bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3897: Stability and safety evaluation of STRO-002, a site-specific anti-folate receptor alpha antibody-drug conjugate for the potential treatment of ovarian and endometrial cancers
Authors: Solis Willy , Almeida Venita De , Abrahams Cristina , Li Xiaofan , Heibeck Tyler , Bruhns Maureen , Galan Adam , Hoffman Heidi , Kiss Robert , Hallam Trevor , Lupher Mark 
Published: August 2019

Abstract
Antibody-drug conjugates (ADCs) constitute an expanding class of therapeutic molecules in preclinical and clinical development for multiple oncology indications. Folate receptor alpha (FolRα) is a glycosylphosphatidylinositol-linked cell-surface glycoprotein that is overexpressed in ovarian, endometrial, lung, and triple negative breast cancers. In contrast, FolRα is minimally expressed on normal tissues, thus, making it an amenable ADC target. STRO-002, a site-specific ADC, is comprised of 3-aminophenyl hemiasterlin cytotoxic drug (SC209) conjugated to an aglycosylated anti-FolRα IgG1 antibody through a protease-cleavable linker at two engineered non-natural amino acids in each heavy chain (DAR ~4).
In vitro and in vivo stability studies, showed that STRO-002 is highly stable in circulation, with the warhead SC209 predominantly accumulating in tumor tissue. Toxicology and toxicokinetic studies were conducted to determine the safety profiles for STRO-002 and its metabolite SC209 in cynomolgous monkeys and rats, respectively. In single-dose toxicology studies in rats, SC209 was tolerated up to 0.6 mg/kg with the main toxicity findings predominantly found in hematopoietic/lymphoid tissue, consistent with tubulin targeting chemotherapeutic drugs. In a tissue cross-reactivity study with normal human tissues, STRO-002-specific membranous staining was detected in Fallopian tubes, kidney (tubules), and placenta (trophoblasts). In a definitive safety study in cynomolgus monkeys, pharmacologically relevant model for toxicity testing, STRO-002 was tolerated at up to 9 mg/kg when intravenously administered on days 1 and 22 followed by a 4-week observation period. The most prominent STRO-002-related antigen-independent toxicity finding was dose-related, minimal to marked, and cyclical neutropenia. There were no antigen-dependent toxicity findings and no evidence of ocular toxicity. Toxicokinetic analysis confirmed dose proportional STRO-002 exposures (total antibody, ADC, and SC209 catabolite) at all doses tested. In summary, STRO-002 ADC has a favorable nonclinical safety and pharmacokinetic profiles and a Phase I study of STRO-002 in patients with ovarian and endometrial cancer has been initiated.
Citation Format: Willy Solis, Venita De Almeida, Cristina Abrahams, Xiaofan Li, Tyler Heibeck, Maureen Bruhns, Adam Galan, Heidi Hoffman, Robert Kiss, Trevor Hallam, Mark Lupher. Stability and safety evaluation of STRO-002, a site-specific anti-folate receptor alpha antibody-drug conjugate for the potential treatment of ovarian and endometrial cancers [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 3897.
Abstract 39: Microvessel-on-a-chip for investigating glioma-vascular interactions
Authors: Gerigk Magda , Bulstrode Harry J. , Huang Yan Yan Shery 
Published: August 2019

Abstract
Introduction: Gliomas, which are heterogeneous tumors made up of malignant glial and stromal cells, can often grow and progress without angiogenesis and thus escape anti-angiogenic therapies. One of the alternative mechanisms of tumor blood supply is vessel co-option, where cancer cells migrate along the pre-existing vessel of the host organ, preserving the blood-brain barrier (BBB). However, studying this phenomenon is currently limited mainly to animal models. With the push to reduce in vivo approaches, developing an experimental, organ-on-a-chip model to encompass one or more tractable microenvironmental factors, will enable us to better understand their mechanistic roles in brain tumor progression.
Methods and Results: An extracellular matrix-integrated PDMS-based microfluidic chip with a rounded microvessel, mimicking the BBB, was generated using a human microvascular cell line (hCMEC/D3), in the presence of flow. In the chip, a vessel of ~100µm diameter was interfaced with a 3D brain cancer cell culture (either U87, glioma neural stem or normal neural stem cell, embedded in a collagen-based ECM). The system was coupled with live-cell imaging and image analysis, which enabled tracking of cell-cell and cell-microenvironment interactions. Changes in gene expression and protein distribution in endothelial cells were successfully quantified, thus enabling the characterization of the influence of cancer cells population on the microvessel.
Conclusions: Development and optimization of the novel device has given us the opportunity to study the influence of glioma cells on normal brain endothelium, when agiogenesis does not occur. Crucially, this can be done in controlled, user-defined environment (i.e. choice of ECM components and stiffness, microvessel size and flow rate) unlike in animal models.
Note: This abstract was not presented at the meeting.
Citation Format: Magda Gerigk, Harry J. Bulstrode, Yan Yan Shery Huang. Microvessel-on-a-chip for investigating glioma-vascular interactions [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 39.
Abstract 3903: Acute toxicity studies of ethanolic fruit-skin extract of Annona muricata
Authors: Iyanda-Joel Wisdom O. , Israel-Ovirih Sandra O. , Chinedu Shalom N. , Iweala Emeka EJ 
Published: August 2019

Abstract
Recent reports have shown that the currently high demand for Annona muricata fruits and plant products is most likely due to their selective cytotoxic activity, where extracts and subsequent pure compounds exhibited more toxicity to cancer cell lines than standard drugs and even increased the viability of normal cells at certain concentrations. The current study explored the phytochemical screening and acute toxicity profile of ethanolic fruit-skin extract of Annona muricata (ESA) in female Wistar rats. Phytochemical screening were carried out following stipulated protocols while twenty-five female Wistar albino rats were treated with 2000 mg kgbwt-1and 5000 mg kgbwt-1 ESA for 24 - 72 hours and after 14 days to evaluate their toxicity against biochemical (ALT, AST, ALP, urea, creatinine, triglycerides, cholesterol, albumin and total protein), hematological (RBC, WBC, PCV, platelet count, MCV, MCH and MCHC, neutrophil, lymphocyte and monocyte) and histopathological parameters. The phytochemical screening of extract collectively revealed the presence of alkaloids, flavonoids, phenols, quinones, saponins, steroids, tannins and terpenoids. No sign of toxicity was observed in animals treated with ESA in the first critical four hours of dosage neither any mortality recorded. Toxicological assessment of ESA showed significant difference in values of extract-treated animals mostly at 5000 mg kgbwt-1 compared to normal control on ALT, ALP, WBC, M, N, PCV, MCH, MCV and platelet count within 72 hours of treatment compared to normal control but mostly later reversed after 14 days. Histopathology results also showed significant differences in morphology of certain organs compared to control with reversal of some lesions after 14 days. Ultimately, ethanolic fruit-skin extract of Annona muricata is non-toxic at moderate concentrations and may serve as a huge potential for nature-friendly antiproliferative and antitumour agents.
Note: This abstract was not presented at the meeting.
Citation Format: Wisdom O. Iyanda-Joel, Sandra O. Israel-Ovirih, Shalom N. Chinedu, Emeka EJ Iweala. Acute toxicity studies of ethanolic fruit-skin extract of Annona muricata [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 3903.
Abstract 3935: PLK4 inhibition as a strategy for non-small cell lung cancer radiosensitization
Authors: Hayman Thomas J. , Bray Mark R. , Mason Jacqueline M. , Mak Tak W. , Contessa Joseph N. 
Published: August 2019

Abstract
Background/Purpose: Lung cancer remains the leading cause of cancer-related death. Concurrent chemoradiation is the standard of care for locally advanced non-small cell lung cancer (NSCLC). Despite advancements in treatment, local control remains an issue and survival is suboptimal, highlighting the need for novel therapeutic approaches. Polo-like kinase 4 (PLK4) is a serine/threonine kinase that controls centriole duplication. PLK4 is highly expressed in multiple malignancies including lung cancer. CFI-400945 is a specific PLK4 inhibitor currently undergoing clinical trial evaluation. As radiation causes cell death primarily via a mitotic death, we hypothesized that disruption of the mitotic machinery by inhibition of PLK4 would enhance the effects of radiation.
Methods: The effects of CFI-400945 on cell survival and radiation sensitivity were examined using the clonogenic survival assay in two KRAS-mutant lung cancer cell lines (H460 and A549). Confocal microscopy was utilized to determine the effects of PLK4 inhibition on radiation-induced mitotic catastrophe (defined as the presence of 2 or more distinct nuclear lobes within a single cell). Cell cycle distribution by flow cytometry was determined after treatment with CFI-400945 and radiation.
Results: Exposure of H460 and A549 lung cancer cell lines to 10nM CFI-400945 for 48h reduced clonogenic survival to 63.9% and 83.1% respectively. CFI-400945 treatment of H460 and A549 cells resulted in radiosensitization of both cell lines with dose enhancement factors (DEF) of 1.60 and 1.31. To understand the mechanism of enhanced radiosensitivity with CFI-400945 treatment the effects on radiation-induced mitotic catastrophe were determined. In both H460 and A549 cells the combination of radiation and PLK4 inhibition enhanced the proportion of cells undergoing mitotic catastrophe. The combination of CFI-400945 and radiation resulted in increased G2/M arrest and appearance of &gt;4N populations by flow cytometric analysis when compared to drug or radiation treatment alone.
Conclusion: PLK4 inhibition with CFI-400945 enhances the radiosensitivity of lung cancer cell lines via mitotic catastrophe and G2/M arrest and these data support additional pre-clinical testing.
Citation Format: Thomas J. Hayman, Mark R. Bray, Jacqueline M. Mason, Tak W. Mak, Joseph N. Contessa. PLK4 inhibition as a strategy for non-small cell lung cancer radiosensitization [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 3935.
Abstract 3942: Animal studies evaluating the safety of Tumor Treating Fields (TTFields) in the torso
Authors: Davidi Shiri , Munster Mijal , Cahal Shay , Giladi Moshe , Kirson Eilon D. , Weinberg Uri , Palti Yoram 
Published: August 2019

Abstract
TTFields therapy is an anti-neoplastic treatment modality targeting dividing cells by disrupting microtubules and septin filaments localization. TTFields therapy received FDA approval for the treatment of glioblastoma based on phase 3 studies demonstrating efficacy and high safety profile. TTFields are currently being tested as a treatment option for solid tumors in the torso. The aim of this work is to study whether TTFields’ safety profile is maintained in the torso, and specifically in tissues with high cellular proliferation rates. TTFields (2-3 V/cm) were applied for 2 weeks using the Novo-TTF 100 system to the rat torso at 150 and 200 kHz, intensities and frequencies known to be effective for the treatment of NSCLC, mesothelioma, pancreatic cancer, ovarian cancer and hepatocellular carcinoma. Throughout the treatment course, all animals underwent daily clinical examination by a certified experienced veterinarian. At the end of treatment, animal were euthanized and an experienced independent pathologist performed histological comparative evaluation of all major internal organs. No changes in the following parameters were observed: activity level, food intake, drinking, stools, motor neurological status and respiration. Further, no changes in weight were observed between the treated and control groups. No significant changes were observed in complete blood count and differential between the different groups. Histological analysis did not reveal any increase in pathological findings in the TTFields treated animals group. Taken together, these results demonstrate that safety of TTFields application at frequencies of 150-200 kHz to the rat torso and specifically to tissues with high cellular proliferation rates. Additional work is now underway to better understand the specificity of TTFields’ effects on rapidly dividing tumor cells.
Citation Format: Shiri Davidi, Mijal Munster, Shay Cahal, Moshe Giladi, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Animal studies evaluating the safety of Tumor Treating Fields (TTFields) in the torso [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 3942.
Abstract 3956: A novel compound screen for enhancing T-cell based immunotherapy identifies aurora kinases as a targetable mechanism for tumor immune escape in pancreatic ductal adenocarcinoma preclinical models
Authors: Ashkin Emily L. , Silverman Deborah , Punt Simone , Manrique Soraya Zorro , Williams Leila , Wang Yunfei , Hwu Patrick 
Published: August 2019

Abstract
Harnessing a patient’s immune system by attenuating endogenous immune checkpoints on T-cells has led to dramatic, durable tumor rejection for multiple tumor types. Nonetheless, many cancers, including pancreatic ductal adenocarcinoma (PDAC), still do not respond to immunotherapy. PDAC remains largely resistant to all therapies, leading to its notoriety as one of the most lethal malignancies, with a 6% 5-year survival rate. We aimed to find novel, targetable mechanisms by which tumors escape the adaptive immune system and resist immunotherapy. We conducted a high throughput screen of 1280 compounds producing a synergistic effect with T-cell killing to assess differences and similarities among distinct pathways inclusive between PDAC and melanoma. These screens identified several aurora kinase inhibitors as synergistic with autologous T-cell killing of tumor target. Here we present results underlying the mechanism by which aurora kinase inhibition enhances autologous T-cell mediated killing and may improve T-cell-mediated cancer immunotherapy. These findings may contribute to the design of new therapeutic combination strategies for enhancing immunotherapy treatment of melanoma, PDAC, and other “immunologically cold” tumors.
Note: This abstract was not presented at the meeting.
Citation Format: Emily L. Ashkin, Deborah Silverman, Simone Punt, Soraya Zorro Manrique, Leila Williams, Yunfei Wang, Patrick Hwu. A novel compound screen for enhancing T-cell based immunotherapy identifies aurora kinases as a targetable mechanism for tumor immune escape in pancreatic ductal adenocarcinoma preclinical models [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 3956.
Abstract 3965: Circulating levels of IFN gammaand neutrophil counts in breast cancer patients who received balixafortide and eribulin combination therapy
Authors: Zimmermann Johann , Douglas Garry , Romagnoli Barbara , Barker Debra , Obrecht Daniel 
Published: August 2019

Abstract
Background: Balixafortide (B) is a highly selective antagonist of the chemokine receptor CXCR4. Clinical proof-of-concept in combination with eribulin (E) was achieved in a recent Phase 1 single arm dose-escalation trial in patients with metastatic HER2-negative breast cancer (NCT01837095). Safety and tolerability of B in combination with E was similar to that of B or E monotherapy.
Anti-cancer effects of CXCR4 antagonists include sensitization of tumor cells to chemotherapy, suppression of metastatic spread, inhibition of angiogenesis, and activation of immune cells.
Methods: Plasma samples from patients who received initial E monotherapy (1.4 mg/m2, run-in cycle) or combination of B and E (escalating doses of B intravenous up to 5.5 mg/kg plus E 1.4 mg/m2 in 21 days cycles) were immediately processed and stored at -80°C. Circulating levels of IFN-γ, an important marker of anti-tumor immune response, were determined by a high-sensitive S-Plex assay (Meso Scale Diagnostics). Absolute neutrophil counts (ANC) were measured by automated hematology instruments.
Results: E monotherapy did not increase IFN-γ levels in the first 8 hours post dosing, but led to an increase after 24 hours. Combination with B modulated IFN-γ levels and led to a sustained ANC increase 5 days post dosing. The increase pre vs post treatment can be up to 100-fold and receded prior to the next treatment cycle. Conclusions: E treatment led to a strong, transient increase of plasma IFN-γ levels in breast cancer patients modulated by B. The ANC increase by B may balance possible neutropenic actions of E.
Citation Format: Johann Zimmermann, Garry Douglas, Barbara Romagnoli, Debra Barker, Daniel Obrecht. Circulating levels of IFN gammaand neutrophil counts in breast cancer patients who received balixafortide and eribulin combination therapy [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 3965.
Abstract 3970: PARP inhibitors increase expression of Type I interferon regulated genes mainly through trapping
Authors: Wielgos Monica E. , Jelinic Petar , Levine Douglas A. 
Published: August 2019

Abstract
Background: Currently, there are multiple ongoing clinical trials testing the efficacy of various poly (ADP-ribose) polymerase (PARP) inhibitors in combination with immune checkpoint blockade across many cancer types. However, there is no rationale as to which PARP inhibitor is best to use in these studies. Two PARPis (rucaparib and talazoparib) have been reported to activate IFN signaling genes through the stimulator of interferon genes (STING) pathway. The objective of this study is to characterize the effect of all clinically active PARPis on Type I interferon (IFN) regulated genes. We also aim to identify whether this effect is dependent on CHK1, which we have previously reported to be activated by PARP trappers (rucaparib, olaparib, niraparib, and talazoparib) and not by the mainly catalytic inhibitor (veliparib).
Methods: CCL5 and CXCL10 gene expression levels were measured using qRT-PCR in 293T after two days of treatment with the PARP inhibitors (velipairb, rucaparib, olaparib, niraparib, and talazoparib). CXCL10 mRNA levels were also measured in HGSOC BRCA wild-type cell lines (OVCAR3 and CAOV3) after two days of treatment with veliparib and talazoparib. We also measured CCL5 and CXCL10 expression after veliparib and niraparib treatment in 293T cells with stable CHK1 overexpression.
Results: The four PARP trappers consistently increased CCL5 and CXCL10 expression in 293T cells. Although, veliparib had little to no effect on the expression of these two genes as compared to the other four PARPis. CXCL10 mRNA levels were significantly upregulated after talazoparib treatment (p&lt;0.01) but not affected after veliparib treatment in CAOV3 cells. Similarly, an increase in CXCL10 gene expression was observed in OVCAR3 cells (p&lt;0.05). Although, veliparib also had a modest but not significant effect on CXCL10 levels. CCL5 and CXCL10 gene expression consistently increased when treated with niraparib in 293T cells with stable CHK1 overexpression. This same effect was not observed after veliparib treatment in 293T cells that stably overexpressed CHK1.
Conclusions: Our results suggest that all PARP trappers promote expression of IFN Type I regulated genes which may be dependent on CHK1 expression. These findings may better define the most ideal PARP and immune checkpoint inhibitor combination.
Citation Format: Monica E. Wielgos, Petar Jelinic, Douglas A. Levine. PARP inhibitors increase expression of Type I interferon regulated genes mainly through trapping [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 3970.
Abstract 3972: Investigation of tumor intrinsic PD1/PD-L1 in canine urothelial carcinomas as a spontaneous translational model for human invasive bladder cancer
Authors: Wang Yu Jia , Pietrzak Katarzyna , Kocikowski Mikolaj , Argyle David , Hupp Ted , Parys Maciej 
Published: August 2019

Abstract
Urothelial carcinoma (UC) is the fourth most common malignancy in human and the most common form of urinary bladder cancer in dogs. This neoplasia tends to be invasive at advanced stages hence novel therapeutic approaches are urgently needed. As urothelial carcinomas share many similarities between the dog and human in the immunological responses, dogs are a perfect model for studying immunotherapeutic approaches. Recently immuno-checkpoint blockade using anti-PD1/PD-L1 antibodies have shown a promising effect and durable responses in the treatment of UC. Although until recently the PD1/PD-L1 axis was considered to be mostly affecting immune cells, recent reports identified, that PD-1/PD-L1 interaction is also capable of pro-tumorigenic signaling in melanoma and other cancers. Yet, little is known regarding this phenomenon in UC. In our study, we aim at identification of the expression level of PD-1 in canine UC and subsequently characterize the effect of overexpression and CRISPR-based knock-out of PD-1 and PD-L1. Using flow cytometry and immunocytochemistry, we identified that PD-1 is expressed on the surface of canine UC cell line. Interestingly, incubation with high concentration of PD-1 antibody decreased the proliferation rate of the tumor. After transfection with a PD-1 overexpression vector, we notice a significant morphological change and decrease in proliferation and colony formation. Our result provides the first report on PD-1 intrinsic signaling play as an important role in tumor growth of canine UC and thus may also be responsive to immune checkpoint blockade. The effect identified further strengthens the dog as a potential translational model for UC immunotherapy.
Citation Format: Yu Jia Wang, Katarzyna Pietrzak, Mikolaj Kocikowski, David Argyle, Ted Hupp, Maciej Parys. Investigation of tumor intrinsic PD1/PD-L1 in canine urothelial carcinomas as a spontaneous translational model for human invasive bladder 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 3972.