tbuckley/cabot-search huggingface dataset:
Abstract 1477: LRG1 blockade normalizes tumor vasculature and improves efficacy of chemotherapy
Authors: Camilla Pilotti, Marie N O'Connor, David Kallenberg, Laura Dowsett, Jestin George, Stephen E. Moss, John Greenwood
Journal: Cancer Research (2020)

Abstract In cancer blood vessels are dysfunctional, poorly perfused and leaky. Malfunctioning vessels contribute to the pro-oncogenic environment and limit the efficacy of current systemically administered drugs. Normalizing the tumor vasculature to improve vessel permeability, reduce hypoxia and vascular leakage and enhance drug delivery, has become an experimental objective in cancer research. This study was carried out to investigate the effect of blocking the secreted glycoprotein leucine-rich alpha-2-glycoprotein 1 (LRG1) on tumor vascular function, and evaluate the impact it has on the efficacy of the common standard of care chemotherapeutic drug cisplatin. Under normal conditions LRG1 is mainly expressed in the liver but also in other tissues such as bone marrow and immune cells. LRG1 has been described in multiple reports to be a serum prognostic biomarker in several cancers, for example lung, prostate, colorectal and breast. LRG1 promotes dysfunctional vessel growth by disrupting TGFβ signaling. We demonstrate that in Lrg1-/- mice and following treatment with a LRG1 function-blocking antibody (15C4) tumor growth was inhibited. In addition, we show using RNAscope that following subcutaneous grafting of the B16F0 and LL2 tumor cell lines in mice, Lrg1 is induced in tumor endothelial cells. Despite having no effect on total vessel area, the density was decreased upon LRG1 blockade, with the persisting larger vessels exhibiting improved vessel structure as evidenced by increased pericyte and basement membrane endothelial cell coverage. Better mural cell association with tumor vascular endothelial cells and basement membrane coverage are also indicators of vessel stabilization and maturation. Using a systemically delivered fluorescent lectin tracer to mark perfused vessels, we observed a significant increase in tumor perfusion in mice treated with 15C4. Lastly, vessel normalization, through LRG1 antibody blockade, significantly enhanced the efficacy of cisplatin chemotherapy as shown by a slower tumor growth rate and increased tumor cell death compared to monotherapy. These data further corroborate the hypothesis that inhibition of LRG1 improves the delivery, and hence efficacy, of a cytotoxic drug. In conclusion, deletion or inhibition of LRG1 results in an improved vascular configuration and function, and the efficacy of chemotherapy. LRG1 blockade may therefore represent a novel strategy to enhance vessel health and improve the efficacy of cancer therapeutics. Citation Format: Camilla Pilotti, Marie N O'Connor, David Kallenberg, Laura Dowsett, Jestin George, Stephen E. Moss, John Greenwood. LRG1 blockade normalizes tumor vasculature and improves efficacy of chemotherapy [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 1477.
Abstract 4018: Interaction site elucidation of the Rac1/Cdc42 inhibitor, MBQ-167
Authors: Julia I. Medina, Marvin Bayro, Eliud Hernandez, Cornelis Vlaar, Ricardo Gonzalez, Suranganie Dharmawardhane
Journal: Cancer Research (2020)

Abstract Metastasis continues to be the primary cause of cancer-related death. Therefore, we focus on designing small molecules inhibitors to block metastasis. The Rho GTPase family members Rac1, and Cdc42 are critical regulators of cancer cell migration and invasion, and thus, metastasis. Rac1 is activated by Guanine Nucleotide Exchange Factors (GEFs), which promote the exchange of GDP to GTP. In most cancers, the homologous Rac1 and Cdc42 are hyperactivated due to the overexpression of GEFs. Therefore, we designed inhibitors to block the activation and interaction of Rac1 and Cdc42 with their GEFs. Our lead compound MBQ-167, is a dual inhibitor of Rac1 and Cdc42 with IC50s of 103 nM and 78 nM, respectively. MBQ-167 inhibited the viability and migration of metastatic cancer cells without affecting non-metastatic or non-cancer cells. Moreover, MBQ-167 reduced mammary tumor growth and metastasis of HER2 positive and triple-negative breast cancer cells in immunocompromised mice by ~ 90%. To further elucidate the mechanism of action of MBQ-167, we tested the hypothesis that MBQ-167 blocks the interaction of specific Rac1/Cdc42 GEFs by interaction with particular amino acid residues in the switch I and II homologous regions of Rac1 and Cdc42 proteins. Therefore, to achieve the objective of elucidating the interaction site of MBQ-167 on Rac1 and Cdc42, we used in silico analysis and Nuclear Magnetic Resonance (NMR) of MBQ-167 with Rac1 in a GDP bound state. These results were biochemically validated by pulldown assays using a G15A nucleotide-free mutant predicted to interact tightly with Rac1/Cdc42 GEFs. In silico, using Autodock Tools, MBQ-167 was docked to the GEF binding domain of Rac1 and Cdc42 with low binding energy, indicating a tight interaction. For the NMR structural analyses, Rac1 was isotopically labeled with 15N and titrated with several concentrations of MBQ-167, at ratios of 1:1, 1:2, 1:3, and 1:4. We were able to detect chemical shift perturbations in key residues in the switch I and II regions that interact with Rac1/Cdc42 GEFs and regulate the activity. Moreover, these perturbations were more intense with increasing amounts of MBQ-167, confirming the specificity of the interaction. Therefore, our data signify the direct interaction of MBQ-167 with Rac1, thus validating the role of MBQ-167 as a specific Rac1/Cdc42 inhibitor. Citation Format: Julia I. Medina, Marvin Bayro, Eliud Hernandez, Cornelis Vlaar, Ricardo Gonzalez, Suranganie Dharmawardhane. Interaction site elucidation of the Rac1/Cdc42 inhibitor, MBQ-167 [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 4018.
Abstract 1616: Elucidating the role of PI3K lipid effectors in BRAF mutant melanoma
Authors: Gennie Parkman, Joseph Cho, Sheri Holmen, Martin McMahon
Journal: Cancer Research (2020)

Abstract Metastatic melanoma accounts for the highest number of skin cancer deaths, and while current treatments for this disease have progressed significantly in recent years, stage IV melanoma currently has only a 15-20% five-year survival rate. This highlights the critical need for new therapeutics to treat this complex disease. The PI3K/AKT pathway and RAS-RAF-MEK-ERK pathway play a major role in melanoma initiation and progression. Mutations in BRAF are found in around 50% of all human melanomas, and although there has been significant success in the development of therapies for BRAF mutant melanomas, most patients will experience primary or secondary resistance. Furthermore, mutant BRAF has been shown to be insufficient for melanomagenesis, yet the mechanism by which mutationally activated BRAF cooperates with oncogenes and loss of tumor suppressors to promote melanoma tumorigenesis and progression is not well understood. Dysregulated PI3K/AKT signaling is frequently observed concurrently with BRAF mutant melanomas; however, pharmacological inhibitors of AKT have been largely ineffective in clinical trials as single agents. Studies in our lab have shown that there is a discordant effect between pharmacological inhibition and genetic targeting of AKT, suggesting that therapeutic inhibition of this protein kinase is insufficient to block its activity in melanoma. We have shown that genetic knockdown of all three AKT paralogs leads to complete cell lethality in multiple human melanoma cell lines, and overexpression of each of the AKT proteins is able to significantly rescue this deleterious effect, which is dependent on functional kinase activity. Based on these preliminary results, we seek to determine if the PI3K pathway depends solely on AKT signaling for its role in melanoma initiation and progression. Dysregulation of the PI3K lipid signaling cascade in melanoma is conventionally believed to occur through activation of AKT, and we have previously shown that either loss of PTEN or mutationally activated PI3K cooperates with mutant BRAF to promote melanoma formation. However, it has not been shown if constitutively active AKT alone is able to substitute for this effect. Further research will elucidate the role of AKT in the initiating stages of melanoma and provide a more thorough understanding of the PI3K/AKT signaling pathway in promoting BRAF mutant melanomagnesis. Citation Format: Gennie Parkman, Joseph Cho, Sheri Holmen, Martin McMahon. Elucidating the role of PI3K lipid effectors in BRAF mutant melanoma [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 1616.
Adherence to medication in patients with rheumatic diseases during COVID-19 pandemic
Authors: Alireza Khabbazi, Hadiseh Kavandi, Roghayeh Paribanaem, Raha Khabbazi, Aida Malek Mahdavi
Journal: Annals of the Rheumatic Diseases (2020)

With great interest, we read the Pineda-Sic et al ’s report on treatment adherence behaviours in rheumatic diseases during COVID-19 pandemic in Latin America.1 They reported that 15.1% of patients with rheumatic disease suspend their medications during COVID-19 crisis.1 Lack of availability (48%) and fear of the immunosuppressive effect of medications (25%) were the most common reasons. To address medication non-adherence in our population, we conducted a study about medication adherence in patients with rheumatic diseases in the East Azarbaijan province, which is one of the provinces of Iran with a high prevalence of COVID-19. The study was conducted in accordance with the Helsinki humanity research declaration (2008). For a period of 2 weeks from 10 to 24 July 2020, information about adherence to medication behaviours of patients after COVID-19 outbreak was obtained by telephone interview in patients with various rheumatic diseases treated with …
Syntheses and characterization of anti-thrombotic and anti-oxidative Gastrodin-modified polyurethane for vascular tissue engineering
Authors: Meng Zheng, Jiazhi Guo, Qing Li, Jian Yang, Yi Han, Hongcai Yang, Mali Yu, Lianmei Zhong, Di Lu, Limei Li, Lin Sun
Journal: Bioactive Materials (2020)

Vascular grafts must avoid negative inflammatory responses and thrombogenesis to prohibit fibrotic deposition immediately upon implantation and promote the regeneration of small diameter blood vessels (<6 mm inner diameter). Here, polyurethane (PU) elastomers incorporating anti-coagulative and anti-inflammatory Gastrodin were fabricated. The films had inter-connected pores with porosities equal to or greater than 86% and pore sizes ranging from 250 to 400 μm. Incorporation of Gastrodin into PU films resulted in desirable mechanical properties, hydrophilicity, swelling ratios and degradation rates without collapse. The released Gastrodin maintained bioactivity over 21 days as assessed by its anti-oxidative capability. The Gastrodin/PU had better anti-coagulation response (less observable BSA, fibrinogen and platelet adhesion/activation and suppressed clotting in whole blood). Red blood cell compatibility, measured by hemolysis, was greatly improved with 2Gastrodin/PU compared to other Gastrodin/PU groups. Notably, Gastrodin/PU upregulated anti-oxidant factors Nrf2 and HO-1 expression in H2O2 treated HUVECs, correlated with decreasing pro-inflammatory cytokines TNF-α and IL-1β in RAW 264.7 cells. Upon implantation in a subcutaneous pocket, PU was encapsulated by an obvious fibrous capsule, concurrent with a large amount of inflammatory cell infiltration, while Gastrodin/PU induced a thinner fibrous capsule, especially 2Gastrodin/PU. Further, enhanced adhesion and proliferation of HUVECs seeded onto films in vitro demonstrated that 2Gastrodin/PU could help cell recruitment, as evidenced by rapid host cell infiltration and substantial blood vessel formation in vivo. These results indicate that 2Gastrodin/PU has the potential to facilitate blood vessel regeneration, thus providing new insight into the development of clinically effective vascular grafts.
Abstract 685: Sortilin receptor-mediated novel cancer therapy: A targeted approach to inhibit vasculogenic mimicry in ovarian and breast cancers
Authors: Jean-Christophe Currie, Michel Demeule, Alain Larocque, Alain Zgheib, Richard Béliveau, Christian Marsolais, Borhane Annabi
Journal: Cancer Research (2020)

Abstract Rational: Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by aggressive, metastatic and genetically deregulated tumor cells. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumor cells. Such system contributes, in part, to current chemoresistance and facilitates tumor progression as well as dissemination of cancer metastases. VM is a process associated with aggressive ovarian cancer and triple-negative breast cancer (TNBC) and is shown to correlate with decreased overall cancer patient survival. Procedures: Targeting VM in ovarian and TNBC tumors, in addition to targeting tumor cells, may thus help circumvent chemoresistance and contribute to more efficient cancer treatments. Sortilin receptor (SORT1) is essential for VM in ovarian and TNBC tumors and high expression of SORT1 in many types of cancers has been associated with their invasion and progression. Results: SORT1 was detected in 3D-tubular structures of ES-2 ovarian cancer and MDA-MB-231 TNBC cells when grown on Matrigel. Peptide-drug conjugates targeting SORT1 significantly decreased the formation of new 3D-structures by 50% (IC50) at low nM concentrations (5-10 nM). In fact, the Doxorubicin-peptide conjugate (TH1904) abolished the formation of 3D-tubular structures of ovarian cancer cells in an in vitro model, whereas unconjugated Doxorubicin or liposomal Doxorubicin (up to 20 µM) had no effect on the formation of the VM structure. Moreover, a Docetaxel-peptide conjugate (TH1902) also showed very potent in vitro activity against the formation of VM in TNBC. IC50 values for VM 3D-tubular structures inhibition was about 30 pM for TH1902 compared to 0.5 nM for Docetaxel. Conclusion: Our results provide insight into future potent ovarian and TNBC therapeutic treatments. Targeting this receptor's functions with peptide-drug conjugates may provide an efficient strategy to increase the binding/internalization of cancer drugs within tumor cells, thereby improving the efficacy of standard anticancer treatments. Our results indicate that peptide-drug conjugates targeting SORT1 strongly inhibit the formation of VM, a phenomenon associated with a more aggressive tumor phenotype and poor prognosis in patients with TNBC or ovarian cancer. Citation Format: Jean-Christophe Currie, Michel Demeule, Alain Larocque, Alain Zgheib, Richard Béliveau, Christian Marsolais, Borhane Annabi. Sortilin receptor-mediated novel cancer therapy: A targeted approach to inhibit vasculogenic mimicry in ovarian and breast cancers [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 685.
Abstract 5315: BPI-28592, a next-generation TRK kinase inhibitor that potently inhibits primary and resistant NTRK mutations
Authors: Bang Fu, Dan Yan, Lingling Liu, Jing Guo, Jisheng Huang, Tianyi Ma, Yinlong Li, Wei Ren, Jie Chen, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang
Journal: Cancer Research (2020)

Abstract Oncogenic NTRK gene fusions occur at very low frequency in common cancers but high frequency in rare tumors including childhood malignances. The 1st-generation TRK inhibitors, e.g., larotectinib and entrectinib, have been used successfully to treat cancers carrying the NTRK fusions with excellent response rate and long duration. Nonetheless, duration of response may eventually be limited by acquired resistance mutations, such as TRKA-G595R or TRKC-G623R. We aimed at identifying a 2nd-generation inhibitor which can cover the primary TRK fusions and overcome the common resistant mutants induced by the 1st -generation TRK inhibitors. Using structural modeling to guide rational drug design, we discovered BPI-28592 as a 2nd-generation TRK inhibitor with desired potency and good drug-like properties. BPI-28592 is of a novel structure and possessed sub-nanomolar potency against a variety of primary TRK fusions. Importantly, the molecule exhibits low nanomolar inhibitory activity against acquired mutants commonly identified in patients who are refractory to 1st-generation TRK inhibitors, including TRKA-G595R TRKA-F589L, TRKA-G667C, and TRKC-G623R, etc. BPI-28592 showed a highly selective profile in a Kinome scan of 468 individual kinases. In cell-based assays, BPI-28592 dose-dependently inhibited proliferation of primary as well as resistant TRK mutant cell lines, blocked TRK protein phosphorylation and downstream signaling. Furthermore, BPI-29592 demonstrated in vivo efficacy in xenograft models derived from primary and resistant TRK mutant cells. BPI-28592 exhibited a profile of high oral exposure across multiple pre-clinical species, favorable ADME properties, and wide therapeutic window in pre-clinical toxicology studies. In conclusion, we discovered BPI-28592 as a novel, potent and selective next-generation TRK kinase inhibitor. The molecule has completed IND-enabling studies and is planned to enter Phase 1 clinical development in early 2020. Citation Format: Bang Fu, Dan Yan, Lingling Liu, Jing Guo, Jisheng Huang, Tianyi Ma, Yinlong Li, Wei Ren, Jie Chen, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang. BPI-28592, a next-generation TRK kinase inhibitor that potently inhibits primary and resistant NTRK mutations [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 5315.
Abstract 358: Cancer cell derived TNF mRNA as a marker of cancer cell budding in colorectal cancer
Authors: Boye Schnack Nielsen, Kim Holmstrom
Journal: Cancer Research (2020)

Abstract Tumor necrosis factor alpha (TNF) is a potent cytokine reported to have several functions, including stimulation of inflammation, directing cell death and cell proliferation. The cellular origin of TNF has generally believed to be the inflammatory cells especially because macrophages are prone to induction of TNF. Using in situ hybridization (ISH) based on TNF mRNA probes (RNAscope) we recently reported that TNF mRNA is also seen in cytokeratin positive cancer cells (CC) and is associated with morphologic appearance interpreted as CC branching (Møller et al, IJMS 2019, doi: 10.3390/ijms20081907). To determine the fraction of CC-derived TNF mRNA signal at different areas in colon cancers we developed a cell and color segmentation-based image analysis tool to process fluorescence signals in digital slides. The approach allowed quantification of the TNF mRNA-positive CC and TNF mRNA-positive stromal cells in the digital slides previously reported, that were also stained for cytokeratin, microRNA-21 (miR-21) and DAPI nuclear stain. In the two cases with most abundant TNF mRNA ISH signal, both showing moderate-to-high budding index, the fraction of TNF-mRNA positive CC in the outer periphery (approximately 500 µm) was 8% and 20%, respectively. The frequency of the TNF-positive CC increased towards the invasive front from 7% (33/500 CC per 0.25 mm2) to 35% (48/137 CC), and from 8% (127/1536 CC per 0.50 mm2) to 28% (108/389 CC), respectively. The upregulation is in agreement with initial qualitative evaluation. In the same areas, the fraction of TNF mRNA positive stromal cells among all TNF mRNA-positive cells was only 8% in both cases, indicating that the majority of the TNF mRNA originates from CC. The fraction of the TNF mRNA-positive CC that were also miR-21 positive was 85% and 43%, respectively, which was higher than the prevalence of the overall miR-21 positive CC, 55% and 30%, suggesting frequent co-expression with miR-21. In conclusion, we have developed a method to obtain quantitative estimates from digital multiplex-stained slides with RNAscope and LNA fluorescence ISH and immunofluorescence. More samples will need to be processed to better understand the importance of TNF expression in cancer cell invasion. Citation Format: Boye Schnack Nielsen, Kim Holmstrom. Cancer cell derived TNF mRNA as a marker of cancer cell budding in colorectal 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 358.
Abstract 18: The CXCR4/CXCL12 axis is a target of a polyphenol extract from olive oil processing with potential cancer prevention and interception activities
Authors: Matteo Gallazzi, Marco Festa, Clementina Sansone, Paola Corradino, Douglas Noonan, Adriana Albini
Journal: Cancer Research (2020)

Abstract The olive mill wastewater polyphenol extracts exhibit chemopreventive properties in lung cancer cell lines, acting on the CXCR4/CXCL12 axis. Lung cancer still is a leading cause of cancer death worldwide. Although avoidance of tobacco use and smoking cessation will have the greatest impact on lung cancer development, (chemo)prevention could prove to be very effective, particularly in high risk individuals. Diverse diet-derived compounds have been reported to exert antioxidant, anti-proliferative and anti-angiogenic effects. Olive oil production involves the generation of an aqueous phase, defined as olive mill wastewater (OMWW), a polluting effluent rich in soluble polyphenols. We established a polyphenol rich, purified extract, from OMWW, that we termed A009. The effect of A009 on cell proliferation was determined by the crystal violet assay, while induction of apoptosis was measured by flow cytometry. The ability of the A009 to regulate the cell migration/invasion axis CXCR4/CXL12 and the production of pro angiogenic factors (VEGF, CXCL8, CCL2), was investigated by flow cytometry. The sprouting assay on Matrigel was used to functional verify the ability of A009 to limit invasive properties. Hydroxytyrosol, the most abundant polyphenols present in our A009, was used as reference molecules in all the assays performed. We found that the A009 limit A549 and H1560 cell proliferation, in a dose and time dependent manner. These effects were associated with induction of apoptosis at 24 and 48 hours of treatment, that was higher in H1650, as compared to A549 cells. The A009 extracts were effective in inhibiting the production of CXCR4 and CXCL12 in both the A549 and H1650 cells, accompanied with reduction in H1650 cell capability to generate invasive sprouts. in a Matrigel layer. Finally, A009 interfere with the production of VEGF, CXCL8 and CCL2 in both the A549 and H1650 cells. Our preliminary results suggest that A009 exhibit promising preventing and interceptive properties on lung cancer cell lines in vitro. Citation Format: Matteo Gallazzi, Marco Festa, Clementina Sansone, Paola Corradino, Douglas Noonan, Adriana Albini. The CXCR4/CXCL12 axis is a target of a polyphenol extract from olive oil processing with potential cancer prevention and interception activities [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 18.