bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2749: Effects of subtype specific chemotherapeutic immunomodulation in bladder cancer
Authors: Kardos Jordan , Bixby Lisa , Truong Andrew , Krishnan Bhavani , Stewart Kyle , Vincent Benjamin , Kim William 
Published: August 2018

Abstract
In patients with bladder cancer, programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors have been shown to be effective in around twenty percent of patients, and there is evidence indicating that the level of immune infiltration and immune suppression within the tumor microenvironment correlates with response to these treatments. We have previously shown that there are intrinsic subtypes of bladder cancer, with the basal subtype characterized by high levels of immune infiltration, and the luminal subtype characterized by immune exclusion. Here we show that treatment with current standard of care chemotherapeutic agents has a subtype specific effect on the tumor microenvironment. Cisplatin-based chemotherapeutic treatment of luminal tumors induces a mesenchymal phenotype, immune infiltration, and a transition to a more basal-like tumor, while not altering these characteristics of the tumor microenvironment in basal tumors. Two of the most widely used standard of care chemotherapeutic regiments are Cisplatin-Gemcitabine (GemCis) and Methotrexate-Vinblastine-Doxorubicin-Cisplatin (MVAC), and we show that MVAC treatment induces significant immune infiltration within the luminal subtype while GemCis treatment does not, indicating there are treatment specific effects on the immune microenvironment. Furthermore, using mouse models of bladder cancer previously developed by our lab that accurately reflect the basal and luminal subtypes of bladder cancer, treatment with a representative chemotherapeutic regimen induced immune infiltration in the luminal mouse model while not affecting the tumor immune microenvironment in the basal mouse model. These results indicate chemotherapeutic regimens have subtype specific effects on the tumor microenvironment which could potentially be used to increase the efficacy of immune checkpoint inhibitors.
Citation Format: Jordan Kardos, Lisa Bixby, Andrew Truong, Bhavani Krishnan, Kyle Stewart, Benjamin Vincent, William Kim. Effects of subtype specific chemotherapeutic immunomodulation in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2749.
Abstract 2754: NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders
Authors: Kuperschmidt Lana , Reuveni Hadas , Carmi Shani , Moskovits Neta , Shraga Netta R. , Solomonov Evgeny , Ronen Ohad , Stemmer Salomon , Haviv Izhak 
Published: August 2018

Abstract
Feedback activation of STAT3 and IGF1R/IRS plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. Both the IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, and altered during EMT and drug resistance. STAT3 has also been known to play an active role in immune-evasion of tumors and inhibition of STAT3, both in the tumor, as well as in the tumor's microenvironment, may therefore potentiate immune attack on the tumor. NT-219 is a dual inhibitor of STAT3 and IRS1/2 developed by TyrNovo Ltd. to overcome cancer drug resistance. NT-219 inhibits STAT3 phosphorylation and eliminates IRS1/2 in a unique 3-step mechanism: dissociation of IRS1/2 from the IGF1 receptor, induction of IRS1/2 serine phosphorylation, and subsequent degradation by the proteasome. We recently demonstrated that the inhibition of both IRS and STAT3 are required and essential for overcoming drug resistance. NT-219 efficacy was demonstrated in Patient-Derived tumor Xenograft (PDX) models of multiple cancer types: melanoma, sarcoma, pancreatic, colon, lung, and head & neck, when added-on to the approved therapies. In these models, NT-219 overcame acquired resistance to several oncology drug families: inhibitors of EGFR (Tarceva®, Erbitux®, Tagrisso®), MEK (Mekinist®), mutated-BRAF (Zelboraf®), mTOR (Afinitor®) as well as with chemotherapy agents (Gemzar®, 5FU, Oxaliplatin). We recently demonstrated that NT-219 works in synergy also with immune-oncology therapies. By using double autologous PDX models we demonstrated that NT-219 converted non-responding tumors to responders to Keytruda®. It also enhanced the immunotherapeutic potential of Cetuximab. The unique mode of action of NT219 may open a new avenue of combined targeted therapies in a wide range of malignancies, and has the potential to expand response duration and target patient population to the applicable drugs.
Citation Format: Lana Kuperschmidt, Hadas Reuveni, Shani Carmi, Neta Moskovits, Netta R. Shraga, Evgeny Solomonov, Ohad Ronen, Salomon Stemmer, Izhak Haviv. NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2754.
Abstract 2769: Targeting malignant mesothelioma with an antibody against the tumor extracellular matrix protein fibulin-3
Authors: Nandhu Mohan Sobhana , Goparaju Chandra , Longo Sharon L. , Pass Harvey I. , Viapiano Mariano S. 
Published: August 2018

Abstract
Malignant mesothelioma (MM) is an aggressive tumor of mesothelial tissues that has poor prognosis and limited therapeutic options. Pass et al. (N Engl J Med 2012) identified the extracellular matrix protein fibulin-3 as an accurate biomarker of MM progression, which can be detected in the tumor parenchyma and in pleural effusions. Here, we report a systematic study of the mechanisms of fibulin-3 in MM and its value as a molecular target. Fibulin-3 activated canonical NFkB signaling and regulated the expression of NFkB-downstream genes, including the proteases MMP9 and MMP13, and the proinvasive proteins TNC and MLCK. Fibulin-3 knockdown downregulated NFkB signaling, reduced MM cell viability and potentiated the cytotoxicity of cisplatin in vitro. We next developed a function-blocking antibody ("mAb428.2") against an epitope of fibulin-3 required for NFkB activation (Nandhu et al., Clin Cancer Res 2017). This antibody blocked fibulin-3 signaling in vitro and reduced the expression of this protein, as well as NFkB-regulated MMP9, in subcutaneous (sc) MM tumors implanted in nude mice. Next, we treated mice carrying sc or intrapleural models of MM with mAb428.2 or control IgG1 (8x 30 mg/kg, q24h) delivered IV. Our anti-fibulin-3 antibody caused a significant reduction of tumor burden and extension of overall survival in both models. Overall, downregulation and inhibition of fibulin-3 proved a successful approach to enhance MM therapy. Given the value of this protein as a MM biomarker, we expect that detection of fibulin-3 may serve to identify patients with the highest chance to respond to combination therapies including anti-fibulin-3 approaches, achieving maximum therapeutic against these aggressive tumors.
Citation Format: Mohan Sobhana Nandhu, Chandra Goparaju, Sharon L. Longo, Harvey I. Pass, Mariano S. Viapiano. Targeting malignant mesothelioma with an antibody against the tumor extracellular matrix protein fibulin-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2769.
Abstract 2780: Engineering human fusion constructs for targeted delivery of granzyme B to CD33 and CEA antigens
Authors: Cheung Lawrence H. , Mohamedali Khalid A. , Hittelman Walter N. , Rosenblum Michael G. 
Published: August 2018

Abstract
Our laboratory has developed a unique platform for the delivery of the highly pro-apoptotic serine protease granzyme B (GrB). The construct contains enzymatically active GrB and therefore does not require release from the targeting carrier by a fragile linker in contrast to conventional antibody-drug conjugates (ADCs). We employed two scFvs targeting the CD33 antigen found on AML and the juxtamembrane epitope of CEA found on numerous solid tumors. These human scFvs (designated HU33 and CEA respectively) were fused to human GrB through an engineered IgG heavy-chain fragment (hinge to Fc and designated Fc) which contains a dimerization domain. The GrB-Fc-HU33 and GrB-Fc-CEA constructs were cloned into the pSECTag vector containing an upstream 5kDa purification tag with an enterokinase (EK) cleavage site for facile removal. The molecules were expressed in transiently-transfected HEK-293E suspension cells and grown at 37°C for 3 days in 5% CO2. The molecules were isolated from culture media and purified by IMAC followed by EK cleavage and SP chromatography to remove the free tag. The yields were 6-10 mg/L for both molecules. Specific binding of each molecule to the antigen target is undergoing Biacore and/or ELISA assessment. The cytotoxicity of the GrB-Fc-HU33 against HL-60 cells showed a specific cytotoxic effect with an IC50 of 120 nM. Tests of this agent against a panel of cells expressing various levels of CD33 are ongoing. The cytotoxic effects of the GrB-Fc-CEA were assessed against HT29, HT1080-CEA and A431 cells and demonstrated IC50 values of 80, 110 and 95 nM respectively. Based on IC50 values, these data demonstrate that the fusion construct targeting CD33 is efficiently internalized and effectively delivers active serine protease to the cytosol even at relatively low antigen expression levels. In addition, the juxtamembrane epitope of the CEA antibody also allows efficient internalization for delivery of GrB to the cytosol. Immunofluorescence and confocal studies to examine the time course of internalization and the pro-apoptotic events triggered by these agents are under examination and will be presented. Research conducted, in part, by the Clayton Foundation for Research.
Citation Format: Lawrence H. Cheung, Khalid A. Mohamedali, Walter N. Hittelman, Michael G. Rosenblum. Engineering human fusion constructs for targeted delivery of granzyme B to CD33 and CEA antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2780.
Abstract 2785: Potency-matched dual cytokine antibody fusion proteins in combination with PD-L1 blockade
Authors: Luca Roberto De , Neri Dario 
Published: August 2018

Abstract
Among the different pharmacological approaches for cancer treatment, antibody-cytokine fusion proteins (also called “immunocytokines”) represent an emerging class of biopharmaceutical products, capable of boosting the immune system to attack tumor cells. These products promote the selective accumulation of pro-inflammatory molecules at the site of disease, mediated by the antibody fragment. These fusion proteins have been designed to reduce the systemic toxicity of traditional cytokines, currently approved for certain malignancies.
Immunocytokine products based on interleukin-2 (IL2), interleukin-12 (IL12) or tumor necrosis factor (TNF) have been extensively studied in mouse model of cancer and in patients.
When used as single agents, immunocytokines are often not able to cure mice and patients. However it as been shown by our group that the combination of IL2- and TNF- based products was capable to completely eradicate tumors in mouse models and to induce complete responses in patients.
The development of combination products at the industrial level leads to a duplication of activities and costs. On the other hand, the opportunity to develop products with two payloads fused into a single molecular entity may facilitate development. This approach is limited by the fact that different cytokines often show different maximal tolerated doses (MTDs), and their relative potency need to be tuned. For example, TNF is administered at a dose, which is ten times lower compered to the one of IL2.
We have recently described a novel class of immunocytokine products, termed “potency-matched dual cytokine antibody fusion proteins” consisting of a tumor-targeting antibody (for example F8, specific to the alternatively spliced EDA domain of fibronectin), simultaneously fused to both IL2 and TNF. To match biological activity of the two payloads a single-point mutation was inserted in the TNF sequence and the resulting product, named IL2-F8-TNFmut was able to selectively localize to lesions with an excellent tumor-to-organ ratios and it was found to completely eradicate soft-tissue sarcomas in immunocompetent mice, which did not respond to standard chemotherapy. We now report that complete responses were observed in a variety of mouse models of cancer and that the therapeutic efficacy of IL2-F8-TNFmut was further improved when used in combination with an anti-PD-L1 antibody.
Potency-matched dual cytokine antibody fusion proteins may find clinical applications for various types of malignancies, used either as single agents or in combination with immune-checkpoint inhibitors.
Citation Format: Roberto De Luca, Dario Neri. Potency-matched dual cytokine antibody fusion proteins in combination with PD-L1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2785.
Abstract 2788: VB6-845d tumor cell killing elicits biologic features of immunogenic cell death
Authors: Dillon Rachelle L. , Chooniedass Shilpa , Premsukh Arjune , MacDonald Glen C. , Cizeau Jeannick , Adams Gregory P. 
Published: August 2018

Abstract
VB6-845d is a Targeted Protein Therapeutic, TPT, that comprises a Fab fragment specific for the Epithelial Cell Adhesion Molecule (EpCAM) genetically fused to deBouganin via a furin protease sensitive linker. DeBouganin (deB) is a de-immunized variant of bouganin, a ribosome inactivating protein (RIP), that when internalized blocks protein synthesis thereby leading to cell death. While all cytotoxic molecules induce tumor cell killing, only some are capable of inducing biological manifestations indicative of immunogenic cell death (ICD). ICD is characterized by the collective appearance of distinct cellular changes termed damage associated molecular patterns, or DAMPs, which play a role in immune cell activation by triggering pro-inflammatory processes. Key DAMPs necessary for defining ICD are cell surface translocation of calreticulin, an endoplasmic reticulum chaperone protein, ATP secretion and release of HMGB1 (high mobility group box 1). To evaluate whether VB6-845d cell killing elicits the hallmark features of ICD, VB6-845d treated tumor cell lines were assessed for the presence of these distinct signaling molecules. In vitro studies showed that VB6-845d cytotoxicity induces the translocation of calreticulin to the cell surface as well as the release of ATP and HMGB1. The expression of other potential immune regulators following VB6-845d treatment was also examined. In summary, the data presented suggests that VB6-845d mediates tumor cell killing by an ICD pathway. The potential cross-priming effect initiated by VB6-845d-induced ICD suggests the use of VB6-845d in combination with immune checkpoint inhibitors may enhance their effectiveness in EpCAM-positive epithelial cancers.
Citation Format: Rachelle L. Dillon, Shilpa Chooniedass, Arjune Premsukh, Glen C. MacDonald, Jeannick Cizeau, Gregory P. Adams. VB6-845d tumor cell killing elicits biologic features of immunogenic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2788.
Abstract 2803: Novel auristatins with high activity on efflux-positive models and demonstrable bystander activity
Authors: Moquist Philip N. , Bovee Tim D. , Waight Andrew B. , Owen Sarah , Mitchell Jamie A. , Zaval Margo , Quick Marsha , Sandall Sharsti , Emmerton Kim K. , Blesie Nicole , Lyon Robert P. , Senter Peter , Doronina Svetlana 
Published: August 2018

Abstract
Auristatins are a class of clinically validated antimitotic agents utilized as payloads in antibody-drug conjugates (ADCs). Auristatins display many of the desirable properties necessary for ADC cytotoxins, such as low nanomolar potency, cell permeability, and activity across multidrug-resistant (MDR+) cell lines. Herein, we report the development of novel auristatins, which have a unique combination of these favorable properties. The hydrophilic monomethyl auristatin F (MMAF) was chosen as the parent structure, and a medicinal chemistry campaign was undertaken to functionalize various sites of the auristatin with hydrophobic moieties in an effort to improve membrane permeability. The structure-activity relationships (SAR) of the new auristatins demonstrated clear trends correlating hydrophobicity, structure, and polarity with permeability and in vitro cytotoxicity. The highest-performing molecules showed a preference for hydrophobic functionalization at the N-terminal dolavaline. The payloads were linked to the C-terminal position of the auristatin with a lysosomally cleavable maleimido-dipeptide linker. Examination of the ADCs revealed low ng/mL activity in CD30+ and CD19+ cell lines in vitro. Anti-CD70 ADCs demonstrated high in vivo efficacy in a 786-O xenograft and complete remissions (CRs) in the efflux-positive renal cell carcinoma model. Anti-CD30 ADCs were dosed in a CD30+ and CD30- admixed Karpas/Karpas-35R xenograft model to demonstrate proof-of-concept in vivo bystander activity. In summary, these novel auristatins showed potential across multiple indications as ADC payloads.
Citation Format: Philip N. Moquist, Tim D. Bovee, Andrew B. Waight, Sarah Owen, Jamie A. Mitchell, Margo Zaval, Marsha Quick, Sharsti Sandall, Kim K. Emmerton, Nicole Blesie, Robert P. Lyon, Peter Senter, Svetlana Doronina. Novel auristatins with high activity on efflux-positive models and demonstrable bystander activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2803.
Abstract 2806: Inhibition of melanoma development by Isatin analogs
Authors: Desai Dhimant H. , Gowda Raghvendra , Gowda Krishne , Dinavahi Saketh S. , Robertson Gavin P. , Amin Shantu G. 
Published: August 2018

Abstract
Despite major breakthroughs in melanoma drug development, there remains a need for new drugs and novel approaches. Of the three forms of skin cancer, malignant melanoma has the most significant impact on human health carrying the highest risk of mortality from metastasis. An estimated 87,110 new cases of invasive melanoma will be diagnosed and 9,730 people will die of melanoma in the USA in 2017. Melanoma accounts for less than one percent of skin cancer cases, but the vast majority of skin cancer deaths. The vast majority of melanomas are caused by the sun. In fact, one UK study found that about 86 percent of melanomas can be attributed to exposure to ultraviolet (UV) radiation from the sun. The estimated 5-year survival rate for patients whose melanoma is detected early is about 98 percent in the USA, whereas, the survival rate falls to 62 percent when the disease reaches the lymph nodes, and 18 percent when the disease metastasizes to distant organs. Thus, novel effective therapies are urgently needed to treat this disease.
The Isatin (1H-indole-2,3-dione) is found as an endogenous molecule in humans and other mammals and its analogs display diverse types of biological activities including anti-cancer activities. Earlier our group synthesized a novel series of 5,7-dibromoisatin analogs. Various melanoma cells were treated with several Isatin derivatives having functional groups like selenocyanate, thiocyanates, thiourea, and selenourea for 72 hours and the cell survival was estimated by MTS assay. Agents were treated with melanoma cell lines UACC 903, 1205 Lu or normal fibroblast cell line FF2441. Treatment with KS99, a thiocyanate analog and KS101, a selenourea analog of 5,7-dibromoisatin effectively killed melanoma cells after 72 h treatment. Overall, IC50 values of Isatin derivatives on melanoma cell lines were 3.0-5.7μM and 2.1-5.7μM, respectively. IC50 value on normal fibroblast cells with these Isatin derivatives was 5.4-20.7μM. KS101 was toxic to the xenograft mice at 1mg/kg body weight, animals developed vein inflammatic symptoms after 20 days of treatment. However, liposomal formulation of KS101 was safe up to 30mg/kg body weight in 1205 xenografted nude mice when treated alternate days by tail vein injection. The melanoma tumor burden was reduced by 47%. We will discuss structural activity relationship (SAR) of Isatin derivatives, and its in vitro and in vivo inhibitory effects against melanoma.
Citation Format: Dhimant H. Desai, Raghvendra Gowda, Krishne Gowda, Saketh S. Dinavahi, Gavin P. Robertson, Shantu G. Amin. Inhibition of melanoma development by Isatin analogs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2806.
Abstract 2807: Cytotoxic activity of novel organotin compounds against different cancer cell lines
Authors: Cherek Paulina , Balogova Michaela , Damodaran Krishna , Ögmundsdottir Helga M. 
Published: August 2018

Abstract
Cisplatin has been a successful drug in oncology for decades. Its use is however limited by toxicity and development of resistance. Efforts for improvement by screening a large number of different platinum compounds have only yielded to new drugs to the clinic, oxaloplatin and carboplatin. An alternative approach is therefore to explore the potential of other metal-containing compounds. The toxic properties of organic tin compounds have been exploited in industry for a long time. More recently such compounds have been studied for potential therapeutic cytotoxic effects yielding promising results. Here we describe the first screening of two novel organotin compounds, based on the same basic structure, containing bromide (SNO7) or chloride (SNO8). The compounds are being screened against the following cancer cell lines: T47-D (breast), A549 (lung), OVCAR-3 (ovarian), Aspc-1 (pancreatic). IC50 was determined from survival analysis by Crystal violet, and induction of apoptosis by Annexin V staining, monitored by IncuCyte. Cisplatin was used as reference. IC50 values (µg/ml) for T47-D and Aspc-1 were, respectively: 44.5 and 13.8 (SNO7), 13.4 and 26.3 (SNO8) and 34.9 and 34.5 (Cisplatin). SNO7 induced apoptosis starting after 24 hours in OVCAR-3 and A549 at 10 µg/ml and also T47-D at 25 µg/ml; SNO8 in T47-D at 25 µg/ml (OVCAR-3 and A549 not tested) and Cisplatin in OVCAR-3 at 10 µg/ml (A549 not tested). These early results indicate differences in sensitivities between compounds and cell lines implying some specificity in mode of action and suggest that tin-containing compounds could be active against cancer cells that are resistant to cisplatin.
Citation Format: Paulina Cherek, Michaela Balogova, Krishna Damodaran, Helga M. Ögmundsdottir. Cytotoxic activity of novel organotin compounds against different cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2807.