tbuckley/cabot-search huggingface dataset:
Abstract 3768: Single-cell characterization and lineage tracking of recurrent pediatric rhabdomyosarcoma
Authors: Anand G. Patel, Elizabeth Stewart, Michael Clay, Xiang Chen, Michael Dyer
Journal: Cancer Research (2019)

Abstract A critical challenge for the effective treatment of pediatric solid tumors is tumor recurrence. In pediatric rhabdomyosarcoma (RMS), 70% of patients with metastatic disease will experience relapse despite treatment with chemotherapy, radiation and/or surgery. Those patients with relapse have particularly dismal outcomes with less than 20% survival over 5 years. These poor outcomes underscore the need for a better understanding of RMS, particularly the biologic processes responsible for recurrence and progression. Currently, a major obstacle towards improving RMS treatment has been that we, as a field, do not know which cells within RMS tumors evade treatment toxicity, and how these cells are selected for in the presence of chemotherapy. We have previously developed a panel of orthotopic patient-derived xenografts (O-PDXs) that encompass the clinical and molecular diversity of RMS. In this study, we have leveraged single-cell RNA-sequencing (scRNA-seq) of our O-PDX system to characterize the intratumoral heterogeneity within this panel. Analysis of single-cell transcriptomic data demonstrate that fusion-negative RMS O-PDXs bear two distinct subpopulations: (1) a major subpopulation encompassing approximately 99% of the tumor cells, and (2) a minor population that are non-cycling and express genes from a variety of mesenchymal lineages. This two-population intratumoral structure is stable within O-PDXs during passaging of xenografts. To extend these findings, we have developed a workflow using lentiviral transduction of O-PDX cells with a high complexity barcode library. This library integrates a unique 18-mer oligonucleotide barcode into each transduced cell within the 3’-untranslated region of blue fluorescent protein. Thus, all cells within an O-PDX with the same barcode are progeny of the same ancestral cell. We have validated longitudinal tracking of barcode diversity using genomic DNA and within the libraries generated during scRNA-seq. Mice bearing barcoded O-PDXs have undergone chemotherapy dosed to pharmacokinetically mimic pediatric therapy regimens; O-PDXs regress during treatment and ultimately recur following completion of therapy, akin to the clinical experience with RMS. Recurrent O-PDXs bear divergent barcodes, indicating that chemotherapy selects for tumor cells independent of the originating lineage of those cells. Further studies to evaluate the changes that occur in recurrent O-PDXs cells are underway. Citation Format: Anand G. Patel, Elizabeth Stewart, Michael Clay, Xiang Chen, Michael Dyer. Single-cell characterization and lineage tracking of recurrent pediatric rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3768.
Abstract 155: Cysteine-rich secretory protein 3 expression leads to invasive prostate cancer by modulating cell motility
Authors: Luc Furic, Marianna Volpert, Jinghua Hu, Anne O'Connor, Richard J. Rebello, Shivakumar Keerthikumar, Jemma Evans, Jo Merriner, John Pedersen, Gail P. Risbridger, Peter McIntyre, Moira K. O'Bryan
Journal: Cancer Research (2019)

Abstract Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly up-regulated proteins during the transition from a healthy human prostatic epithelium to prostate cancer. The role of CRISP3 within this process has not however, been defined. Here we show using a genetically engineered mouse model of prostate cancer, that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo. This observation was further validated using both human and mouse prostate cancer cell lines, which showed that exposure to CRISP3 enhanced cell motility and invasion. Further,using mass spectrometry, we showed that this activity is induced, at least in part, via changes in cell-cell adhesion proteins, including LASP1 and TJP1 both in vivo and in vitro. Collectively, these data identify CRISP3 as being pro-tumorigenic in the prostate and validate it as a bona fide marker of aggressive prostate cancer and a potential target for therapeutic intervention. Citation Format: Luc Furic, Marianna Volpert, Jinghua Hu, Anne O'Connor, Richard J. Rebello, Shivakumar Keerthikumar, Jemma Evans, Jo Merriner, John Pedersen, Gail P. Risbridger, Peter McIntyre, Moira K. O'Bryan. Cysteine-rich secretory protein 3 expression leads to invasive prostate cancer by modulating cell motility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 155.
Plasma Peptidylarginine Deiminase IV Promotes VWF-Platelet String Formation and Accelerates Thrombosis After Vessel Injury
Authors: Nicoletta Sorvillo, Daniella M. Mizurini, Carmen Coxon, Kimberly Martinod, Ronak Tilvawala, Deya Cherpokova, Ari J. Salinger, Robert J. Seward, Caleb Staudinger, Eranthie Weerapana, Nathan I. Shapiro, Catherine E. Costello, Paul R. Thompson, Denisa D. Wagner
Journal: Circulation Research (2019)

Rationale: PAD4 (peptidylarginine deiminase type IV), an enzyme essential for neutrophil extracellular trap formation (NETosis), is released together with neutrophil extracellular traps into the extracellular milieu. It citrullinates histones and holds the potential to citrullinate other protein targets. While NETosis is implicated in thrombosis, the impact of the released PAD4 is unknown. Objective: This study tests the hypothesis that extracellular PAD4, released during inflammatory responses, citrullinates plasma proteins, thus affecting thrombus formation. Methods and Results: Here, we show that injection of r-huPAD4 in vivo induces the formation of VWF (von Willebrand factor)-platelet strings in mesenteric venules and that this is dependent on PAD4 enzymatic activity. VWF-platelet strings are naturally cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type-1 motif-13). We detected a reduction of endogenous ADAMTS13 activity in the plasma of wild-type mice injected with r-huPAD4. Using mass spectrometry and in vitro studies, we found that r-huPAD4 citrullinates ADAMTS13 on specific arginine residues and that this modification dramatically inhibits ADAMTS13 enzymatic activity. Elevated citrullination of ADAMTS13 was observed in plasma samples of patients with sepsis or noninfected patients who were elderly (eg, age &gt;65 years) and had underlying comorbidities (eg, diabetes mellitus and hypertension) as compared with healthy donors. This shows that ADAMTS13 is citrullinated in vivo. VWF-platelet strings that form on venules of Adamts13 −/− mice were immediately cleared after injection of r-huADAMTS13, while they persisted in vessels of mice injected with citrullinated r-huADAMTS13. Next, we assessed the effect of extracellular PAD4 on platelet-plug formation after ferric chloride-induced injury of mesenteric venules. Administration of r-huPAD4 decreased time to vessel occlusion and significantly reduced thrombus embolization. Conclusions: Our data indicate that PAD4 in circulation reduces VWF-platelet string clearance and accelerates the formation of a stable platelet plug after vessel injury. We propose that this effect is, at least in part, due to ADAMTS13 inhibition.
Results of the PI3Kδ inhibitor ME-401 alone or with rituximab in relapsed/refractory (R/R) follicular lymphoma (FL).
Authors: Andrew David Zelenetz, Deepa Jagadeesh, Nishitha M. Reddy, Anastasios Stathis, Huda S. Salman, Adam Steven Asch, Vaishalee Padgaonkar Kenkre, Haresh S. Jhangiani, Alexia Iasonos, Jacob D. Soumerai, Judith Llorin, John M. Pagel
Journal: Journal of Clinical Oncology (2019)

7512 Background: ME-401, a potent and selective oral PI3kδ inhibitor, is being evaluated in a Phase 1b study in patients (pts) with R/R B-cell malignancies (NCT02914938). 70 pts were treated; we report here results in FL. Methods: Pts with ECOG ≤2, no prior PI3K therapy and progression of disease (POD) after ≥1 prior therapy were initially enrolled in a dose escalation phase (60-180 mg) then in 60 mg expansion cohorts as monotherapy or in combination with rituximab. ME-401 was given initially on a daily continuous schedule (CS) until POD or unacceptable toxicity. An intermittent schedule (IS) on days 1-7 of a 28-day cycle was then evaluated after 2 cycles (n = 18) or ≥3 cycles (n = 9) of CS. Toxicity on CS managed by switch to IS. POD on IS managed by switch to CS. Results: 48 FL pts received ME-401 alone (n = 39) or with rituximab (n = 9). Median age 64.5 yrs. (range 38-81), median prior therapies 2 (range 1-10), 30 had ≥3 prior therapies and 25 were POD24. 28 pts remain on therapy with median follow-up of 9.3 months (range 0.5-22.5) and 20 discontinued: 9 POD, 4 adverse events (AEs), 4 withdrew consent, and 3 for stem cell transplant. Delayed (&gt; Cycle 2) grade 3 immune related AEs (irAEs), primarily diarrhea/colitis and rash, reported in 9/30 (30%) on CS and 2/18 (11%) switched to IS after 2 cycles, with irAEs noted 15 and 18 days after switch. 4 pts with grade 3 irAEs had a drug holiday and corticosteroids then resumed ME-401 on IS without AE recurrence. Objective responses in 34/43 pts (79%) with follow-up disease assessment: 79% with ME-401 alone (including 26% morphologic/metabolic CR), 78% with ME-401 plus rituximab, 91% in POD24, and 75% in ≥3 rd line therapy. 24/27 (89%) IS pts continue therapy, 20 on IS and 4 who switched to CS due to POD on IS, and 3 pts discontinued due to persistent POD after switch to CS. Conclusions: ME-401 achieves a high rate of durable responses in R/R FL. IS appears to reduce the incidence of irAEs and maintains responses. POD on IS can be salvaged by reverting to CS. A randomized study to evaluate ME-401 given by IS or CS is enrolling pts with R/R FL, with switch to IS for irAEs and switch to CS if POD on IS. Clinical trial information: NCT02914938. [Table: see text]
Abstract LB-106: Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology
Authors: Philipp Rene Spycher, Julia Carina Frei, Jöri Elias Wehrmüller, Isabella Attinger-toller, Dragan Grabulovski, Torsten Hechler, Michael Kulke, Andreas Pahl, Martin Behe, Roger Schibli
Journal: Cancer Research (2019)

Abstract We introduce a novel and versatile ADC-linker technology that is based on site-specific enzymatic payload conjugation to ‘off-the-shelf’ antibodies, i.e., without the need to reduce or engineer the antibody. The functionalization takes place site-specifically and stoichiometrically (drug-to-antibody ratio, DAR = 2.0) at the Fc-part of antibodies. The resulting ADCs show favorable biophysical properties such as high solubility and stability using different payloads. Additionally, initial ELISA findings show that our modification does not interfere with Fc-gamma receptor and FcRn binding. Importantly, our ADCs showed superior efficacy in different tumor animal models as compared to control Thiomab™ ADCs. Using native trastuzumab (non-engineered) as the targeting antibody and amanitin as payload, we generated within 36 hours highly homogeneous and pure ADCs with a well-defined DAR of 2.0 as confirmed by LC-MS. In in-vitro assays our ADCs demonstrated potent cytotoxicity in all tested cell-lines (SKBR-3, BT-474, JIMT-1, and NCI-N87) as compared to the control Thiomab™ ADCs, most strikingly for the JIMT-1 cell-line: EC50 of 0.15nM vs 2.5nM. In the mouse JIMT-1 tumor model, our anti-HER2 ADC was highly potent and resulted in complete tumor remission in all mice (10/10 mice) at a single dose of 2mg/kg. In contrast, the control Thiomab™-functionalized ADC showed tumor regrowth in 4 out of 10 animals, starting on day 50. The same high potency was observed for the NCI-N87 xenograft model at a dose of 3mg/kg in which tumor growth inhibition was significantly delayed versus the reference ADC (8/10 vs 4/10 animals alive on day 110). These encouraging results obtained so far indicate that our linker technology a) allows for fast (&amp;lt; 36 hours) and straightforward manufacturing of ADCs using different payloads without protein engineering efforts, b) results in ADCs with favorable biophysical properties and a clear defined drug-to-antibody ratio, and c) enables the generation of highly potent and stable, thus safer, next-generation ADCs. Citation Format: Philipp Rene Spycher, Julia Carina Frei, Jöri Elias Wehrmüller, Isabella Attinger-toller, Dragan Grabulovski, Torsten Hechler, Michael Kulke, Andreas Pahl, Martin Behe, Roger Schibli. Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-106.
Abstract 4664: Massively parallel sequencing-based analysis of synchronous gastric cancer and lung cancer
Authors: Nandie Wu, Rutian Li, Yang Shao, Lifeng Wang, Baorui Liu, Jia Wei
Journal: Cancer Research (2019)

Abstract Synchronous gastric cancer(GC) and lung cancer(LC) have been suggested to represent independent primary tumors rather than metastatic disease. We subjected sporadic synchronous GC/LC from five patients to whole-exome massively parallel sequencing, which revealed a median of and 1174 and 830 nonsynonymous somatic mutations in the synchronous GC and LC repectively. DNA mutations range between 292 to 2421 in lung samples and 287 to 1995 in stomach sample. Common mutations varies between 41 and 145. The substitution of C&amp;gt;A, C&amp;gt;T and T&amp;gt;C accounts for the most common mutations in both lung and stomach cancers. Tumor mutation burden (TMB ) varies from 2.7 to 11.0 Mut/Mb in Lung cancer and from 1.8 to 30.4 Mut/Mb in gastric cancer. We further did pathway analysis based on the list of mutant genes. Top 20 pathways enriched in each patient were analyzed. We found MAPK signaling pathway was most commonly enriched pathways in lung cancer patients, whereas PI3K-Akt signaling and Hedgehog signaling pathway were most commonly enriched pathways in stomach cancer patients. This result suggests the potential benefit of targeted therapeutic treatments involved in these pathways. Citation Format: Nandie Wu, Rutian Li, Yang Shao, Lifeng Wang, Baorui Liu, Jia Wei. Massively parallel sequencing-based analysis of synchronous gastric cancer and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4664.
Phase I combination study of plitidepsin and carboplatin in advanced solid tumours
Authors: A. Oaknin, R. Plummer, R. Salazar, A. Robinson, B. Pardo, A. A. Razak, C. Cuadra, L. Flores, M. A. Izquierdo, H. Calvert
Journal: Journal of Clinical Oncology (2007)

2558 Background: Plitidepsin is a cyclic depsipeptyde isolated from the marine tunicate Aplidium albicans, nowadays manufactured by synthesis. It is a rapid and potent inductor of apoptosis. In phase I trials, muscle (myalgia and CPK increase) and liver toxicities were dose-limiting and preliminary activity was observed in malignant melanoma, renal, head and neck, lung, neuroendocrine, colorectal and hematological malignancies. Preclinical synergism with carboplatin (CBCDA) against solid tumors and acute leukaemia suggest plitidepsin can reverse platinum chemoresistance in vivo through reduction of glutathione levels. This phase I trial was initiated in order to evaluate the safety, pharmacokinetics (PK) and antitumour activity of the combination of CBCDA and weekly administration of plitidepsin (Recommended dose (RD) in monotherapy: 3.2 mg/m 2 ). Methods: Patients (pts) with advanced solid tumours and good performance status (WHO PS = 2) were enrolled. Plitidepsin was given over 1 hr infusion on days 1 , 8 and 15 every 4 weeks followed by CBDCA (AUC 5) as a 1 hr infusion on day 1. Dose levels planned for plitidepsin were 1.8, 2.4 and 3.0 mg/m 2 in cohorts of 3 pts. PK sampling was performed during the first cycle (cy) of treatment. Results: 18 pts have been treated to date (8M/10F). Median age (range): 59 (39–73) yrs. WHO PS&gt;0: 3pts. Tumour types included colorectal (5), malignant melanoma (4), ovary (2), other gastrointestinal tumors (7). No DLT was observed at plitidepsin 1.8 and 2.4 mg/m 2 (3 pts treated in each cohort). Two out of 5 pts exhibited DLT at pltidepsin 3.0 mg/m 2 , consisting of delay of second cy &gt;2 weeks (grade 3 transaminitis and grade 3 thrombocytopenia) and omission of second infusion in first cy (grade 3 ALT increase). Plitidepsin at 2.4 mg/m 2 was expanded to 8 pts. There were 4 pts with stable disease (cholangio, liver, colorectal, gatro-esophageal junction and esophagus carcinomas). Conclusions: The RD for the combination is plitidepsin 2.4 mg/m 2 (0.8 mg/m 2 lower than in monotherapy) days 1, 8 and 15 every 4 weeks followed by CBDCA (AUC 5). DLTs of the combination at the highest dose were different vs single plitidepsin (liver and haematological vs muscular). PK analyses from the three cohorts to detect interactions and updated safety data for the RD cohort are in progress. [Table: see text]
Abstract 393: Deoxymab: A targeted biologic that is synthetically lethal to TNBC brain metastases
Authors: Shenqi Zhang, Christopher May, Anupama Shirali, Valentina Dubljevic, James A. Campbell, Jiangbing Zhou, James E. Hansen
Journal: Cancer Research (2019)

Abstract Brain metastases in triple-negative breast cancer (TNBC) harbor defects in homology-directed DNA repair that may be exploited to develop new therapeutic strategies. However, these tumors are protected by the blood-brain barrier (BBB), and mechanisms of DNA repair are sequestered in the nucleus. Methods to cross the BBB and target intranuclear processes are needed. 3E10 is a nuclear-penetrating lupus anti-DNA autoantibody that inhibits the DNA damage response to selectively kill cancer cells with defects in DNA repair. 3E10 localizes to DNA in tumor environments, and penetrates cells via the ENT2 equilibrative nucleoside transporter. ENT2 is expressed in the BBB, and 3E10 has previously delivered cargo proteins to the brain. We believe 3E10 can be turned against TNBC brain metastases, and used MDA-MB-231-BR brain-seeking human TNBC cells and tumors as a model system to test this hypothesis. We re-engineered 3E10 into an optimized fragment, called Deoxymab-1 (DX1), to maximize effect on cancer cells and minimize toxicity. DX1 expressed in CHO cells was purified over a HiTrap Capto S column by FPLC, and purity and quality was confirmed by SDS-PAGE and SEC-HPLC. Immunostaining and colony formation assays demonstrated that DX1 penetrated the nuclei of ~100% of MDA-MB-231-BR cells in culture and was synthetically lethal to the cells, with doses of 5 and 10 μM reducing surviving fractions to 0.47±0.15 (P&amp;lt;0.03) and 0.29±0.07 (P&amp;lt;0.01), respectively. TNBC brain metastases were established in nude mice by intracardiac injection of 1.75x105 MDA-MB-231-BR cells transfected with luciferase. One week later the presence of brain metastases was confirmed by IVIS. Mice were treated with tail vein injection of vehicle control (n=7) or DX1 (20 mg/kg) (n=7) 3x/week for 3 weeks. Tumor burden was monitored by weekly IVIS. DX1 significantly suppressed growth of the brain metastases (Table 1). These results establish proof of the novel concept of use of a modified lupus autoantibody against TNBC brain metastases. Table 1:Brain Radiance Efficiencies (x105)TreatmentWeek 0Week 1Week 2Week 3Control1.2±0.22.5±0.45.1±0.720±5DX11.3±0.21.4±0.32.0±0.23.8±0.8Pns&amp;lt;0.01&amp;lt;0.01&amp;lt;0.02 Citation Format: Shenqi Zhang, Christopher May, Anupama Shirali, Valentina Dubljevic, James A. Campbell, Jiangbing Zhou, James E. Hansen. Deoxymab: A targeted biologic that is synthetically lethal to TNBC brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 393.
A multicenter, randomized phase III study of asciminib (ABL001) versus bosutinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs).
Authors: Michael J. Mauro, Andreas Hochhaus, Carla Boquimpani, Yosuke Minami, Alex Allepuz, Fotis Polydoros, Véronique Bédoucha, Paola Aimone, Delphine Réa
Journal: Journal of Clinical Oncology (2019)

TPS7070 Background: There is a need for new treatment options for pts with CML who are intolerant/resistant to currently available BCR-ABL1 ATP-binding site targeted TKIs. Asciminib is a potent and specific BCR-ABL1 inhibitor with a novel allosteric mechanism of action targeting the ABL1 myristoyl pocket. This results in a mutation-driven resistance profile different from that of ATP binding-site TKIs, providing potential for both monotherapy and combination therapy with ATP-binding-site TKIs. In a phase 1 study (NCT02081378), asciminib showed clinical activity and good safety/tolerability in CML pts with resistance/intolerance to ≥2 TKIs and in pts with the T315I mutation. The recommended dose for asciminib monotherapy in CML pts without the T315I mutation was established as 40 mg BID. An ongoing phase 3 study (NCT03106779) is evaluating asciminib monotherapy vs bosutinib in pts with CML who have been treated with ≥2 prior ATP-binding-site TKIs. Methods: Eligible pts are adults with CML-CP who previously received ≥2 TKIs, with intolerance or failure to the most recent TKI. Treatment failure is defined per 2013 European LeukemiaNet (ELN) recommendations. Pts harboring T315I or V299L mutations are excluded. Pts are randomized 2:1 – stratified by baseline cytogenetic response status – to receive asciminib 40 mg BID or bosutinib 500 mg QD (planned enrollment: N = 222). Primary and key secondary objectives are to compare the rate of major molecular response ( BCR-ABL1 IS ≤0.1%) with asciminib vs bosutinib at 24 and 96 weeks, respectively. In a recent protocol amendment, the baseline BCR-ABL1 IS threshold for enrollment was lowered from ≥1% to &gt; 0.1% for pts with intolerance to the most recent TKI. This change was implemented to align with clinical practice and satisfy the treatment need to avoid waiting for an increase in BCR-ABL1 IS levels to ≥1%. In addition, pts with documented bosutinib treatment failure as per ELN recommendations may switch to receive asciminib therapy at any time, as such pts may have limited treatment options outside of this study. This study is ongoing with 149 participating study sites in 30 countries. Clinical trial information: NCT03106779.