7, which suggests they could be related to resistance to idelalisib.
- Imbruvica (ibrutinib) / AbbVie, J&J
The Development of a Precision Medicine Platform to Overcome Ibrutinib Resistance in Mantle Cell Lymphoma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2315;
Molecular matching with in vitro drug screening were utilized to develop a precision medicine platform for MCL to combat therapeutic resistance . This platform can be translated into a clinical setting to directly benefit the MCL patient population through treatment with therapies directly tailored to each patient.
- FLT3-ITD Enhances Proliferation and Survival of AML Cells through Activation of RSK1 to Upregulate the mTORC1/eIF4F Pathway Cooperatively with PIM or PI3K and to Inhibit Bad and Bim (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2251;
Our findings reveal that FLT3-ITD but not BCR/ABL activates RSK1 as well as RSK2 and upregulates RSK1 expression to promote proliferation and survival of leukemic cells through upregulation of the mTORC1 pathway and modification of eIF4B in collaboration with the PI3K/Akt and STAT5/PIM pathways and additionally through inhibitory modification of the proapoptotic proteins Bad and Bim (Figure). Thus, RSK1 represents a promising molecular target particularly in combination with PIM or PI3K for novel therapeutic strategies against therapy-resistant FLT3-ITD-positive AML.
- Mekinist (trametinib) / Novartis
Genome-Wide CRISPR Screening in Acute Myeloid Leukemia Cells Identifies Genes in the PI3K/AKT/mTOR and MEK/ERK Pathways That Define Sensitivity to Trametinib (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2221;
Cells engineered to have loss-of-function for these genes as well as cells cultured for resistance to trametinib showed perturbed signaling in downstream PI3K/AKT/mTOR and MEK/ERK signaling cascades . Our work identified genes whose loss of function in the disease-implicated pathways confer trametinib resistance in AML and provide a rationale for selecting combinatorial trametinib/FLT3 inhibitors treatment based on unique patient mutational and gene expression landscapes.
- | Journal: TRIM22 knockdown suppresses chronic myeloid leukemia via inhibiting PI3K/Akt/mTOR signaling pathway. (Pubmed Central) - Nov 6, 2019
Furthermore, we demonstrated that TRIM22 knockdown inhibited the activation of PI3K/Akt/mTOR pathway by decreasing the level of the phosphorylated form p-Akt and p-mTOR in K562 cell. In conclusion, loss of TRIM22 suppresses the progression and invasion of CML through regulation of PI3K/Akt/mTOR pathway, suggesting that TRIM22 might be as a potential target for the treatment strategy of CML.
- | Journal: HIV-1 Envelope Glycoproteins Induce the Production of TNF-α and IL-10 in Human Monocytes by Activating Calcium Pathway. (Pubmed Central) - Nov 6, 2019
Accordingly, addition of BAPTA-AM and cyclosporine-A, fully and partially inhibited IL-10 and TNF-α respectively...In conclusion, this study revealed the crucial calcium signaling pathway triggered by HIV-1 gp120 to control the production of these two cytokines: TNF-α and IL-10. The finding could help in the development of a new therapeutic strategy to alleviate the chronic hyper-immune-activation observed in HIV-1 infected patients.
- | Journal: Different Isoforms of the Neuronal Guidance Molecule Slit2 Directly Cause Chemoattraction or Chemorepulsion of Human Neutrophils. (Pubmed Central) - Nov 6, 2019
Slit2-S induced multiple pseudopods. These data suggest that Slit2 isoforms use similar receptors but different intracellular signaling pathways and have different effects on the cytoskeleton and pseudopods to induce neutrophil chemoattraction or chemorepulsion.