Current Standard Of Care Therapy Research Articles

Enhancing Neuroblastoma Immunotherapies by Engaging iNKT and NK Cells.

Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and significant treatment-related morbidities associated with current standard of care therapies belie the critical need for more tolerable and effective treatments for this disease. While the monoclonal antibody dinutuximab has demonstrated the potential for immunotherapy to improve overall NB outcomes, the 5-year overall survival of high-risk patients has not yet substantially changed. The frequency and type of invariant natural killer T cells (iNKTs) and natural killer cells (NKs) has been associated with improved outcomes in several solid and liquid malignancies, including NB. Indeed, iNKTs and NKs inhibit tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs), kill cancer stem cells (CSCs) and neuroblasts, and robustly secrete cytokines to recruit additional immune effectors. These capabilities, and promising pre-clinical and early clinical data suggest that iNKT- and NK-based therapies may hold promise as both stand-alone and combination treatments for NB. In this review we will summarize the biologic features of iNKTs and NKs that confer advantages for NB immunotherapy, discuss the barriers imposed by the NB tumor microenvironment, and examine the current state of such therapies in pre-clinical models and clinical trials.

Evaluation of canonical Hedgehog signaling pathway inhibition in canine osteosarcoma

Canine osteosarcoma (OSA), the most common canine primary bone malignancy, has a highly aggressive biologic behavior. Despite current standard of care therapies, including amputation and adjuvant chemotherapy, most dogs still succumb to metastatic disease. Further investigations into molecular mechanisms and pathways driving OSA are needed to improve therapeutic options. The Hedgehog (HH) cell-signaling pathway has demonstrated involvement in human OSA. Several studies in canine OSA have found changes in expression of some HH pathway genes and demonstrated a role for HH transcription factors. However, the role of this pathway as well as the translational value of its targeting in canine OSA are still undefined. The objectives of this study were to determine the expression of HH components directly in canine OSA tissues and to evaluate the biologic impact of HH signaling inhibition in canine OSA cells. In situ hybridization was used to detect HH family mRNA expression in archived canine OSA tissues and revealed variable expression levels of these mRNAs in canine OSA tissues. The effect of a commercially available Smoothened inhibitor, vismodegib, was studied in established canine OSA cell lines. Alterations in cellular growth as well as assessment of downstream HH targets were evaluated. Although changes in cell growth were noted following Smoothened inhibition, inconsistent decreases in target gene expression were found. While treatment with vismodegib had a negative impact on canine OSA cell growth and viability, the mechanism remains unclear. Further studies are warranted to evaluate the clinical significance of canonical HH signaling in canine OSA.

Relationship Between pH Shifts and Rate of Healing in Chronic Nonhealing Venous Stasis Lower-Extremity Wounds

Venous stasis ulcers represent the majority of lower-extremity ulcers and place a considerable financial burden on the American health care system. Current standard of care therapies remain sub-optimal with 50% of venous stasis ulcers remaining unhealed after 4 months. Sixteen consecutive wounds were enrolled across 8 participants at a single center and underwent pH-driven therapy in addition to standard care as dictated by physicians. Following wound debridement, the pH of the wound bed was measured using pH strips. If acidic, normal saline was used to rinse the wound at every dressing change. If alkaline, nonsterile gauze was soaked in 0.25% acetic acid and applied to the wound for a minimum of 30 seconds. Participants were followed for 4 weeks with research staff observing compliance throughout. All 16 wounds had an alkaline pH at baseline, with an average pH of 8.25 ± 0.55 (range 7.5 to 9). Average area of the wound at the time of enrollment was (mean ± standard deviation) 285.48 ± 43.68 mm2, and average age of the wound was 37.5 ± 20.3 months (range 3 to 72). A simple linear regression model found a moderate relationship between pH and the rate of healing of chronic nonhealing venous stasis lower-extremity wounds (correlation coefficient = 0.61). For every 1-unit change in pH, we can expect to see a change in wound size of 116.05 mm2. This is the first US-based, open-label, prospective study that examined the effect of pH on the rate of healing in chronic nonhealing venous stasis ulcer lowerextremity wounds.

Abstract P3-11-04: A phase II study of pembrolizumab, letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer

Abstract Background: The combination of CDK4/6 inhibitor and aromatase inhibitor is the current standard of care therapy for patients with estrogen receptor positive (ER+) metastatic breast cancer (MBC). Single agent immune check point inhibitor (ICI) pembrolizumab has a response rate of 12% in selected patients (PD-L1+), and preclinical studies demonstrated immune-modulatory effect of CDK4/6 inhibitors. The combination of CDK 4/6 inhibitors and ICI might turn “immune-cold” breast cancer tumors into “immune-hot” tumors. This study was designed to evaluate the safety and efficacy of adding pembrolizumab to letrozole and palbociclib in patients with ER+ MBC. Methods: This is an open-label single arm study enrolling patients with biopsy proven ER+ MBC with measurable disease by RECIST1.1, ECOG performance status 0-1. Patient received letrozole (2.5mg po daily), palbociclib (125mg po daily 3 weeks on, 1 week off), and pembrolizumab (200mg iv q3wks). Two cohorts were included: cohort 1 for patients who were previously on letrozole and palbociclib for > 6 months and had pembrolizumab added on C1D1, and cohort 2 for patients who had all 3 drugs started on C1D1. Premenopausal patients received ovarian suppression prior to C1D1. The primary objective was to determine the safety and tolerability of the combination. The secondary objectives were RR, PFS, and OS. For both cohorts, a three-at-risk design (modified rolling design) was used for safety-lead to ensure the triplet was well-tolerated. This design permitted only 3 patients to be a risk for DLT at any one time during the “safety lead-in” and permitted continuing accrual if ≤1 DLT occurred in the first 6 patients. Secondary consideration was response (cohort 2 only), with an a priori requirement of at least 9 responses to warrant further evaluation. Baseline tumor specimen, peripheral blood plasma, and PBMCs were collected for immune correlative analysis. Results: A total of 20 patients were accrued to this trial (4 in cohort 1, 16 in cohort 2), with 19 eligible for response assessment because one patient was determined to be TNBC upon repeat of biopsy. Median age was 49 years, with 40% Hispanic, and 60% non-Hispanic. There were 2 DLTs (1 biopsy site infection and delay in treatment that was possibly related to treatment in cohort 1, and 1 pneumonitis in cohort 2). 9/20 patients (45%) had dose delay and 9/20 patients (45%) had dose reduction, with the most common cause being neutropenia. Gr 4 AEs included neutropenia (n=4), WBC (n=3), LFT (n=1), and bowel perforation (n=1). Grade 3 AEs included neutropenia (n=11), WBC (n=9), LFT (n=3), PLT (n=2), and pneumonitis, pruritus, anemia, biopsy site infection (n=1 each). Other immune-related toxicities of Grade 2 included: hypothyroidism, colitis, LFTs, and dermatitis (n≤2 each). Responses were CR 1/19 (5.3%), PR 8/19 (42.1%), SD 6/19 (31.6%) and PD 4/19 (21.1%). Median follow up was 13.7 (95% CI 6.4-16.9) months and median PFS was not reached. No association of baseline tumor PD-L1 (22C3) and clinical response were observed (data available on 13 patients). PBMC flow from the first 9 patients (5 PR, 4 SD) showed lower percentage of naïve CD8+ T cells (CD8+CD45RA+ CD27+), and higher level of non-naïve KLRG1+CD8+ T cell (CD8+CD45RA− CD27− KLRG1+) were associated with clinical response (p<0.05). Conclusion: The combination of letrozole, palbociclib, and pembrolizumab is well tolerated in patients with ER+ MBC. Citation Format: Yuan Yuan, Susan E Yost, Jin Sun Lee, Colt Egelston, Paul H Frankel, Christopher Ruel, Simran Padam, Aileen Tang, Norma Martinez, Jana Portnow, Christina Yeon, Cary Presant, Swapnil Rajurkar, Mina Sedrak, Niki Patel, Peter Lee, Joanne Mortimer. A phase II study of pembrolizumab, letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-04.

Mutation-Driven Therapy in MDS.

Genetic sequencing in myelodysplastic syndrome (MDS) has provided an improved understanding of the complexity and heterozygosity of the disease. More importantly, our molecular understanding of MDS is leading to rapid advancements and personalized therapy for our patients. Herein, we review the current mutation-driven treatment landscape in MDS, first focusing on individual mutations. We then discuss the effect of specific gene mutations on response and outcomes to standard therapies as well as to cutting edge investigational therapies. Molecular annotation of MDS can predict response rates and outcomes to our current standard of care therapies including hypomethylating agents, lenalidomide, and allogeneic stem cell transplantation. Clinical trials targeting molecular subsets of MDS are underway with some in very early stages while others advancing to phase III trials. Targeting TP53 and IDH1/2 mutations appear to be promising targets with substantial efficacy seen in several trials to date. Furthermore, novel therapeutic strategies such as immuno-oncology agents are of significant interest with future investigation required to understand the molecular predictors of response. Mutation-driven therapy in MDS is rapidly expanding and has tremendous potential in a disease where limited standard therapy options exist.

Combined Venetoclax and Hypomethylating Agent (HMA) Therapy Induces High Response Rates in Patients with Myelodysplastic Syndrome Including Patients Previously Failing HMA

Combined Venetoclax and Hypomethylating Agent (HMA) Therapy Induces High Response Rates in Patients with Myelodysplastic Syndrome Including Patients Previously Failing HMA

An Open-Label Phase I/IIa Study to Evaluate the Safety and Efficacy of CCS1477, a First in Clinic Inhibitor of the p300/CPB Bromodomains, As Monotherapy in Patients with Advanced Haematological Malignancies

An Open-Label Phase I/IIa Study to Evaluate the Safety and Efficacy of CCS1477, a First in Clinic Inhibitor of the p300/CPB Bromodomains, As Monotherapy in Patients with Advanced Haematological Malignancies

The Use of CEP (Lomustine, Etoposide and Prednisone), an All-Oral Palliative Chemotherapy Regimen, in Aggressive Lymphomas

The Use of CEP (Lomustine, Etoposide and Prednisone), an All-Oral Palliative Chemotherapy Regimen, in Aggressive Lymphomas

2459 Is Shorter Course of Gleceprevir and Pibrentasvir (MAVYRET) for Hepatitis C Treatment Possible? A Case Series

INTRODUCTION: Direct-acting oral antiviral agents (DAA) including a combination of Gleceprevir and Pibrentasvir (Mavyret), among others, is the current standard of care therapy for chronic hepatitis C (HCV) infection. These medications have demonstrated high rates of sustained virological response at 12 weeks post-therapy (SVR12) in all genotypes of HCV. More specifically for Mavyret, multiple clinical trials have demonstrated SVR12 in HCV patients after 8, 12, or 16 weeks of therapy. There is, however, no data to support a shorter therapy course. In this small case series, we report 5 subjects who achieved SVR12 with Mavyret after 2 or 4 weeks of therapy. CASE DESCRIPTION/METHODS: Clinical data from a large cohort of patients treated for HCV was retrospectively reviewed for patients treated from 2015-2019. Data extracted and analyzed included patient demographics, HCV treatment regimen, HCV genotype, HCV RNA levels, fibrosis state and sustained virological response (SVR). DISCUSSION: Results: Among the 5 patients identified there were 4 males and 1 female. In total, 4 patients had genotype 1a and 1 patient had genotype 1b. The single patient with SVR12 after 2 weeks of therapy was genotype 1a. The remaining patients received 4 weeks of therapy. Fibrosis Score ranged from F0 to F1, HCV RNA levels ranged from 83,400-8,420,000 and all patients had a documented history of intravenous drug use (Table 1). Conclusion: In this small case series, we present 5 patients who achieved SVR12 after only 2 or 4 weeks of Mavyret therapy. When considering factors such as the cost of therapy, possible history of substance abuse, and/or poor socioeconomic status, opting for a shorter course of therapy may be beneficial. Further large-scale prospective clinical trials are needed to support these findings.

Efficacy and safety of intensified platinum-based neoadjuvant chemotherapy in locally advanced triple-negative breast cancer: Preliminary results of non-randomized phase II study.

e12116 Background: patients with locally-advanced triple negative breast cancer (TNBC) have dismal prognosis with current standard of care therapy. Pathologic complete response (pCR) is the most important prognostic factor for long-term survival of these patients. Methods: this was non-randomized prospective single-center phase II study. Key inclusion criteria were histologically verified locally advanced TNBC, non-eligibility for primary surgical treatment (ie, TNM stage Т2-4N 2-3M0) and no evidence of metastatic disease. Patients were treated with 8 cycles of neoadjuvant doxorubicine, paclitaxel and cisplatin chemotherapy (ATP; doxorubicine 40 mg/m2 day 1, paclitaxel 160 mg/m2 day 1 and cisplatin 50 mg/m2 day 1 every two weeks) with G-CSF support (filgrastim 5 mcg/kg day 2-6). After 8 cycles of chemotherapy patients were referred for surgical treatment; adjuvant radiation therapy was prescribed to all patients. Primary end point was pCR assessed in modified intention-to-treat population (ie, in patients who underwent surgical treatment). Key secondary endpoints were disease-free survival (DFS) and pCR rate according to BRCA status. Results: we enrolled 80 patients, 79 (98.7%) of them underwent surgical treatment and were included in the analysis. Median age was 46 years (25-68), 22 (27.1%) patients had BRCA1 mutations, 5382insC was the most common mutation (17 [77.2%] of patients); 1 (1.2%) patient had CHEK2 mutation. pCR was achieved in 51 (64.5%) patients. In with BRCA1-mutation carriers pCR rate was 61.9%, in patients with 5382insC – 81.2%. 2-year DFS was 77.3%; 2-year overall survival was 91.0% . Most common grade 3-4 adverse events were anemia (29.3%), neutropenia (17.8%), neuropathy (4.9%), stomatitis (3.7%) and thrombocytopenia (1.8%). Conclusions: the ATP regimen was effective in treatment of locally-advanced TNBC, especially in patients with founder 5382insC BRCA1 mutation for Slavic population and deserves further investigation.

Rapid Early Tumor Progression is Prognostic in Glioblastoma Patients.

Determine the prognostic significance of rapid early tumor progression before radiation and chemotherapy for glioblastoma patients. A retrospective review of glioblastoma patients was performed. Rapid early progression (REP) was defined as new enhancing tumor or >25% increase in enhancement before radiotherapy. The pre/postoperative magnetic resonance imaging was compared with the preradiation magnetic resonance imaging to determine REP. A blinded review of imaging was performed. Kaplan-Meier curves were generated to compare progression-free and overall survival (OS). Univariate analysis was performed using the log-rank test for categorical variables and Cox proportional hazards for continuous variables. Multivariable logistic regression was performed to assess factors related to early progression and Cox proportional hazards model was used for multivariate analysis of OS. Eighty-seven patients met entry criteria. A total of 52% of patients developed REP. The OS in the REP group was 11.5 months (95% confidence interval [CI]: 7.4-17.6) and 20.1 months (95% CI: 17.8-26.1) without REP (P=0.013). On multivariate analysis including significant prognostic factors, presence of REP was found to increase the risk of death (hazard ratio: 2.104, 95% CI: 1.235-3.583, P=0.006). A total of 74% of patients recurred in the site of REP. REP was common and independently predicted for a worse OS. Integrating REP with MGMT promotor methylation improved prognostic assessment. The site of REP was a common site of tumor progression. Our findings are hypothesis generating and may indicate a particular subset of glioblastoma patients who are resistant to current standard of care therapy. Further study to determine other molecular features of this group are underway.

Intracavitary radioimmunotherapy of high-grade gliomas: present status and future developments.

There is a distinct need for new and second-line therapies to delay or prevent local tumor regrowth after current standard of care therapy. Intracavitary radioimmunotherapy, in combination with radiotherapy, is discussed in the present review as a therapeutic strategy of high potential. We performed a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The available body of literature on intracavitary radioimmunotherapy (iRIT) in glioblastoma and anaplastic astrocytomas is presented. Several past and current phase I and II clinical trials, using mostly an anti-tenascin monoclonal antibody labeled with I-131, have shown median overall survival of 19-25months in glioblastoma, while adverse events remain low. Tenascin, followed by EGFR and variants, or smaller peptides have been used as targets, and most clinical studies were performed with I-131 or Y-90 as radionuclides while only recently Re-188, I-125, and Bi-213 were applied. The pharmacokinetics of iRIT, as well as the challenges encountered with this therapy, is comprehensively discussed. This promising approach deserves further exploration in future studies by incorporating several innovative modifications.

CD99 Expression in Glioblastoma Molecular Subtypes and Role in Migration and Invasion.

Glioblastoma (GBM) is the most aggressive type of brain tumor, with an overall survival of 17 months under the current standard of care therapy. CD99, an over-expressed transmembrane protein in several malignancies, has been considered a potential target for immunotherapy. To further understand this potentiality, we analyzed the differential expression of its two isoforms in human astrocytoma specimens, and the CD99 involved signaling pathways in glioma model U87MG cell line. CD99 was also analyzed in GBM molecular subtypes. Whole transcriptomes by RNA-Seq of CD99-siRNA, and functional in vitro assays in CD99-shRNA, that are found in U87MG cells, were performed. Astrocytoma of different malignant grades and U87MG cells only expressed CD99 isoform 1, which was higher in mesenchymal and classical than in proneural GBM subtypes. Genes related to actin dynamics, predominantly to focal adhesion, and lamellipodia/filopodia formation were down-regulated in the transcriptome analysis, when CD99 was silenced. A decrease in tumor cell migration/invasion, and dysfunction of focal adhesion, were observed in functional assays. In addition, a striking morphological change was detected in CD99-silenced U87MG cells, further corroborating CD99 involvement in actin cytoskeleton rearrangement. Inhibiting the overexpressed CD99 may improve resectability and decrease the recurrence rate of GBM by decreasing tumor cells migration and invasion.

Zephyr Endobronchial Valves Improve FEV1 and Quality of Life in Heterogenous Emphysema

Synopsis: In patients with severe heterogenous emphysema and little or no collateral ventilation in target lobes, Zephyr Endobronchial Valve treatment provides statistical and clinical benefits in lung function and quality of life compared with current standard of care therapies over a 12-month period. Source: Criner GJ, Sue R, Wright S, et al. LIBERATE Study Group. A multicenter randomized controlled trial of Zephyr endobronchial valve treatment in heterogenous emphysema (LIBERATE). Am J Respir Crit Care Med 2018;198:1151–1164.

Therapy for Mycobacterium kansasii Infection: Beyond 2018.

The current standard of care therapy for pulmonary Mycobacterium kansasii infection is isoniazid (300 mg/day), rifampin (600 mg/day), and ethambutol (15 mg/kg/day) for 12 months after achieving sputum culture negativity. Rifampin is the key drug in this regimen. The contribution of isoniazid is unclear since its in vitro MICs against M. kansasii are near the peak achievable serum levels and more than 100-fold greater than the MICs for Mycobacterium tuberculosis. Ethambutol likely decreases the emergence of rifampin resistant organisms. There are several new drug classes (e.g., quinolones, macrolides, nitroimidazoles, diarylquinolines, and clofazimine) that exhibit antimycobacterial activities against M. tuberculosis but have not yet been adequately studied against M. kansasii infections. The evaluation of in vitro activities of these agents as well as their study in new regimens in comparison to the standard of care regimen in mouse infection models should be undertaken. This knowledge will inform development of human clinical trials of new regimens in comparison to the current standard of care regimen. It is likely that shorter and more effective therapy is achievable with currently available drugs.

Buprenorphine for the Treatment of Neonatal Abstinence Syndrome.

Objective: To summarize the available data for using buprenorphine in neonatal abstinence syndrome and discuss these data in context of the current standard of care therapies, oral morphine and oral methadone. Data Sources: A literature search was conducted using PubMed (1949-May 2018) and EMBASE (1980-May 2018). Combinations of the search terms "buprenorphine," "neonatal," and "neonatal abstinence syndrome" were used. Study Selection and Data Extraction: All full-length, English-language studies were included in this review. Data Synthesis: A total of 4 studies were included in this review including 1 retrospective cohort study, 2 prospective single-center open-label randomized trials, and 1 prospective single-center, double-blind study. Oral morphine was the comparator in 3 studies, and oral methadone was the comparator in one. Buprenorphine was associated with a significant reduction in duration of treatment in 3 of the 4 studies and was associated with a significant reduction in duration of hospital stay in 3 of the 4 studies. In the randomized, double-blinded trial, buprenorphine had a significantly reduced duration of treatment (15 vs 28 days, P < .001) and duration of hospital stay (21 vs 33 days, P < .001). The requirement of adjunct treatment was similar between groups in all 4 studies, and buprenorphine did not have any significant adverse reactions in comparison with morphine and methadone. Conclusions: Buprenorphine appears to be a safe option for treating neonatal abstinence syndrome that is potentially superior to the current standard of care therapies with respect to duration of treatment and hospital length of stay.

Abstract P1-06-01: Putting multigene signatures to the test: Prognostic assessment in population-based contemporary clinical breast cancer

Abstract Background Gene expression signatures hold promise for a molecularly driven division of primary breast cancer with clinical implications. A gap still remains in the application/validation of such signatures in actual clinical treatment groups from unselected, population-based, primary breast cancer receiving current standard of care therapy. We analyzed classification proportions and overall survival (OS) of 14 reported gene expression phenotypes (GEPs) and risk predictors (RPs) in seven clinical treatments groups from an 3273-sample breast cancer cohort representative of population-based disease in the South Swedish healthcare region. Patients and methods Between 2010-09-01 to 2015-03-31, 5101 (87%) of 5892 patients with invasive primary disease in the healthcare region were included in the SCAN-B study (ClinicalTrials.gov ID: NCT02306096). Inclusion criteria included no generalized/prior contralateral disease and known surgery/treatment status (neo- or adjuvant). 3273 tumors were profiled by RNA sequencing and matched to clinicopathological patient data from the National Breast Cancer Register, with distribution of clinicopathological characteristics reflecting proportions in the catchment region. RNA profiles were classified according to 14 reported gene signatures featuring both GEPs (PAM50, IC10, CIT, TNBCtype) and specific risk predictors (e.g. Oncotype Dx, 70-gene, 76-gene, ROR-variants, genomic grade index). Classifications were investigated for association with patient OS by univariate and multivariate analyses in seven adjuvant clinical treatment groups: TNBC-ACT (adjuvant chemotherapy, n=228), TNBC-untreated (n=83), HER2+/ER- with trastuzumab + ACT treatment (n=101), HER2+/ER+ with trastuzumab + ACT + endocrine treatment (n=210), ER+/HER2- with endocrine treatment (n=1477), ER+/HER2- with endocrine + ACT treatment (n=637), and ER+/HER2- untreated (n=216). Results For the majority of signatures, analysis of classification demonstrated prognostic value limited to ER+/HER2- tumors given follow-up time. Several signatures (including Oncotype Dx, 70-gene, ROR-variants) showed strong predictive value in identifying a subset of ER+/HER2- patients receiving a combination of endocrine and ACT therapy with excellent overall survival (&amp;gt;96%), indicating appropriate therapy selection. In addition, for both ER+/HER2- treatment groups signature analysis identified high-risk groups of patients in clear need of additional treatment beyond standard therapeutic regimes, even with less than 5-years of follow-up. Conclusions Our results support the prognostic association of gene expression signatures in large unselected population-based primary breast cancer cohorts even with a short follow-up of OS.Importantly, prognostic associations are limited to specific subgroups for different classifiers and in population-based breast cancer some clinically important subgroups constitute a small proportion of cases. In this context, continued population-based inclusion and broad transcriptional profiling of breast cancer patients provides an opportunity for application to broader patient groups (e.g. TNBC and HER2+), and for consensus classification of individual risk assessments that could potentially provide more stable predictions. Citation Format: Staaf J, Vallon-Christersson J, Häkkinen J, Saal LH, Hegardt C, Larsson C, Ehinger A, Ryden L, Loman N, Malmberg M, Borg Å. Putting multigene signatures to the test: Prognostic assessment in population-based contemporary clinical breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-01.

PP28. THERAPEUTIC COMPOUND DISCOVERY AND VALIDATION OF DRUGS TARGETING A RECURRENT GLIOBLASTOMA (GBM) PHENOTYPE USING LINCS COMPOUNDS VIA QUADRATIC ANALYSES

Glioblastoma (GBM) is the most prevalent and aggressive of malignant primary brain tumours. Despite multi-modal therapy, including surgical resection, radiotherapy and chemotherapy, GBM continues to be uniformly lethal, with a median survival of 12–18 months from the time of diagnosis. The resistance to therapy and ultimate recurrence is thought to originate from a sub-population of cells residing in the initial tumour, identified as glioma-initiating or glioma-stem cells (GSC). These GSC have been shown to be intrinsically more invasive, with enhanced repair and drug-efflux pathways mediating resistance to chemo-radiation therapies. The purpose of this study was to use and validate a novel connectivity mapping procedure to identify candidate compounds targeting therapy-resistant and recurrent GBM. This procedure was developed by O’Reilly and colleagues (“QUADrATiC: A Scalable Approach to Repurposing FDA-approved therapeutics”, under review in Bioinformatics), and in this study, was performed on publicly available NCBI GEO microarray datasets. Based on the cancer stem cell theory whereby the resistant GSCs repopulate and are enriched in recurrent tumours, primary and recurrent GBM gene expression profiles were compared and the connections between the identified gene lists and drug responses were mapped. To validate that this connectivity mapping procedure is reliable at identifying effective treatments to target therapeutic resistance and recurrence, we tested one of the top ten compounds identified, rosiglitazone (rosi), a ligand of the peroxisome proliferator activated receptor gamma (PPARγ). The efficacy of rosi alone and in combination with the current standard of care therapies, temozolomide and radiation, at killing GSC was assessed in vitro using the clonogenic survival assay. Our data indicated that rosi significantly reduced survival of both non-stem glioma cells and GSC, alone and in combination with radiation and temozolomide. The p53 pathway was identified as a pathway by which rosi may induce permanent cell cycle arrest and cell death. Further work is ongoing to fully elucidate the downstream mechanisms of cell death. This work is proof-of-principle that the current connectivity mapping procedure can be instrumental in identifying more targeted therapeutic interventions for GBM resistance and prevent recurrence.

Assessing the Feasibility of Pathology Informatics Approaches for Subtyping Diffuse Large B-Cell Lymphoma (DLBCL)

IntroductionPatients (pts) with DLBCL can experience marked difference in overall survival (OS) based on clinical characteristics, race, and biological subtype. Immunohistochemistry (IHC) algorithms can stratify pts into the germinal center B-cell-like (GCB) or activated B-cell-like (ABC) subtype, which is associated with worse OS with current standard of care therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP; Meyer et al. 2011). However, these algorithms can be challenging to perform in clinical practice. We evaluated the frequency of GCB and non-GCB subtypes in a retrospective cohort of patients and evaluated the feasibility of performing automated pathology informatics computer segmentation algorithms to assess DLBCL subtype.MethodsWe included all patients diagnosed with DLBCL at Emory University from 1995-2016. We collected demographic, clinical, laboratory and pathologic data on all patients. We evaluated GCB and non-GCB status using the Hans algorithm as performed during routine clinical care, collected IHC slides for H&E, CD10, CD20, CD30, BCL2, BCL6, C-MYC, and MUM1, and assessed the feasibility of performing automated computer segmentation algorithms to assess DLBCL subtype using these materials.ResultsOut of 364 patients with DLBCL in our database, 151 had available data for DLBCL classification by the Hans algorithm and 103 had available slides for computational algorithms. For the entire dataset the median age was 61 years, 51% were male, 31% had stage III/IV disease. Among patients who had classification data, the median age was 61 years, 53% were male, 45% had stage III/IV disease, and 47% GCB DLBCL and 53% had non-GCB. Among patients with slides available for computational algorithms the median age was 64 years, 53% were male, 48% had stage III/IV disease.ConclusionsIn this retrospective cohort study, the group of patients with available slides for performing computer segmentation algorithms had similar demographics and disease characteristics to patients in the general population of DLBCL at an academic medical center. This dataset and associated pathology images provides a useful resource to evaluate whether computational algorithms can aid in defining the prognosis for DLBCL patients. Future directions for this work will involve the establishment of an online DLBCL digital archive to develop a more precise, repeatable and objective image-analysis based scoring of DLBCL tissues to improve the prognostic accuracy and classification of DLBCL. DisclosuresFlowers:NIH: Research Funding; Genentech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; Mayo Clinic: Research Funding; Infinity: Research Funding; Millenium/Takeda: Research Funding; ECOG: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding.

Abstract 72: Therapeutic compound discovery targeting a recurrent glioblastoma (GBM) phenotype using LINCS compounds via QUADrATiC analyses

Abstract Glioblastoma (GBM) is the most prevalent and aggressive of malignant primary brain tumours. Despite multi-modal therapy, including surgical resection, radiotherapy and chemotherapy, GBM continues to be uniformly lethal, with a median survival of 12-18 months from the time of diagnosis. The resistance to therapy and ultimate recurrence is thought to originate from a sub-population of cells residing in the initial tumour, identified as glioma-initiating or glioma-stem cells (GSC). These GSC have been shown to be intrinsically more invasive, with enhanced repair and drug-efflux pathways mediating resistance to chemo-radiation therapies. The purpose of this study was to use and validate a novel connectivity mapping procedure to identify candidate compounds targeting therapy-resistant and recurrent GBM. This procedure was developed by O’Reilly and colleagues (“QUADrATiC: A Scalable Approach to Repurposing FDA-approved therapeutics”, under review in Bioinformatics), and in this study, was performed on publicly available NCBI GEO microarray datasets. Based on the cancer stem cell theory whereby the resistant GSCs repopulate and are enriched in recurrent tumours, primary and recurrent GBM gene expression profiles were compared and the connections between the identified gene lists and drug responses were mapped. To validate that this connectivity mapping procedure is reliable at identifying effective treatments to target therapeutic resistance and recurrence, we tested one of the top ten compounds identified, rosiglitazone (rosi), a ligand of the peroxisome proliferator activated receptor gamma (PPARγ). The efficacy of rosi alone and in combination with the current standard of care therapies, temozolomide and radiation, at killing GSC was assessed in vitro using the clonogenic survival assay. Our data indicated that rosi significantly reduced survival of both non-stem glioma cells and GSC, alone and in combination with radiation and temozolomide. The p53 pathway was identified as a pathway by which rosi may induce permanent cell cycle arrest and cell death. Further work is ongoing to fully elucidate the downstream mechanisms of cell death. This work is proof-of-principle that the current connectivity mapping procedure can be instrumental in identifying more targeted therapeutic interventions for GBM resistance and prevent recurrence. Citation Format: Shahnaz T. Al Rashid, Paul O’Reilly, Philip D. Dunne, Matthew Alderdice, Thomas J. Flannery, Kevin M. Prise, Shu-Dong Zhang, Darragh G. McArt. Therapeutic compound discovery targeting a recurrent glioblastoma (GBM) phenotype using LINCS compounds via QUADrATiC analyses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 72.