scholarly journals DDRE-06. CELLULAR STRESS RESPONSE IN DIPG THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii62-ii62
Author(s):  
Sreepradha Sridharan ◽  
Arif Harmanci ◽  
Robert Siddaway ◽  
Tara Dobson ◽  
Jyothishmathi Swaminathan ◽  
...  
Keyword(s):  
Stress Response ◽  
Single Cell ◽  
Synthetic Lethality ◽  
Clonal Evolution ◽  
Single Agent ◽  
Objective Response ◽  
Hdac Inhibitors ◽  
Pediatric Brain Tumor ◽  
Dominant Negative ◽  
Cellular Stress Response

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor of the pons and brainstem. Therefore, there is a desperate need for new therapeutics. Genomic profiling of tumors identified a highly prevalent dominant negative somatic mutation at lysine (K)-27 in histone genes HIST1H3B and H3F3A. Clonal evolution modeling suggests these mutations are truncal, and studies have demonstrated their contribution to tumorigenesis. ONC201, a first-in-class DRD2 antagonist and ClpP agonist is an anticancer drug developed by Oncoceutics, which targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling and is actively being investigated in patients with recurrent H3 K27M-mutant gliomas. In adults with recurrent glioma, single agent studies showed benign-safety, no dose-limiting toxicities and a durable objective response when administered orally. In addition, intra-tumoral drug levels exceeded therapeutic thresholds, and induced tumor cell apoptosis. Based on this and response seen in a pediatric patient with DIPG for whom compassionate use of ONC201 was approved, a multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) is actively accruing patients. However, the strength of UPR and ISR in DIPGs and their effect on DIPG response to ONC201 is not known. Our group employed bulk/single cell transcriptomic and single cell proteomic approaches to demonstrate substantial heterogeneity in UPR and ISR signaling in human DIPG samples. Consistent with this, DIPG cell lines exhibited considerable variability in sensitivity to ONC201. Single cell profiling identified tumor sub-populations with significant proliferative capacity even after ONC201 exposure. Incomplete response promotes recurrence. To target these cells, we performed a synthetic lethality screen with a library of 360 FDA-approved CNS penetrant compounds, which identified HDAC inhibitors and DNA damage-inducing chemotherapy as having synergy with ONC201. Thus, we suggest that tumor heterogeneity impacts sensitivity to ONC201 and that this can be reduced by combination treatments.

scholarly journals Induction and transmission of oncogene-induced senescence

2020 ◽  
Author(s):  
Nattaphong Rattanavirotkul ◽  
Kristina Kirschner ◽  
Tamir Chandra
Keyword(s):  
Stress Response ◽  
Single Cell ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
End Points ◽  
Oncogene Activation ◽  
Suppressor Mechanism ◽  
Bona Fide ◽  
Organ Level ◽  
Complex Scenario

Abstract Senescence is a cellular stress response triggered by diverse stressors, including oncogene activation, where it serves as a bona-fide tumour suppressor mechanism. Senescence can be transmitted to neighbouring cells, known as paracrine secondary senescence. Secondary senescence was initially described as a paracrine mechanism, but recent evidence suggests a more complex scenario involving juxtacrine communication between cells. In addition, single-cell studies described differences between primary and secondary senescent end-points, which have thus far not been considered functionally distinct. Here we discuss emerging concepts in senescence transmission and heterogeneity in primary and secondary senescence on a cellular and organ level.

A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8000-8000 ◽  
Author(s):  
A. Younes ◽  
M. Fanale ◽  
B. Pro ◽  
P. McLaughlin ◽  
S. Neelapu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Hdac Inhibitors ◽  
Response Analysis ◽  
Transcriptional Level ◽  
Cell Transplant ◽  
Tumor Reduction ◽  
Refractory Hodgkin Lymphoma

8000 Background: MGCD0103 is a non-hydroxamate, isotype-selective, inhibitor of human HDACs. Abnormal regulation of HDAC activity is associated with malignant disease in humans, and small molecule HDAC inhibitors are a novel drug class with anticancer potential. Their proposed anti-Hodgkin activity is through regulation of aberrant gene expression at the transcriptional level by inhibiting proliferation, inducing apoptosis, and/or initiating differentiation in cancer cells. Methods: A phase II trial of MGCD0103 (110 mg 3x/week in 4- week cycles) is ongoing in patients (pts) with relapsed/refractory Hodgkin Lymphoma (RRHL). The primary endpoint is a composite of objective response and stable disease. Results: As of Dec 15th, 2006, 18 pts out of a planned 12–35 have been enrolled; median age 28 (range: 21–62). All pts were previously treated with autologous and/or allogeneic stem cell transplant. The median number of cycles received to date is 2 (range: 1–4). Seven pts have completed =8 weeks (2 cycles) of therapy and are evaluable for response analysis; 5 of these had tumor reduction ranging between 21% and 70% by CT, which is associated with a significant reduction in FDG-PET activity in 4 pts. Of the 18 pts, 5 have had dose reductions/discontinuations due to: mucositis (n=1); fatigue/nausea/diarrhea (n=1); nausea/vomiting (n=1); fatigue (n=1) and pancreatitis/hypotension (n=1). Significant HDAC inhibition (>20% of total activity), was seen in PBMCs from 7/9 pts with samples. Treatment is ongoing in 14 pts; including those with tumor reduction. Criteria have been met to expand to the second stage of the study (>1 response demonstrated in the first 12 patients). Conclusions: Preliminary results suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in RRHL and is well tolerated at a Phase II dose of 110mg in this ongoing trial. No significant financial relationships to disclose.

EXTH-30. HARNESSING CELLULAR STRESS FOR IMMUNE TARGETING OF DIPGS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi169-vi170
Author(s):  
Vidya Gopalakrishnan ◽  
Ajay Sharma ◽  
Sreepradha Sridharan ◽  
Donghang Cheng ◽  
Juan Bournat ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Clinical Investigation ◽  
Cellular Stress ◽  
Single Agent ◽  
Pediatric Brain Tumor ◽  
Cytolytic Activity ◽  
Dominant Negative ◽  
Dominant Negative Mutation

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor. An almost ubiquitous dominant negative mutation at lysine (K)-27 in genes encoding histone genes HIST1H3B and H3F3A found in patient tumors is a driver of DIPG development. ONC201, a small molecule DRD2 antagonist and ClpP agonist developed by Chimerix Inc, targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling. It is under clinical investigation in patients with recurrent H3K27M DMGs. In adults, single agent studies have shown durable objective responses when administered orally. A multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) for pediatric patients with H3K27M DMGs is open and accruing. Preliminary results suggest that the drug has a favorable safety profile and holds promise for patients with DIPGs and other midline gliomas. However, the mechanism of action of ONC201 against DIPGs warrants further study. Here, we show that ONC201 is cytotoxic to DIPGs in vitro and in vivo. RNA Seq analyses revealed cell context specific deployment of PERK-activated UPR and calcium signaling-associated RON tyrosine kinase-macrophage stimulating protein (MSP) signaling in DIPGs. Single cell proteomic assays revealed substantial heterogeneity in the sensitivity of DIPG cells to ONC201, and identified stem-like sub-populations of H3K27M DIPGs with intrinsic insensitivity to the drug. ONC201 treatment, which induces cellular stress, also sensitized DIPG cells to cytolytic activity by ex-vivo expanded and activated innate immune cells, in vitro. Ongoing in vivo experiments are expected to support a novel investigational study in patients with midline gliomas.

scholarly journals High Clonal Complexity of Resistance Mechanisms Occurring at Progression after Single-Agent Targeted Therapy Strategies in Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Ella R Thompson ◽  
Tamia Nguyen ◽  
Yamuna Kankanige ◽  
Mary Ann Anderson ◽  
Sasanka M. Handunnetti ◽  
...  
Keyword(s):  
Single Cell ◽  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Cell Analysis ◽  
Clonal Evolution ◽  
Single Agent ◽  
Resistance Mechanisms ◽  
Lymphocytic Leukemia ◽  
Advisory Committees

Progression of chronic lymphocytic leukemia (CLL) on venetoclax (VEN) and BTK inhibitors (BTKi) is associated with acquired genomic variants in BCL2/MCL1/BCL2L1 and BTK/PLCG2, respectively, in some patients. We aimed to assess the clonal structure and evolution of resistance in patients (pts) with progressive disease treated with single agent VEN or BTKi (or both as sequential monotherapies) using next generation sequencing (NGS) and single cell sequencing. Seven pts with CLL and 1 with mantle cell lymphoma (MCL) with disease progression on VEN, ibrutinib (IBR) or zanubrutinib (ZANU) were identified from patients treated at our institutions. Pts were selected on the basis of multiple known resistance mechanisms from previous analysis of mutations (muts) and copy number changes detected using clinical bulk NGS targeting genes of interest including BCL2, MCL1, BCL2L1, BAX, BAK1, BTK, PLCG2, CXCR4, as well as TP53 and SF3B1. Of the 8 pts selected for single cell analysis, all had disease that was relapsed/refractory to chemotherapy prior to receiving either VEN (3 pts), BTKi (2 pts) or sequential VEN-BTKi (3 pts). 6,520-16,378 individual cells from 9 samples (8 pts) were analyzed (total 103,388 cells) using a custom panel targeting pt-specific muts on the Tapestri platform (Mission Bio). A summary of genomic abnormalities detected across the cohort is presented in Figure 1. We first evaluated the relationship between genomic resistance mechanisms within the context of single agent (VEN or BTKi) as well as sequential VEN-BTKi treatment. In CLL pts treated with a single agent, all BCL2 muts in VEN pts and BTK muts in IBR or ZANU pts were identified in different subclones consistent with an oligoclonal pattern of disease progression with independent clonal acquisition of resistance mechanisms. Both pts who received ZANU (either as a single agent or sequentially) harbored the BTK L528W mut (previously described as enriched in ZANU progressors; Handunnetti ASH 2019) in independent clones from BTK C481 muts. In pts who received sequential VEN-BTKi treatment, clones were observed that harbored established or novel dual genomic resistance mechanisms within the same cell (BTK mut/MCL1 amp in CLL, BTK/BAX muts in MCL). However, this was not observed in all clones or for all pts, suggesting the presence of further undetected resistance mechanisms (genetic or other). Given the unique ability of single cell sequencing to resolve mut context within a clonal hierarchy, we next assessed this phenomenon within our cohort utilizing other muts known to be present in these tumors. Analysis of TP53 muts exemplified the diversity of clonal patterns observed, with resistance muts being detected subclonally to parental TP53 muts in some pts and independently of TP53 muts in others. In addition, further evolution of resistant clones was observed through the development of TP53 muts within clones harboring acquired resistance muts, consistent with continued clonal evolution within the resistant disease compartment. In one pt, post-resistance clonal evolution was identified through the clonal acquisition of a CXCR4 mut within a BTK mutated population. Finally, to understand the contribution of BTK zygosity and gender to BTKi resistance (given its location on the X-chromosome), we performed single cell analysis on a disease specimen from a female pt with progressive MCL harboring multiple BTK mutations following treatment with sequential VEN-BTKi. Analysis revealed four clonally independent heterozygous BTK muts inferring the sufficiency of a single mutant allele to drive resistance in this context. Interestingly, this pt also harbored a BCL2 mut and a BAX mut, the latter co-occurring with a BTK mut (BCL2 not assessable). This pt therefore represents the first description of BCL2 or BAX muts occurring in a pt with progressive MCL on VEN and the first of a BTK L528W mut in MCL progressing on ZANU. In summary, these data highlight the significant clonal complexity of CLL progression on VEN and BTKi. Our data show that disease progression in this context is consistently oligoclonal with separate clones harboring distinct identifiable resistance mechanisms. These data have pt-specific implications for the potential utility of cycling back to previously efficacious targeted therapies as well as providing a strong rationale for the early use of disease-appropriate combination targeted therapies. Disclosures Anderson: Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Handunnetti:AbbVie: Other: Travel expenses; Roche: Honoraria; Gilead: Honoraria. Yeh:Novartis: Honoraria; Gilead: Research Funding. Tam:BeiGene: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Seymour:Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nurix: Honoraria. Roberts:Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding; Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties. Blombery:Amgen: Consultancy; Novartis: Consultancy; Invivoscribe: Honoraria; Janssen: Honoraria.

scholarly journals IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB– and caspase-8–dependent mechanisms

2021 ◽  
Vol 5 (19) ◽  
pp. 3776-3788
Author(s):  
Liang Zhou ◽  
Yu Zhang ◽  
Mark B. Meads ◽  
Yun Dai ◽  
Yanxia Ning ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Caspase 8 ◽  
Apoptotic Pathway ◽  
Apoptosis Protein

Abstract Interactions between the inhibitor of apoptosis protein antagonist LCL161 and the histone deacetylase inhibitor panobinostat (LBH589) were examined in human multiple myeloma (MM) cells. LCL161 and panobinostat interacted synergistically to induce apoptosis in diverse MM cell lines, including those resistant to bortezomib (PS-R). Similar interactions were observed with other histone deacetylase inhibitors (MS-275) or inhibitors of apoptosis protein antagonists (birinapant). These events were associated with downregulation of the noncanonical (but not the canonical) NF-κB pathway and activation of the extrinsic, caspase-8–related apoptotic cascade. Coexposure of MM cells to LCL161/LBH589 induced TRAF3 upregulation and led to TRAF2 and NIK downregulation, diminished expression of BCL-XL, and induction of γH2A.X. Ectopic expression of TRAF2, NIK, or BCL-XL, or short hairpin RNA TRAF3 knock-down, significantly reduced LCL161/LBH589 lethality, as did ectopic expression of dominant-negative FADD. Stromal/microenvironmental factors failed to diminish LCL161/LBH589–induced cell death. The LCL161/LBH589 regimen significantly increased cell killing in primary CD138+ cells (N = 31) and was particularly effective in diminishing the primitive progenitor cell–enriched CD138–/19+/20+/27+ population (N = 23) but was nontoxic to normal CD34+ cells. Finally, combined LCL161/LBH589 treatment significantly increased survival compared with single-agent treatment in an immunocompetent 5TGM1 murine MM model. Together, these findings argue that LCL161 interacts synergistically with LBH589 in MM cells through a process involving inactivation of the noncanonical NF-κB pathway and activation of the extrinsic apoptotic pathway, upregulation of TRAF3, and downregulation of TRAF2/BCL-XL. Notably, this regimen overcomes various forms of resistance, is active against primary MM cells, and displays significant in vivo activity. This strategy warrants further consideration in MM.

scholarly journals 353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Open Label ◽  
Safety And Efficacy ◽  
Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

scholarly journals Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

2021 ◽  
Author(s):  
Yu-bo Zhou ◽  
Yang-ming Zhang ◽  
Hong-hui Huang ◽  
Li-jing Shen ◽  
Xiao-feng Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Targets ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Preclinical Study ◽  
Parp Cleavage ◽  
Rpmi 8226 ◽  
Ongoing Phase

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

scholarly journals Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 99
Author(s):  
Shweta Devi ◽  
Vijay Kumar ◽  
Sandeep Kumar Singh ◽  
Ashish Kant Dubey ◽  
Jong-Joo Kim
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Neurodegenerative Disorders ◽  
Cell Damage ◽  
Cellular Stress ◽  
Clinical Manifestations ◽  
Cellular Stress Response ◽  
Dramatic Rise ◽  
Cellular Stress Responses

Neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

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