scholarly journals Rational combination strategies to enhance venetoclax activity and overcome resistance in hematologic malignancies

2017 ◽  
Vol 59 (6) ◽  
pp. 1292-1299 ◽  
Author(s):  
Steven Grant
Keyword(s):  
Hematologic Malignancies ◽  
Combination Strategies ◽  
Rational Combination

scholarly journals Overactive IGF1/Insulin Receptors and NRASQ61R Mutation Drive Mechanisms of Resistance to Pazopanib and Define Rational Combination Strategies to Treat Synovial Sarcoma

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 408 ◽  
Author(s):  
Cinzia Lanzi ◽  
Laura Dal Bo ◽  
Enrica Favini ◽  
Monica Tortoreto ◽  
Giovanni Beretta ◽  
...  
Keyword(s):  
Cell Line ◽  
Synovial Sarcoma ◽  
Molecular Mechanisms ◽  
Soft Tissue Sarcomas ◽  
Insulin Receptors ◽  
Mek Inhibitor ◽  
Combination Strategies ◽  
Rational Drug ◽  
Rational Combination ◽  
Induced Apoptosis

Pazopanib is approved for treatment of advanced soft tissue sarcomas, but primary and secondary drug resistance limits its clinical utility. We investigated the molecular mechanisms mediating pazopanib resistance in human synovial sarcoma (SS) models. We found reduced cell sensitivity to pazopanib associated with inefficient inhibition of the two critical signaling nodes, AKT and ERKs, despite strong inhibition of the main drug target, PDGFRα. In the CME-1 cell line, overactivation of IGF1 and Insulin receptors (IGF1R/InsR) sustained AKT activation and pazopanib resistance, which was overcome by a combination treatment with the double IGF1R/InsR inhibitor BMS754807. In the highly pazopanib resistant MoJo cell line, NRASQ61R mutation sustained constitutive ERK activation. Transfection of the NRAS mutant in the pazopanib sensitive SYO-1 cell line increased the drug IC50. MoJo cells treatment with pazopanib in combination with the MEK inhibitor trametinib restored ERK inhibition, synergistically inhibited cell growth, and induced apoptosis. The combination significantly enhanced the antitumor efficacy against MoJo orthotopic xenograft abrogating growth in 38% of mice. These findings identified two different mechanisms of intrinsic pazopanib resistance in SS cells, supporting molecular/immunohistochemical profiling of tumor specimens as a valuable approach to selecting patients who may benefit from rational drug combinations.

scholarly journals Combination strategies to overcome resistance to the BCL2 inhibitor venetoclax in hematologic malignancies

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
XiaoYan Yue ◽  
Qingxiao Chen ◽  
JingSong He
Keyword(s):  
Intracellular Signaling ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
The United States ◽  
Resistance Mechanisms ◽  
Lymphocytic Leukemia ◽  
Bcl2 Family ◽  
Combination Strategies ◽  
United States Food ◽  
Major Factors

Abstract Venetoclax has been approved by the United States Food and Drug Administration since 2016 as a monotherapy for treating patients with relapsed/refractory chronic lymphocytic leukemia having 17p deletion. It has led to a breakthrough in the treatment of hematologic malignancies in recent years. However, unfortunately, resistance to venetoclax is inevitable. Multiple studies confirmed that the upregulation of the anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family mediated by various mechanisms, such as tumor microenvironment, and the activation of intracellular signaling pathways were the major factors leading to resistance to venetoclax. Therefore, only targeting BCL2 often fails to achieve the expected therapeutic effect. Based on the mechanism of resistance in specific hematologic malignancies, the combination of specific drugs with venetoclax was a clinically optional treatment strategy for overcoming resistance to venetoclax. This study aimed to summarize the possible resistance mechanisms of various hematologic tumors to venetoclax and the corresponding clinical strategies to overcome resistance to venetoclax in hematologic malignancies.

Characterization of 1,387 NSCLCs with MET exon 14 (METex14) skipping alterations (SA) and potential acquired resistance (AR) mechanisms.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9511-9511
Author(s):  
Mark M. Awad ◽  
Jessica Kim Lee ◽  
Russell Madison ◽  
Anthony Classon ◽  
Jamie Kmak ◽  
...  
Keyword(s):  
Donor Site ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Acceptor Site ◽  
Polypyrimidine Tract ◽  
Comprehensive Overview ◽  
Functional Sites ◽  
Paired Samples ◽  
Combination Strategies ◽  
Rational Combination

9511 Background: METex14 SA are oncogenic drivers in NSCLC. Due to the numerous sites around ex14 that bind the spliceosome complex, many variations can result in deleterious alterations (alts). We present a comprehensive overview of these ex14 SA across 1,387 NSCLCs and characterized potential AR mechanisms. Methods: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on samples from 60,495 NSCLC patients (pts). A scoring system was applied leveraging our large database of samples with METex14 SA to optimize accurate reporting of these variants. Paired samples were collected ≥ 60 days apart (median 462). Results: 1,393 METex14 SA were identified in samples (1,278 tissue, 109 circulating tumor DNA (ctDNA)) from 1,387 NSCLC pts (2.3%) spanning multiple functional sites: donor (42%), acceptor (4.7%), poly-pyrimidine tract (15%), acceptor and polypyrimidine tract (13%), D1010 (23%), Y1003 (2.1%), and whole exon deletions (0.3%). 6 samples (5 tissue, 1 ctDNA) harbored 2 METex14 SA, each including a mutation (mut) at the donor or acceptor site. MDM2 and CDK4 amplifications (amps) co-occurred in 32% and 19% of METex14 samples, respectively, but were more common with polypyrimidine tract (37% and 23%) vs donor site (32%, p = 0.07 and 18%, p = 0.07) alts. MET co-amp was present in 12% of cases and frequency did not significantly differ by functional site. 66 (4.8%) cases (57 tissue, 9 ctDNA) had known NSCLC co-drivers, including KRAS (68%) and EGFR (14%) mut, a subset of which may represent AR. Paired samples with a METex14 SA in the 1st sample were available for 36 pts. The METex14 SA was detected in the 2nd sample for 32 pts, excluding 3 with low ctDNA. 22/36 (61%) had reportable acquired alts detected including 9 with ≥1 acquired MET muts [D1228X (4), Y1230X (3), Y1003F (1), D1228A/E/H + L1195V (1)] and 3 with acquired MET amp. Other acquired alts included ERBB2 amp and mut (1 each), EGFR ex19ins (1), KRAS amp (1), PIK3CA mut (1), AKT2 amp (1) and others with unknown functional significance. Potential AR alts were present with primary METex14 SA spanning all functional sites. Conclusions: In a dataset of > 60,000 advanced NSCLCs, METex14 SA were present in 2.3% of cases, and represented 6 major subtypes. Among paired cases, potential AR mechanisms included secondary MET alts (33%), and acquired alts in EGFR, ERBB2, KRAS, and PI3K pathways. Acquired alts were independent of the type of METex14 SA. Characterizing common co-occuring may be critical for predicting responses to MET inhibitors and informing rational combination strategies.

scholarly journals Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1087 ◽  
Author(s):  
Lim ◽  
Greer ◽  
Lipkowitz ◽  
Takebe
Keyword(s):  
Predictive Biomarkers ◽  
Cancer Therapeutics ◽  
Hematologic Malignancies ◽  
Resistance Mechanisms ◽  
Protein Protein Interaction ◽  
Combination Strategies ◽  
Successful Induction ◽  
Apoptosis Pathways ◽  
Apoptosis Process ◽  
Apoptosis Inducing Agents

: Evasion from apoptosis is an important hallmark of cancer cells. Alterations of apoptosis pathways are especially critical as they confer resistance to conventional anti-cancer therapeutics, e.g., chemotherapy, radiotherapy, and targeted therapeutics. Thus, successful induction of apoptosis using novel therapeutics may be a key strategy for preventing recurrence and metastasis. Inhibitors of anti-apoptotic molecules and enhancers of pro-apoptotic molecules are being actively developed for hematologic malignancies and solid tumors in particular over the last decade. However, due to the complicated apoptosis process caused by a multifaceted connection with cross-talk pathways, protein–protein interaction, and diverse resistance mechanisms, drug development within the category has been extremely challenging. Careful design and development of clinical trials incorporating predictive biomarkers along with novel apoptosis-inducing agents based on rational combination strategies are needed to ensure the successful development of these molecules. Here, we review the landscape of currently available direct apoptosis-targeting agents in clinical development for cancer treatment and update the related biomarker advancement to detect and validate the efficacy of apoptosis-targeted therapies, along with strategies to combine them with other agents.

Phase II study of 2-methoxyestradiol NanoCrystal dispersion (2ME2) alone and in combination with sunitinib (SU) in patients with metastatic renal cell carcinoma (mRCC) progressing on SU

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16116-e16116
Author(s):  
M. R. Harrison ◽  
R. Pili ◽  
T. Logan ◽  
G. Wilding ◽  
J. Eickhoff ◽  
...  
Keyword(s):  
Disease Progression ◽  
Metabolic Response ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Clinical Activity ◽  
Combination Strategies ◽  
Rational Combination ◽  
Grade 3 ◽  
Number Of Cycles

e16116 Background: Panzem NCD (2ME2) is a non-estrogenic derivative of estradiol with antiproliferative and antiangiogenic activity that downregulates HIF-1α. One mechanism of VEGFR TKI failure may be upregulation of HIF-1α. We hypothesized that 2ME2 may have single-agent activity in pts who previously progressed on SU and that addition of 2ME2 may restore response in pts progressing on SU. Methods: Pts with clear cell mRCC who had previously received or were currently receiving SU with disease progression were eligible. Pts who had previously received SU were treated with 2ME2 alone (arm A). Pts currently on SU continued on the 4:2 schedule, with the addition of 2ME2 (arm B). All pts received 2ME2 at 1,500 mg PO TID, repeated in 6 wk cycles. The primary endpoint was objective response (OR) rate by RECIST. An exploratory endpoint was metabolic response on FDG-PET. Simon optimal 2-stage design was used with plans to enroll 21 pts/arm, and if activity was seen to continue enrollment for a total of 41 pts/arm. Results: 17 pts were enrolled (A: 10; B: 7). Median number of cycles on study was 1 (range <1 to 5). A pt remains on study in cycle 8. Adverse events (AE) of grade 3 or greater occurred in 4 pts (29%). Most frequent AE were: fatigue (71%), diarrhea (50%), dysgeusia (29%), anemia or decreased hemoglobin (29%), and anorexia (21%). Reasons for treatment discontinuation include: disease progression (7), pt/doctor discretion (3), AE (3), and noncompliance (1). No ORs by RECIST were seen. Conclusions: 2ME2 appears to have some single-agent activity, with an MR in a pt removed from study due to AE and a metabolic PR (ΔSUVmax -84%) in a pt with SD by RECIST. With 6/17 pts discontinuing therapy before meeting any OR endpoint, 2ME2 was not tolerable in this population. The study was closed to accrual knowing that a more promising 2ME2 analog is currently under development for oncologic use. The rationale to target HIF-1α after (and during) SU therapy remains of interest. This study design provides a unique way to assess both single-agent and rational combination strategies in pts with mRCC and should be utilized with other agents to seek evidence for clinical activity. [Table: see text]

scholarly journals Pembrolizumab and its role in relapsed/refractory classical Hodgkin’s lymphoma: evidence to date and clinical utility

2018 ◽  
Vol 9 (4) ◽  
pp. 89-105 ◽  
Author(s):  
Polina Shindiapina ◽  
Lapo Alinari
Keyword(s):  
Monoclonal Antibodies ◽  
Hodgkin’S Lymphoma ◽  
Immune Cell ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Malignant Cell ◽  
Hodgkin's Lymphoma ◽  
Molecular Signaling ◽  
Chl A ◽  
Combination Strategies

Immune evasion is a critical mechanism of malignant cell survival, and relies in part on molecular signaling through the programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) axis that contributes to T cell exhaustion. Immune modulatory therapy with monoclonal antibodies against PD-1 designed to enhance antitumor immune response have shown promise in the treatment of advanced solid tumors and hematologic malignancies. Classical Hodgkin’s lymphoma (cHL), a unique B cell malignancy characterized by an extensive but ineffective immune cell infiltrate surrounding a small number of tumor cells, has shown significant response to anti-PD-1 directed therapy. The anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have shown similarly remarkable activity in relapsed/refractory cHL and have been approved by the Food and Drug Administration for treatment of this disease. In this article we review the rationale of targeting the PD-1/PD-L1 axis in cHL and the pharmacology of pembrolizumab, and summarize the data on activity and safety profile of this agent in the treatment of relapsed/refractory cHL. We also discuss the potential benefits and pitfalls of using PD-1 blockade in the setting of allogeneic stem-cell transplantation, and summarize ongoing prospective trials of single-agent pembrolizumab and combination strategies as well as future directions.

scholarly journals Emerging Therapies for Advanced Cholangiocarcinoma: An Updated Literature Review

2021 ◽  
Vol 10 (21) ◽  
pp. 4901
Author(s):  
Anthony Vignone ◽  
Francesca Biancaniello ◽  
Marco Casadio ◽  
Ludovica Pesci ◽  
Vincenzo Cardinale ◽  
...  
Keyword(s):  
Unmet Need ◽  
Present Review ◽  
Driver Mutations ◽  
Current Evidence ◽  
Combination Strategies ◽  
Emerging Therapies ◽  
Tumor Stages ◽  
Rational Combination ◽  
New Treatment

Cholangiocarcinoma is a group of malignancies with poor prognosis. Treatments for the management of advanced-stage cholangiocarcinoma are limited, and the 5-year survival rate is estimated to be approximately 5–15%, considering all tumor stages. There is a significant unmet need for effective new treatment approaches. The present review is provided with the aim of summarizing the current evidence and future perspectives concerning new therapeutic strategies for cholangiocarcinoma. The role of targeted therapies and immunotherapies is currently investigational in cholangiocarcinoma. These therapeutic options might improve survival outcomes, as shown by the promising results of several clinical trials illustrated in the present review. The co-presence of driver mutations and markers of susceptibility to immunotherapy may lead to rational combination strategies and clinical trial development. A better understanding of immunologically based therapeutic weapons is needed, which will lead to a form of a precision medicine strategy capable of alleviating the clinical aggressiveness and to improve the prognosis of cholangiocarcinoma.

scholarly journals Identification of glioblastoma immune subtypes and immune landscape based on a large cohort

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Huiyuan Zhang ◽  
Ying Chen
Keyword(s):  
Structure Learning ◽  
Cox Regression ◽  
Expression Profiles ◽  
Treatment Options ◽  
Prognostic Significance ◽  
Gene Expression Profiles ◽  
Immune Checkpoints ◽  
Combination Strategies ◽  
Rational Combination ◽  
Graph Structure Learning

AbstractGlioblastomas (GBM) are the most common primary brain malignancy and also the most aggressive one. In addition, GBM have to date poor treatment options. Therefore, understanding the GBM microenvironment may help to design immunotherapy treatments and rational combination strategies. In this study, the gene expression profiles and clinical follow-up data were downloaded from TCGA-GBM, and the molecular subtypes were identified using ConsensusClusterPlus. Univariate and multivariate Cox regression were used to evaluate the prognostic value of immune subtypes. The Graph Structure Learning method was used for dimension reduction to reveal the internal structure of the immune system. A Weighted Correlation Network Analysis (WGCNA) was used to identify immune-related gene modules. Four immune subtypes (IS1, IS2, IS3, IS4) with significant prognosis differences were obtained. Interestingly, IS4 had the highest mutation rate. We also found significant differences in the distribution of the four subtypes at immune checkpoints, molecular markers, and immune characteristics. WGCNA identified 11 co-expressed module genes, and there were significant differences among the four subtypes. Finally, CD1A, CD1E, and IL23R genes with significant prognostic significance were selected as the final feature genes in the brown module. Overall, this study provided a conceptual framework for understanding the tumor immune microenvironment of GBM.

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