bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6625: Cancer neoepitope identification in soluble HLA from patient plasma
Authors: Rumble Julie M. , Pisano Michael , Jones Richard , Ford Michael 
Published: September 2020

Abstract
The roles of the Major Histocompatibility Complexes (MHC) in anti-cancer immunity are well established. Cytotoxic immune cells can recognize MHC presentation of unique peptides from altered proteins on the surface of tumor cells (tumor neoantigens) or the downregulation of MHC itself and kill the affected cells. One of the hallmarks of cancer progression is the evasion of anti-tumor immunity by various mechanisms, including the upregulation of checkpoint proteins. Checkpoint inhibitors, which have recently seen dramatic success in the clinic in some cancers, act by inducing potent immune responses to tumor neoantigens. In addition, the promise of personalized medicine lies in the theoretical ability to teach the immune system through vaccination to recognize and kill tumor cells bearing MHC-presented neoantigens. Aside from MHC on cell surfaces, the presence of soluble MHC (sMHC) has been shown in a variety of bodily fluids, including blood. Soluble MHC may be an important component of the tumor arsenal for inhibiting anti-tumor immune responses. The precise function of sMHC may be disease-dependent, but it has been postulated to play an inhibitory role, presumably through signaling cognate TCRs in the absence of a cellular signal (signal 2). Presence of sMHC carrying cancer-associated neoantigens could predict success of vaccination therapy or checkpoint therapy. Furthermore, sMHC-associated peptides could help to identify neoantigens that have already induced T cell anergy and would hence not be good targets. Here, data are presented describing the plasma immunopeptidome of advanced non small-cell lung cancer subjects under a variety of treatment paradigms.
Citation Format: Julie M. Rumble, Michael Pisano, Richard Jones, Michael Ford. Cancer neoepitope identification in soluble HLA from patient plasma [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 6625.
Abstract 665: Discovery and preclinical characterization of PQR626: A potent, orally available, and brain-penetrant mTOR inhibitor for the treatment of tuberous sclerosis complex
Authors: Borsari Chiara , Keles Erhan , Rageot Denise , Melone Anna , Bohnacker Thomas , Batchelor Lucinda Kate , De Pascale Martina , Hebeisen Paul , Hillmann Petra , Fabbro Doriano , Wymann Matthias 
Published: September 2020

Abstract
Mechanistic target of rapamycin (mTOR), a key player in cell proliferation, growth and survival, is overactivated in tumors and neurological disorders.[1] Rapalogs have recently been explored to alleviate epileptic seizures in Tuberous Sclerosis Complex (TSC).[2] Herein, we combined pharmacophore features of PQR620[3], the first-in-class brain penetrant ATP-competitive mTOR kinase inhibitor showing efficacy in a TSC mouse model, and PQR617[4], a potent, highly selective mTOR inhibitor. An extensive chemical exploration of the morpholine ring led to the discovery of PQR626, a highly potent, selective, brain penetrant inhibitor of mTORC1/2 kinase. In male Sprague Dawley rats and female C57BL/6J mice, PQR626 displayed an excellent brain penetration compared to everolimus, which possessed a limited ability to cross the blood-brain-barrier (brain/plasma levels ~ 1.4:1 vs 1:92). An additional pharmacokinetic comparative study with everolimus and AZD2014 confirmed the superiority of PQR626 [brain/plasma levels: ~ 1:25 (AZD2014), ~ 1:61 (everolimus), ~ 1.8:1 (PQR626)]. PQR626 showed very good tolerability in mice (MTD 100-150 mg/kg). Efficacy studies, using mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1GFAPCKO mice), were performed in a dose-range finding study. PQR626 (50 mg/kg, BID - twice a day) showed a significant effect on survival and significantly prevented/decreased mortality as compared to the vehicle. On the basis of its favorable pharmacological parameters, excellent brain penetration, safety profile and efficacy in Tsc1GFAPCKO mice, PQR626 qualifies as a novel mTOR inhibitor with potential application in the treatment of epilepsy and neurological disorders. [1] Wymann M. P. and Schneiter R. Nat. Rev. Mol. Cell Biol. 2008, 9, 162-176. [2] Krueger D. A. et. al. Neurology 2016, 87, 2408-2415. [3] Rageot D. et. al. J Med Chem. 2018, 61 (22), 10084-10105. [4] Borsari C. et. al. J Med Chem. 2019, 62 (18), 8609-8630.
Citation Format: Chiara Borsari, Erhan Keles, Denise Rageot, Anna Melone, Thomas Bohnacker, Lucinda Kate Batchelor, Martina De Pascale, Paul Hebeisen, Petra Hillmann, Doriano Fabbro, Matthias Wymann. Discovery and preclinical characterization of PQR626: A potent, orally available, and brain-penetrant mTOR inhibitor for the treatment of tuberous sclerosis complex [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 665.
Abstract 6674: Multi-dimensional time-series analysis to reveal pharmacodynamic changes induced by immunotherapy
Authors: Wang Jingjing , Wang Panpan , Zhang Wenli , Zhang Qiyao , Gu Qingyang , Ji Qunsheng 
Published: September 2020

Abstract
Background: Immune checkpoint inhibitors currently represent the most promising cancer therapeutics to produce durable responses. Many studies have highlighted checkpoint inhibitors' targets for future monotherapies or combination therapies. However, due to the complexity of tumor microenvironment, different types of cells exhibit different reaction time and order. To understand the MoA of immune checkpoint inhibitors in cell or animal models, time-series analysis will help select proper PD sampling time, as well as administration time & order in combination therapy. However, such analysis has limited application in syngeneic tumor models in the early stage of drug treatment due to the small tumor volumes.
Methods and Results: In this study, we combined NanoString technology and flow cytometry in an in-vivo efficacy study to explore the therapeutic response mechanism in mouse breast cancer EMT-6 model by the combinational treatment with anti-PD1 and an undisclosed compound A. Through time-course sampling of tumor tissues of EMT-6 xenograft tumors in the early stage of treatment, we found that anti-PD1 could enhance antigen-presentation and T cell priming as a single agent, and this effect could be enhanced by combination with compound A. In addition, we found the change of antigen-presentation induced by anti-PD1 occurs at RNA level, but not at protein level by flow cytometry analysis, which might imply to employ different time points to combine with RNA-targeted or protein-targeted drugs on T cell priming.
Summary: We have developed a time-series analysis combining in vivo efficacy study and NanoString technology with flow cytometry, to evaluate the dynamic changes of TME after immune checkpoint blocker treatment. This can be a powerful method to reveal time-dependent drug-induced pharmacodynamic changes, and help us to select the best time course for combination therapy.
Citation Format: Jingjing Wang, Panpan Wang, Wenli Zhang, Qiyao Zhang, Qingyang Gu, Qunsheng Ji. Multi-dimensional time-series analysis to reveal pharmacodynamic changes induced by immunotherapy [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 6674.
Abstract 6685: A retrospective observational study of telomerase peptide immunotherapy in heavily treated solid cancer patients
Authors: Choi Jonggwon 
Published: September 2020

Abstract
Background: Telomerase is an active enzyme that produces and maintains telomere which is located at the end of chromosomes. In general, telomere become shorter as the number of cells divide increases, leading to apoptosis. However, telomerase prolongs and maintains the length of the telomere so that tumor cells continue proliferation without cell death. When the telomerase is reduced, the telomere DNA is not produced and maintained and the chromosomes become shorter and shorter. Telomerase is not well observed in normal cells and known to act as a specific antigen by over-expression in various cencer cell types. The riavex(GV1001) which is 16 amino acid sequences from the telomere combines with HLA classI to induce an immune response through activates the CD4 T cell.
Methods: We analyzed 50 patients who were injected riavex. The riavex was provided through the application for emergency medication from the korea food and drug administration. Most patient who were given riavex failed several standard chemotherapy. The administration methods was injected riavex 0.2mili-liter in intradermal three times at first week and one time at 2weeks, 3weeks, 4 weeks, 6 weeks and then once per 28 days. A total of 12 doses were given to each patient. After the end of the administration, we evaluated anti-tumor response by RECIST 1.1 and quality of life by EORTC QLO-C30 and EQ-5D.
Results: Partial response was founded in one patient with renal cell carcinoma. The rest of the patients showed a stable or progress response. However, quality of life was significantly improved in 19 patient and fifteen of them have applied for re-treatment. Only three patients had a fever of more than 38 celsius degree and no significant side effects were observed in other patients
Conclusion:, Riavex as a anti-cancer vaccine is relatively safe to heavily treated solid cancer patient and is assessed to improve quality of life, although the treatment response is not promising.
Keywords: Telomerase, Riavex, Quality of life, Safety
Citation Format: Jonggwon Choi. A retrospective observational study of telomerase peptide immunotherapy in heavily treated solid cancer patients [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 6685.
Abstract 6686: SO-C101 displays strong anti-tumor effect in TC-1 and TRAMP-C2 tumor mice and in combination with PD-1 blockade prevents tumor development in a NK and CD8+ T cells dependent manner
Authors: Adkins Irena , Mikyskova Romana , Hradilova Nada , de Martynoff Guy , Bechard David , Moebius Ulrich , Reinis Milan , Spisek Radek 
Published: September 2020

Abstract
SO-C101 (RLI-15) is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain designed to bypass the need of endogenous IL-15Rα, thereby leveraging the activity of IL-15 in vivo on target immune cells and reducing the toxicity of IL-15 as such. SO-C101 was previously shown to exhibit a potent anti-metastatic activity in Renca, B16F10 melanoma and delayed tumor growth in T cell-based mouse tumor models (CT26, MC38). Here we investigated the anti-tumor efficacy in predominantly natural killer (NK)-cell based mouse tumor models TC-1 and TRAMP-C2. We showed that SO-C101 monotherapy was effective in the treatment of established TC-1 tumors, which was dependent on the presence of both NK and CD8+ T cells, but not CD4+ T cells. In an early treatment setting SO-C101 significantly decreased the rate of tumor development also in dependence on NK and CD8+ T cells. SO-C101 effectively reduced tumor growth in TRAMP-C2 mice in early and advanced treatment settings. However, only in combination with anti-PD-1 antibody treatment the tumor development was prevented in majority of mice. This effect was durable, and the new tumor development was further significantly delayed after a tumor cell re-challenge, which suggests the involvement of memory T cells despite an important NK cell role in anti-tumor efficacy in these models. The efficacy of SO-C101 and anti-PD-1 treatment was not dependent on CD4+ T cells, but mainly on NK and CD8+ T cells. Interestingly, SO-C101 and anti-PD-1 treatment in double NK/CD8+ T cell-depleted mice decreased tumor growth which suggests an involvement of other immune cell populations in the anti-tumor efficacy. SO-C101 stimulated the proliferation and the cytotoxic activity of NK cells and memory CD8+ T cells without significant expansion of regulatory T cells. These data show the importance of various immune cell populations during SO-C101 monotherapy and the treatment in combination with anti-PD-1 antibodies, and set a base for further complex analysis of SO-C101 behavior. The therapeutic potential of SO-C101 is currently being tested in an ongoing Phase I clinical study in cancer patients.
Citation Format: Irena Adkins, Romana Mikyskova, Nada Hradilova, Guy de Martynoff, David Bechard, Ulrich Moebius, Milan Reinis, Radek Spisek. SO-C101 displays strong anti-tumor effect in TC-1 and TRAMP-C2 tumor mice and in combination with PD-1 blockade prevents tumor development in a NK and CD8+ T cells dependent manner [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 6686.
Abstract 669: Combined inhibition of AKT & TBK1 for the treatment of breast cancer
Authors: Habelhah Hasem , Zhnag Laiqun 
Published: September 2020

Abstract
Breast cancer (BC) is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in Western women. In ~80% of BC cases, the PI3K-AKT pathway is aberrantly activated, due to the alterations in genes encoding the pathway components, such as Ras, Her2, PTEN, PIK3C and AKT. This pathway regulates multiple cellular processes to promote BC development, growth, metastasis, and drug resistance. Consequently, over 100 clinical trials are currently underway worldwide to evaluate the therapeutic efficacy of PI3K and AKT inhibitors in BC; however, initial data reported so far revealed that inhibition of this pathway is either not effective or often results in development of resistance and relapse of the disease. Thus, identification of additional targets and therapeutic combinations are urgently needed. We previously mapped TRAF2 phosphorylation sites (Ser-11 and Ser-55), identified PKC and TBK1 are the relevant kinases, and reported that TRAF2 phosphorylation enhances NF-κB activation to promote cancer cell survival under conditions of cellular stresses. Recently, we discovered that inhibition of AKT leads to increased phosphorylation of TRAF2 at Ser-11 by TBK1 in 4 out of 6 commonly used BC cell lines. TBK1 (aka T2K for TRAF2-associated kinase) and its close homologue IKKϵ are serine/threonine kinases overexpressed in ~70% of BC and play critical roles in BC cell survival. Interestingly, all 4 BC cell lines that exhibited enhanced TRAF2 phosphorylation were completely resistant to AKT inhibition-induced apoptosis in vitro, and combined inhibition of both AKT and TBK1/IKKϵ synergistically induced apoptosis in these BC lines. Importantly, combined inhibition of AKT and TBK1/IKKϵ also significantly suppresses xenograft BC tumor growth in vivo. Mechanistically, AKT did not directly inhibit TBK1, IKKϵ or TRAF2; it seems that an unknown kinase suppressed by AKT in cancer cells in normal culture conditions enhances TBK1-mediated TRAF2 Ser-11 phosphorylation in BC cells upon AKT inhibition. Nevertheless, our data suggest that inhibition of the PI3K-AKT pathway derepresses the pro-survival TBK1-TRAF2 pathway, which in turn confers resistance to PI3K-AKT inhibition in BC, and that combined inhibition of AKT and TBK1 effectively suppresses BC tumor growth. These findings also provide strong rationales for PDX and clinical investigation of combined AKT and TBK1 inhibition for the treatment of human BCs.
Citation Format: Hasem Habelhah, Laiqun Zhnag. Combined inhibition of AKT & TBK1 for the treatment of breast 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 669.
Abstract 671: mTORC1 suppression in Paneth cells prevents tumors in a mouse model of intestinal cancer
Authors: Parihar Manish , Dodds Sherry G. , Hasty Paul , Sharp Zelton Dave 
Published: September 2020

Abstract
The mechanistic (or mammalian) target of rapamycin, mTOR, is a highly conserved PI3K-related kinase that regulates cell growth, proliferation, survival, transcription, and protein synthesis. It forms two different complexes, mTOR complex-1 (mTORC1) and -2 (mTORC2). Rapamycin is an allosteric inhibitor specific to mTORC1 and extends life and health span with chronic use. Previous research from our lab shows that an enteric release formulation of rapamycin, eRapa, enhances the lifespan of mice mutated for adenomatous polyposis coli (Apc) tumor suppressor (ApcMin/+ mice), which normally develop intestinal cancer. These mice model familial adenomatous polyposis (FAP) in humans. eRapa restored a normal (and in 60% of the mice longer) life span in female ApcMin/+ mice. Mutations in Apc, a part of the Wnt/β-catenin pathway, accelerate the initiation of the adeno-carcinoma in FAP, resulting in numerous colorectal polyps at a young age, and if left untreated these polyps progress to colorectal cancer.eRapa treatment prevents polyposis in ApcMin/+ mice but the precise mechanism of action remains to be determined. We used a cross sectional and survival approach to test the preventive effects of eRapa and gain mechanistic insights. Four-week-old male and female animals were put on a diet containing either 42 ppm of eRapa or empty microcapsules. A subset of the animals was sacrificed to harvest tissue for analysis at 16 weeks of age and the rest were allowed to live out their lifespans.eRapa prevented polyposis in the small intestine of ApcMin/+ mice with only a few to no tumors in both males and females. In addition to adenomas in the intestine, ApcMin/+ mice also suffer from severe anemia. Hematocrits from the animals showed anemia in the control mice, however, eRapa treated animals did not have anemia. There was a reduction in phosphorylation of ribosomal protein S6 in the small intestine tissue, showing suppression of mTORC1 activity with eRapa. Histological analysis revealed that this suppression occurred in the Paneth cells of the small intestinal crypt. The Paneth cells, along with the stem cells at the base of the crypt form a niche and signaling between this niche maintains homeostasis in the crypt. Although the polyps are believed to originate from stem cells, our results suggest involvement of Paneth cells in tumor prevention perhaps by signaling changes in the niche. These are novel effects of rapamycin and help define its mechanisms of cancer prevention.
Citation Format: Manish Parihar, Sherry G. Dodds, Paul Hasty, Zelton Dave Sharp. mTORC1 suppression in Paneth cells prevents tumors in a mouse model of intestinal 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 671.
Abstract 685: Sortilin receptor-mediated novel cancer therapy: A targeted approach to inhibit vasculogenic mimicry in ovarian and breast cancers
Authors: Currie Jean-Christophe , Demeule Michel , Larocque Alain , Zgheib Alain , Béliveau Richard , Marsolais Christian , Annabi Borhane 
Published: September 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.