bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2840: Development of a model of dihomo-gamma-linolenic acid interference with platelet promotion of ovarian cancer
Authors: Isingizwe Zitha Redempta , Benbrook Doris M. 
Published: September 2020

Abstract
Background: Cancer is the second leading cause of deaths worldwide after cardiovascular diseases. A commonality between cancer and cardiovascular diseases is disregulation of platelets. Platelets and cancer are known to promote each other in a feedforward mechanism that is poorly understood. A long chain polyunsaturated fatty acids dihomo-gamma-linolenic acid (DGLA) was shown to reduce cardiovascular events in a platelet dependent manner while the exact mechanism of DGLA-mediated cancer cells death is yet to be explored.
Objectives: The objective of our study was to develop an experimental model to study interventions that could disrupt the cancer/platelets loop.
Methods: The effects of a range of DGLA concentrations on platelet aggregation and growth of high grade serous ovarian cancer cell lines (OVCAR3, MesOV, OVSAHO), normal human fallopian tube secretory epithelial cells (hFTSECs) primary culture and an immortalized hFTSEC cultures were determined with an MTT assay. Cocultures were used to evaluate effects of platelets on ovarian cancer cell line spheroid formation and size and effects of ovarian cancer cells and hFTSECs on platelet aggregation. Results: The minimal cytotoxic DGLA concentrations for cancer and normal epithelial cells were above physiologically-achievable concentrations, and the half maximal inhibitory concentrations (IC50's) were similar across epithelial cell types with the IC50's for hFTSEC primary culture (261 µM) and immortalized culture (206 µM) falling within the range of cancer cell IC50's (153-275 µM). DGLA inhibited platelet aggregation at concentrations ≥250 µM. Platelets increased cancer spheroid sizes in a concentration-dependent manner and cancer cells, but not hFTSECs, induced platelet aggregation in cocultures.
Conclusions: Our model incorporates both platelet effects on cancer cells and cancer cell effects on platelets. Physiologically-achievable DGLA concentrations that affect platelet aggregation without affecting epithelial cells were identified. Minimal doses of DGLA needed to cause cytotoxicity against cancer and normal cells are above levels that are physiologically achievable. Future studies will utilize DGLA doses that can interfere with platelet aggregation without directly causing cytotoxicity to cancer or healthy cells. This experimental model will allow study of DGLA's potential for interfering with platelet promotion of ovarian cancer in the absence of direct effects of DGLA on cancer cells. Funded by NCI R01 CA196200
Citation Format: Zitha Redempta Isingizwe, Doris M. Benbrook. Development of a model of dihomo-gamma-linolenic acid interference with platelet promotion of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2840.
Abstract 2862: Cetuximab-Triptolide conjugate suppresses growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II
Authors: Zhang Keqiang , Ma Yuelong , Guo Yuming , Sun Ting , Wu Jun , Horne David , Raz Dan 
Published: September 2020

Abstract
Triptolide (TPL), a natural compound isolated from a traditional Chinese medicine Thunder God Vine, exhibits strong anticancer activities; however, its clinical use is limited by low water-solubility and high systemic toxicity. To overcome these disadvantages, we developed a novel antibody drug conjugate (ADC) to specifically delivered TPL to cancer cells overexpressing EGFR which is frequently found in many types of human cancers including 70% of non-small cell lung cancers (NSCLC). The ADC is made by conjugation of TPL to Cetuximab, a clinically available anti-EGFR monoclonal antibody, via lysine residues of the antibody. Biochemical analysis showed that the average of drug-to-antibody ratio (DAR) of Cet-TPL is about 5, and the conjugation has little effect on the solubility and binding affinity of Cetuximab. The antitumor efficacy and toxicity of Cet-TPL were assessed and compared to that of TPL, Cetuximab, and a combination of these two. And the results demonstrated that Cet-TPL drastically suppresses in vitro proliferation and in vivo growth of these EGFR-overexpressing cancers including A549 and H1299 NSCLC cell lines, and two NSCLC patient-derived xenografts (PDXs); and SCC6 head-neck cancer cell line, while it did not significantly inhibit the proliferation and growth of NSCLC H520 that barely expresses EGFR. Furthermore, immunofluorescent analysis revealed that Cet-TPL is effectively transported into lysosomes of cancer cells that overexpress EGFR proteins, spared cells that don't express EGFR. Similar to TPL, which inhibits RNA polymerase II (Pol II) mediated transcription, Cet-TPL can also effectively target Pol II and significantly induce apoptosis in these EGFR-overexpressing cancers. Compared to Triptolide, Cetuximab, or their combinations, Cet-TPL displays higher target-specific cytotoxicity against EGFR-expressed cancers and much lower in vivo systematic toxicity. In addition, Cet-TPL efficiently suppresses activated EGFR pathway in SCC6 cancer cells. Taken together, Cet-TPL represents a potent targeted therapeutic agent against EGFR-overexpressing NSCLC and other cancers.
Citation Format: Keqiang Zhang, Yuelong Ma, Yuming Guo, Ting Sun, Jun Wu, David Horne, Dan Raz. Cetuximab-Triptolide conjugate suppresses growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2862.
Abstract 287: A nuclear cAMP microdomain suppresses tumor growth by Hippo Pathway inactivation
Authors: Drozdz Marek M. , Doane Ashley , Desman Garrett , Wang Jenny , Reilly Michael , Aguirre Kelsey , Kane Elsbeth , Wolchok Jedd , Merghoub Taha , Elemento Olivier , Piskounova Elena , Zippin Jonathan 
Published: September 2020

Abstract
Cyclic AMP can both promote and suppress tumor growth; however, how this single second messenger can simultaneously have such disparate effects on cancer remains largely undefined. It is well appreciated that cAMP does not diffuse within a cell but is made in microdomains, which consist of a unique adenylyl cyclase, one or more phosphodiesterases, and cAMP effector proteins, but the role of specific cAMP microdomains in cancer is unclear. Examination of human tissue biopsies revealed that the nuclear cAMP microdomain, defined by the soluble adenylyl cyclase (sAC), is upregulated early in tumorigenesis, but is lost with melanoma invasion and metastasis. Further, we showed that loss of sAC led to the transformation of melanocytes and reintroduction of sAC, only into the nucleus, was sufficient to block tumorigenesis in vitro and in mice. Neither mitochondrial, nor cytoplasmic cAMP microdomains affected tumor cell growth. Activation of nuclear sAC led to significant changes in chromatin accessibility suggesting that this cAMP microdomain regulates numerous transcription factors. Specifically, activation of nuclear sAC led to reduced chromatin accessibility for the TEAD and SMAD family of transcription factors, the key effectors of the Hippo Pathway. Consistent with those data, nuclear sAC suppressed TEAD-dependent pro-cancer gene expression profiles (e.g., MYC) by inhibiting YAP, one of the main oncoproteins in this signaling cascade. Moreover, we showed that nuclear cAMP evokes the same YAP-dependent inhibition of the Hippo Pathway in a variety of cancers, suggesting tumor suppression by nuclear sAC is not limited to melanoma. These studies reveal that a cAMP microdomain wholly contained within the nucleus is a pivotal a tumor suppressor that acts via Hippo Pathway inactivation.
Citation Format: Marek M. Drozdz, Ashley Doane, Garrett Desman, Jenny Wang, Michael Reilly, Kelsey Aguirre, Elsbeth Kane, Jedd Wolchok, Taha Merghoub, Olivier Elemento, Elena Piskounova, Jonathan Zippin. A nuclear cAMP microdomain suppresses tumor growth by Hippo Pathway inactivation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 287.
Abstract 2891: Targeting breast cancer stem cells with anti-EMP2 immunotoxins delivering granzyme b
Authors: Mohamedali Khalid A. , Su-yin Kok , Cheung Lawrence H. , Dhawan Naina , Rosenblum Michael G. , Wadehra Madhuri 
Published: September 2020

Abstract
Despite new therapies, breast cancer remains one of the leading causes of cancer-related death in women worldwide. Part of the issue remains the inability of these therapies to target cancer stem cells (CSCs). These cells show unique resistance to chemotherapy and have enhanced capacity for self-renewal. Recently, our group has shown that Epithelial membrane protein-2, or EMP2, is expressed on CSCs defined by increased aldehyde dehydrogenase activity (ALDH+). Clinical data supports the role of EMP2 in advanced breast cancer as increased expression of the protein is observed in metastatic lesions compared to primary tumors and its expression is enhanced in chemotherapy resistant tumors. In parallel, EMP2 expression correlated with enhanced mammosphere formation, an accepted surrogate for cells with enriched stem cell capacity. We have recently developed a novel IgG1 monoclonal antibody to EMP2, which has been shown to reduce tumor load. As the antibody-antigen complex rapidly internalizes, we hypothesized that its anti-tumor effects could be enhanced through the creation of a fusion protein. Granzyme B (GrB) is a serine protease that plays a critical role in the body's defense against viral infection and tumor development by initiating the apoptotic cascade via both caspase-dependent and -independent mechanisms. We developed novel fusion proteins composed of the anti-EMP2 backbone as the targeting moiety and granzyme B as the cytotoxic payload. Our initial design comprised of the active GrB fused to the IgG heavy chain (Fc) domain containing 2 single-chain antibodies against EMP2, a format that results in a longer plasma retention time. This new construct showed high and specific affinity for EMP2 (10−10M) using both flow cytometry and ELISA based formats. Moreover, treatment with these agents induced cell death to EMP2 positive cells, including those characterized by high ALDEFLUOR activity. Preclinical assessment of the anti-EMP2 immunotoxins showed no acute toxicity and acceptable plasma retention. Preliminary results using a 4T1 model system produced a significant reduction in tumor burden. Our results suggest that continued development of these agents may be successful at targeting advanced disease.
Research supported, in part, by NCI R21 CA234642 and the Clayton Foundation for Research.
Citation Format: Khalid A. Mohamedali, Kok Su-yin, Lawrence H. Cheung, Naina Dhawan, Michael G. Rosenblum, Madhuri Wadehra. Targeting breast cancer stem cells with anti-EMP2 immunotoxins delivering granzyme b [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2891.
Abstract 290: Development and characterization of antibodies specific for the SS18-SSX fusion protein in synovial sarcoma
Authors: Desilets Curtis , Chen Fang , Comeau Christopher , Costa Katrina , Crosby Katherine , Ferrante Michelle , Grange Christopher , Patrikas Maggie , McBride Matthew , Baranov Esther , Hornick Jason , Kadoch Cigall 
Published: September 2020

Abstract
Synovial sarcoma (SS) is a soft tissue cancer characterized by the fusion of the SS18 gene, which encodes for a subunit of the BAF ATP-dependent chromatin remodeling complex, with either SSX1, SSX2, or SSX4 genes. The resulting SS18-SSX fusion protein is incorporated into the BAF complex, where it evicts wild-type SMARCB1 (BAF47) and retargets the complex to polycomb-repressed chromatin domains, thus activating oncogenic gene expression to drive tumor progression. Traditional means of diagnosis of SS include immunohistochemical staining, including that for the biomarker TLE1, but TLE1 is not overexpressed in all tumors and cases ultimately need to be confirmed by either FISH or PCR assays to detect the SS18-SSX fusion. We have developed the first highly specific, recombinant monoclonal antibodies for the detection of SS18-SSX fusion proteins by immunohistochemistry and for the capture of SS18-SSX-containing BAF complexes in cells, with downstream utility in biochemistry and genomics-centered approaches such as ChIP-seq. The E9 × 9V clone directly targets the highly conserved fusion breakpoint, while the E5A2C clone detects the C-terminus of the SSX protein family and is capable of recognizing alternative breakpoints. Taken together, our data show that these antibodies can accurately and reproducibly detect the SS18-SSX fusion protein in SS cells and tissues.
Citation Format: Curtis Desilets, Fang Chen, Christopher Comeau, Katrina Costa, Katherine Crosby, Michelle Ferrante, Christopher Grange, Maggie Patrikas, Matthew McBride, Esther Baranov, Jason Hornick, Cigall Kadoch. Development and characterization of antibodies specific for the SS18-SSX fusion protein in synovial sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 290.
Abstract 2906: SGN-B6A: A new MMAE ADC targeting integrin beta-6 in multiple carcinoma indications
Authors: Lyon Robert P. , Schmitt Michael W. , Jonas Mechthild , Franz Christopher E. , Trueblood Esther S. , Yumul Roma , Westendorf Lori , Ryan Maureen C. 
Published: September 2020

Abstract
The integrins are a large family of cell surface receptors with diverse roles in cellular adhesion, motility, and cytokinesis. Functional integrins exist as heterodimers consisting of single alpha and beta chains. Within this family, integrin beta-6 (which dimerizes exclusively with isoform alpha-v) is of particular note for its role in cancer. Integrin beta-6 is overexpressed in numerous solid tumors and multiple investigators have noted its expression as a negative prognostic indicator in diverse cancers including colorectal, non-small cell lung, gastric, and cervical. SGN-B6A is an antibody-drug conjugate (ADC) targeting integrin beta-6 to deliver the clinically validated payload monomethyl auristatin E (MMAE). The antibody component of SGN-B6A is specific for integrin beta-6 and does not bind other alpha-v family members. In preclinical studies, this ADC has demonstrated activity in vivo in models derived from pancreatic, pharyngeal, and bladder carcinomas spanning a range of antigen expression levels at doses of 1 or 3 mg/kg given weekly for three doses. In exploratory toxicology studies in cynomolgus monkeys, doses of up to 5 mg/kg weekly for three doses or 6 mg/kg every 3 weeks for two doses were tolerated. Hematologic toxicities typical of MMAE ADCs were dose limiting and no evidence of target-mediated toxicity was observed. A Phase I first-in-human study is planned to evaluate the safety and antitumor activity of SGN-B6A in a variety of solid tumors known to express integrin beta-6.
Citation Format: Robert P. Lyon, Michael W. Schmitt, Mechthild Jonas, Christopher E. Franz, Esther S. Trueblood, Roma Yumul, Lori Westendorf, Maureen C. Ryan. SGN-B6A: A new MMAE ADC targeting integrin beta-6 in multiple carcinoma indications [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2906.
Abstract 3010: VKNG 1 reverses multidrug resistance by inhibiting ABCG2 mediated drug transport in vitro and in vivo
Authors: Narayanan Silpa , Gujarati Nehaben A. , Teng Qiuxu , Wang Jingquan , Cai Chao-Yun , Yang Yuqi , Chintalapati Anirudh Jaganna , Korlipara Vijaya L. , Chen Zhe-Sheng 
Published: September 2020

Abstract
The emergence of multidrug resistance (MDR) to chemotherapeutic drugs continues to be a major problem in the treatment of cancer. Drug resistance, either intrinsic or extrinsic is responsible for the recurrence of cancer related deaths. Understanding the drug resistant mechanisms of cancer is necessary for developing an effective treatment. ATP-binding cassette transporters are the integral transmembrane proteins which play a role in the expulsion of chemotherapeutic drugs, make the MDR more complicated. Breast cancer resistance protein (BCRP/ABCG2) is one among the MDR transporters with a wide range of substrates and overexpressed in various kinds of cancers like breast, colon, ovarian and lung cancers. An analysis of various new compounds leads to the
discovery of VKNG-1 that selectively inhibits ABCG2 transporter and reverses the resistance to chemotherapeutic drugs both in vitro and in vivo. VKNG-1 selectively causes the ABCG2 inhibition and sensitizes the ABCG2 overexpressing resistant cells to the substrate anti-cancer drugs. The mechanism of action of VKNG-1 is its ability to prevent the efflux function of ABCG2 and thereby increases the intracellular accumulation of substrate drugs. In addition, there was a decrease in the expression of ABCG2 at both mRNA and protein level, but the protein translocation did not happen in the presence of VKNG-1. The induced-fit docking studies suggest the existence of strong interactions between VKNG-1and BCRP protein. In addition, VKNG-1 maintains the anti-cancer effect of irinotecan in ABCG2 overexpressing tumor xenografts and combination of VKNG-1 and irinotecan greatly inhibited the growth of S1-M1-80 resistant tumors. These results suggest that potent and selective action of VKNG-1 makes it as a promising treatment option in overcoming drug resistance in cancer.
Citation Format: Silpa Narayanan, Nehaben A. Gujarati, Qiuxu Teng, Jingquan Wang, Chao-Yun Cai, Yuqi Yang, Anirudh Jaganna Chintalapati, Vijaya L. Korlipara, Zhe-Sheng Chen. VKNG 1 reverses multidrug resistance by inhibiting ABCG2 mediated drug transport in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3010.
Abstract 3030: Different pharmacodynamic profiles of ERK1/2 inhibition can elicit comparable anti-tumor activity
Authors: Hindley Christopher , Bevan Luke , Braithwaite Hannah , Courtin Aurélie , Fazal Lynsey , Ferraldeschi Roberta , Martins Vanessa , Muench Sandra , Wallis Nicola , Wilsher Nicola , Lyons John , Munck Joanne 
Published: September 2020

Abstract
The MAPK pathway is frequently dysregulated in cancer, resulting in constitutive phosphorylation and activation of its downstream signaling node ERK1/2 (ERK). The direct targeting of activated ERK is being explored in several phase I clinical trials. A good understanding of the relationship between inhibition of pathway activity and inhibition of tumor growth allows dose scheduling in the clinic to maximise response to an inhibitor. We have recently described the development of a novel, potent and selective small molecule inhibitor of both ERK activity and phosphorylation using fragment-based drug discovery. Using this inhibitor as a tool compound, we explored the relationship between duration of ERK inhibition and inhibition of tumor growth. We examined the in vivo activity of our ERK inhibitor in a Colo205 xenograft model. Inhibition of the ERK pathway was monitored by measuring phosphorylation of a direct substrate of ERK, RSK90 (pRSK), and phosphorylated ERK itself (pERK) to determine pharmacodynamic profiles. We observed that pathway inhibition was consistent with the pharmacokinetic profile of the ERK inhibitor and that the duration of pathway inhibition was primarily determined by dosing frequency rather than the total dose of ERK inhibitor. High, single doses (50 or 40 mg/kg) of ERK inhibitor produce strong maximal pathway inhibition at 2 h post dose (pRSK levels 8% of control levels for a single dose of 40 mg/kg) but pRSK levels have returned to levels close to control values by 12 h post dose. In contrast, 3x equally spaced doses of 20 mg/kg have a lower maximal pathway inhibition at 2 h post dose (pRSK levels 29% of control) but extend pathway inhibition beyond 12 h (pRSK levels 21% of control at 14 h). Despite these two different pharmacodynamic profiles, we observed comparable tumor growth inhibition following daily dosing either at 1 × 50 mg/kg (maximal tumor growth inhibition of 21%) or 3 × 20 mg/kg (maximal tumor growth inhibition of 15%). These data suggest that a short duration of ERK inhibition rather than constant suppression can be sufficient to provide anti-tumor activity. This may allow flexibility in clinical dosing schedules to improve tolerability without a loss in efficacy.
Citation Format: Christopher Hindley, Luke Bevan, Hannah Braithwaite, Aurélie Courtin, Lynsey Fazal, Roberta Ferraldeschi, Vanessa Martins, Sandra Muench, Nicola Wallis, Nicola Wilsher, John Lyons, Joanne Munck. Different pharmacodynamic profiles of ERK1/2 inhibition can elicit comparable anti-tumor activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3030.