bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1056: Potent in vivo anti-tumor activity of D-1553 as a single agent and in combination with targeted therapeutics in a broad spectrum of patient-derived xenograft tumor models with KRas G12C mutation
Authors: Shi Zhe , Weng Jifang , Fan Xiaochong , Zhu Qingqing , Robb Emily , Moriarty Alyssa , Wick Michael , Jiang Yueheng , Zhang Ling , Dai Xing , Wang Yaolin 
Published: July 2021

Abstract
Ras protein plays a critical role in cell growth and proliferation by transmitting signal from cell surface receptor tyrosine kinase to downstream cellular proteins such as RAF and MEK. KRas is one of the most frequently mutated oncogenes, with mutations at residues G12, G13, and Q61, found in lung, colon, pancreatic and other solid malignancies. We have developed an orally bioavailable, covalent inhibitor of KRas G12C, D-1553, with potent in vitro biochemical, cellular activity and in vivo efficacy. Here we report the efficacy of D-1553 in a large panel of patient-derived xenograft (PDX) tumor models with KRas G12C mutation. In the lung cancer PDX models, D-1553 exhibited tumor growth inhibition (TGI) from 43.6% to 124.3%, with 4 out of 8 models showing tumor regression. In the colorectal cancer PDX models, the range of TGI was from 60.9% to 105.7%, with 3 out of 9 models showing regression. Combination treatment of D-1553 with chemotherapy and targeted agents demonstrated enhanced anti-tumor activity resulting in more tumor regression compared to single agent treatment. These observations from PDX models support the combination treatment as a key to increased overall response rate to KRas G12C inhibitor in clinical trial. D-1553 is currently in a Phase 1/2 clinical trial for patients with advanced solid tumors harboring KRas G12C mutation (NCT04585035).
Citation Format: Zhe Shi, Jifang Weng, Xiaochong Fan, Qingqing Zhu, Emily Robb, Alyssa Moriarty, Michael Wick, Yueheng Jiang, Ling Zhang, Xing Dai, Yaolin Wang. Potent in vivo anti-tumor activity of D-1553 as a single agent and in combination with targeted therapeutics in a broad spectrum of patient-derived xenograft tumor models with KRas G12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1056.
Abstract 1083: A novel role of SRC in mediating bypass resistance to MEK inhibition in colorectal cancer stem cells
Authors: Yang Mingli , Davis Thomas B. Davis B. , Nebozhyn Michael V. , Loboda Andrey , Wang Heiman , Schell Michael J. , Pflieger Lance , Thota Ramya , Pledger W. Jack , Yeatman Timothy J. 
Published: July 2021

Abstract
Colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors (KRASi/BRAFi/MEKi/ERKi), has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms including intrinsic and adaptive resistance. Here we report a central role of SRC in mediating intrinsic and adaptive “bypass”-resistance to MEK inhibition in cancer stem cells (CSCs). The SRC oncogene is a well-studied non-receptor tyrosine kinase that can regulate multiple signaling pathways involved in the control of cell proliferation, survival, differentiation, adhesion, invasion and motility. Previously, our laboratory was the first to document that human CRC truncating mutations in the negative regulatory domain of SRC result in SRC activation (Nat Genet 1999). Now our integrated and expansive gene expression signature analyses in &gt;2000 human CRCs reveal that MEKi bypass-resistance is strikingly-correlated with SRC activation, which is associated clinically with regional metastasis, disease recurrence and poor overall survival, and associated biologically with EMT and “stemness”. In support of this, SRC-associated MEKi resistance is strongly related to the CMS4 subtype that has a mesenchymal CSC phenotype. The finding is further supported by in vitro analyses demonstrating that CSCs vs. non-CSCs display greater levels of MEKi-resistance, which is attenuated by a SRC inhibitor. These results support a novel notion that SRC may serve as a common targetable node in MEKi resistance mechanisms, permitting effective cancer stem cell targeting. These pre-clinical data, based on strikingly-correlated pathway analyses of thousands of human tumors, support the “fast-track” development of a biomarker-driven (MEKi + SRCi) drug combination targeting problematic SRC-mediated, mesenchymal CSCs.
Citation Format: Mingli Yang, Thomas B. Davis B. Davis, Michael V. Nebozhyn, Andrey Loboda, Heiman Wang, Michael J. Schell, Lance Pflieger, Ramya Thota, W. Jack Pledger, Timothy J. Yeatman. A novel role of SRC in mediating bypass resistance to MEK inhibition in colorectal cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1083.
Abstract 1109: A novel strategy to cope with osimertinib resistance in non-small cell lung cancer by treatment with a PIM kinase inhibitor in combination with a MERTK-selective kinase inhibitor
Authors: Yan Dan , Tan Zikang , Wang Xiaodong , Frye Stephen V. , Earp H. Shelton , DeRyckere Deborah , Graham Douglas K. 
Published: July 2021

Abstract
Osimertinib is currently the preferred treatment for EGFR-mutated non-small cell lung cancer (NSCLC) patients due to its superior therapeutic efficacy and prolonged overall survival compared to earlier generation EGFR tyrosine kinase inhibitors, but durable responses to osimertinib treatment are rare due to acquired drug resistance. Thus, there is an urgent need for novel strategies to treat osimertinib-resistant NSCLC. Recently, we found that treatment with MRX-2843, a novel MERTK-selective kinase inhibitor currently in Phase I clinical trials, resulted in dose-dependent inhibition of cell expansion and colony formation in an osimertinib-resistant (osiR) H4006 derivative cell line. An unbiased screen of 378 kinase inhibitors was carried out to identify compounds that synergized with MRX-2843 to inhibit expansion of an osiR derivative of the EGFR-mutated H4011 cell line. Treatment with 1µM PIM kinase inhibitor SGI-1776 or 100nM MRX-2843 alone reduced cell density by 5±3% and 44±7%, respectively, while treatment with MRX-2843 and SGI-1776 combined mediated an 82±0.4% decrease. Synergy was also observed in H4006 osiR and H1650 osiR derivative cell lines. Furthermore, treatment with PIM447, a structurally distinct PIM kinase inhibitor, and MRX-2843 decreased cell expansion more effectively than either agent alone. Mechanistically, treatment with a PIM kinase inhibitor in combination with MRX-2843 decreased downstream PI3K-AKT and MAPK-ERK signaling more effectively than single agents. Additionally, combined treatment with MRX-2843 and SGI-1776 prevented colony formation, while single agents had limited effect. In all, these data indicate that combining MRX-2843 and a PIM TKI may control osimertinib resistant tumor growth, providing a potential treatment strategy for osimertinib resistant EGFR-mutated NSCLC patients for whom the choices are still limited.
Citation Format: Dan Yan, Zikang Tan, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, III, Deborah DeRyckere, Douglas K. Graham. A novel strategy to cope with osimertinib resistance in non-small cell lung cancer by treatment with a PIM kinase inhibitor in combination with a MERTK-selective kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1109.
Abstract 115: Neutrophil extracellular traps express PD-L1 which promotes T cell exhaustion in the tumor microenvironment
Authors: Kaltenmeier Christof , Yazdani Hamza , Tohme Samer 
Published: July 2021

Abstract
Neutrophil extracellular traps (NETs) have recently been implicated in the growth of tumors, however their impact on immune cells within the tumor microenvironment (TME) remain incompletely understood. We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. We performed liver Ischemia/Reperfusion (I/R) in an established colorectal cancer metastasis model to induce NET formation in the TME. In this NET-rich TME we discovered elevated levels of phenotypically and functionally exhausted T cells. We demonstrated that the majority of CD4 and CD8 T cells are not effector cells, but rather express multiple inhibitory receptors and are highly dysfunctional, with reduced cytokine production and proliferative capacity. This effect was limited to the T cells present the the NET-rich TME in comparison to T cells isolated from the spleen. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion; an effect abrogated by using PD-L1 KO NETs. This exhausted state was directly linked to mitochondrial dysfunction in the T cells. Furthermore, NETs were targeted in vivo by treating mice with DNAse or anti-PD-L1 at time of I/R. Treatment caused decreased metastatic burden, decreased NET formation and higher levels of functioning non-exhausted T cells. Conversely, injecting NETs in tumors led to acceleration of tumor growth and T cell exhaustion in the TME. In addition, we measured sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. High levels of both markers were significantly associated with decreased disease free survival. Neutrophils isolated from patients after surgery were primed to form NETs that caused a similar exhaustion and dysfunction of human CD4 and CD8 T cells. Our data thus reveal that NETs have the capability of suppressing T cell responses and promoting tumor growth. This mechanism of T cell suppression by NETs represents a viable target for sustaining immune competence within the TME.
Citation Format: Christof Kaltenmeier, Hamza Yazdani, Samer Tohme. Neutrophil extracellular traps express PD-L1 which promotes T cell exhaustion in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 115.
Abstract 117: Inhibition of Hedgehog signaling alters fibroblast composition in pancreatic cancer
Authors: Steele Nina G. , Biffi Giulia , Kemp Samantha , Zhang Yaqing , Drouillard Donovan , Syu LiJyun , Hao Yuan , Oni Tobiloba , Brosnan Erin , Elyada Ela , Doshi Abhishek , Hansma Christa , Espinoza Carlos , Abbas Ahmed , The Stephanie , Irizarry-Negron Valerie , Halbrook Christopher , Franks Nicole , Hoffman Megan , Carpenter Eileen , Nwosu Zeribe , Park Youngkyu , Crawford Howard , Lyssiotis Costas , Frankel Timothy , Rao Arvind , Bednar Filip , Dlugosz Andrzej , Preall Jonathan , Tuveson David , Allen Benjamin , Pasca di Magliano Marina 
Published: July 2021

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog (HH) pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of HH signaling in PDAC have been contradictory, with HH signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how HH pathway inhibition reprograms the PDAC microenvironment.
Experimental Design: We used a combination of pharmacologic inhibition, gain- and loss- of-function genetic experiments, CyTOF, and single cell RNA-sequencing to study the roles of HH signaling in PDAC.
Results: We find that HH signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAFs) compared to inflammatory CAFs (iCAFs). SHH overexpression promotes tumor growth, while HH pathway inhibition with the Smoothened antagonist LDE225 impairs tumor growth. Further, HH pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in Tregs, consistent with increased immune suppression.
Conclusions: HH pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.
Citation Format: Nina G. Steele, Giulia Biffi, Samantha Kemp, Yaqing Zhang, Donovan Drouillard, LiJyun Syu, Yuan Hao, Tobiloba Oni, Erin Brosnan, Ela Elyada, Abhishek Doshi, Christa Hansma, Carlos Espinoza, Ahmed Abbas, Stephanie The, Valerie Irizarry-Negron, Christopher Halbrook, Nicole Franks, Megan Hoffman, Eileen Carpenter, Zeribe Nwosu, Youngkyu Park, Howard Crawford, Costas Lyssiotis, Timothy Frankel, Arvind Rao, Filip Bednar, Andrzej Dlugosz, Jonathan Preall, David Tuveson, Benjamin Allen, Marina Pasca di Magliano. Inhibition of Hedgehog signaling alters fibroblast composition in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 117.
Abstract 1282: IND-enabling characterization of the selective GPER agonist, LNS8801
Authors: Natale Chris , Garyantes Tina 
Published: July 2021

Abstract
LNS8801 is the first-in-class, small molecule, orally bioavailable, agonist of GPER being developed for the treatment of patients with advanced cancer. LNS8801 is highly selective for GPER over the classical nuclear hormone estrogen receptors α and β, and it was also highly selective for GPER in Eurofins' Safety47 panel. LNS8801 has very low aqueous solubility and is highly protein bound. Pharmacokinetic studies demonstrate that LNS8801 has high clearance and moderate, solubility-dependent, oral bioavailability. The rank ordering of metabolic liability in hepatocytes is dog&lt;human&lt;mouse&lt;rat, which is consistent with the observed clearance rates in these species. LNS8801 metabolism, and thus clearance, is slower in dogs. Oral bioavailability is ~80% and dose proportional in human formulations tested in dogs. LNS8801 is primarily metabolized by oxidation followed by phase II conjugation. In vitro metabolism studies indicate that LNS8801 is a potential substrate for several cytochrome P450 enzymes and thus has a low potential for participating in drug-drug interactions (DDIs). Given that maximal efficacy is expected at low exposures (Cmax of ≤5 nM) and that LNS8801 is highly protein bound, it is unlikely that these effects will cause adverse DDIs in humans. In the pivotal 28-day toxicity studies, the no-observed-adverse-effect level (NOAEL) was &gt;1000 mg/kg/day (the maximum feasible dose) in the rat and 30 mg/kg/day in the dog. Exposure was higher in dogs than in rats due to considerable accumulation. In the dog, mortality at doses that gave very high exposures was attributed to myelopoietic hypocellularity of the bone marrow and subsequent lymphoid depletion in associated organs. The primary target organs were identified as bone marrow, lymphoid tissues, and reproductive organs. Exposure at the canine NOAEL was more than 24,000 times the predicted maximally efficacious exposure in humans, and thus LNS8801 is anticipated to be very safe.
Citation Format: Chris Natale, Tina Garyantes. IND-enabling characterization of the selective GPER agonist, LNS8801 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1282.
Abstract 1401: MYC mediates retinoic acid resistance by suppressing cellular retinoic acid-binding protein (CRABP2) transcription in HER2-enriched breast cancers
Authors: Choi Won-Shik , Liu Rong-Zong , Godbout Roseline 
Published: July 2021

Abstract
Introduction: HER2-positive (HER2+) breast cancers express high levels of the growth-promoting HER2 protein. The development of a targeted drug, trastuzumab, has greatly improved clinical outcome for HER2+ patients. However, intrinsic and acquired resistance to trastuzumab are common. Clearly, additional therapeutic interventions are required for the clinical management of HER2-enriched breast cancers. Retinoic acid (RA) is a vital signaling molecule that regulates multiple biological processes, including cell proliferation, differentiation, and death. RA has been successfully used in the treatment of acute promyelocytic leukemia. RA also holds promise for the treatment of solid cancers like breast cancer. RA action is mediated through transcription factor RARα and the RA binding protein CRABP2, which deliver RA to RARα in the nucleus. The HER2 gene (ERBB2) is frequently co-amplified with the gene encoding RARα, a key determinant of RA sensitivity. It seems surprising, therefore, that HER2+ breast cancers are refractory to RA treatment. MYC is an oncogene that inhibits RARα activity in leukemia cells. Importantly, MYC is preferentially amplified and overexpressed in HER2+ breast cancers. My research aims to elucidate the mechanism underlying RA resistance in HER2+ breast cancers, with a special focus on the role of MYC.
Hypothesis: MYC attenuates RA action by inhibiting the CRABP2-RARα pathway.
Results: RNA levels of MYC are negatively correlated with CRABP2 RNA levels. Depletion of MYC upregulates CRABP2 at both the RNA and protein levels. Furthermore, we found that MYC binds to the CRABP2 promoter region suggesting that MYC may directly suppress CRABP2 gene transcription activity. Our results show that ectopic expression of MYC inhibits, whereas depletion of MYC activates RAR activity. Consistently, ectopic expression of MYC increases RA resistance, whereas depletion of MYC sensitizes cells to RA treatment. When CRABP2 is depleted along with MYC-knockdown, cell proliferation is rescued, suggesting that MYC mediates RA resistance, at least partially through downregulation of CRABP2. We also found that RA treatment enhances trastuzumab responsiveness in HER2+ breast cancer cells.
Significance: This study sheds light on the role and mechanism of MYC in governing RA resistance in HER2+ breast cancer cells. Our results support the use of RA and trastuzumab for the treatment of subsets of patients with HER2+/low MYC breast cancers.
Citation Format: Won-Shik Choi, Rong-Zong Liu, Roseline Godbout. MYC mediates retinoic acid resistance by suppressing cellular retinoic acid-binding protein (CRABP2) transcription in HER2-enriched breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1401.
Abstract 1446: GRP78 targeting peptides deliver liposomal doxorubicin specifically to cancer and enhance the efficacy of radiation therapy
Authors: Singh Abhay K. , Shyam Chandresh , Lewis Calvin , Zhang Wendy , Deore Sapna , Kapoor Vaishali , Hallahan Dennis E. 
Published: July 2021

Abstract
Traditional radiation therapy is often associated with significant toxicity to normal cells that could limit cancer therapy's success. The greater understanding of the molecular differences between cancer cells and normal cells has led to targeted therapies in cancer treatment. We discovered the radiation-inducible expression of Glucose regulated protein 78kDa (GRP78) in cancer using phage-display peptide libraries. In this study, we screened a peptide library and discovered novel peptides targeting GRP78. The top ten peptides were further evaluated for their affinity of binding to recombinant GRP78 using surface plasmon resonance technology. Since GRP78 is induced on cancer cells' surface, we irradiated the lung cancer cell lines A549 and H460 to evaluate peptide binding. Flow cytometry analysis of Dylight 488 conjugated peptides led to identifying peptides A and K with the highest binding level to irradiated A549 and H460. Peptides A and K were compared for their efficacy to deliver liposomal doxorubicin specifically to tumors. Copper-free click-chemistry was used to conjugate peptides to the liposome surface. Whole-body near-infrared imaging was performed to evaluate the biodistribution of the peptide conjugated liposomes in nude mice bearing A549 and H460 tumors. Both peptides A and K specifically delivered liposomes to the tumors compared to the non-targeted liposomes. In pilot tumor growth experiments, we found that GRP78 targeting peptide conjugated liposomes delayed the growth of tumors in nude mice compared to non-targeted liposomes. The inhibition of tumor growth was further enhanced in combination with radiation, indicating efficient delivery of the radiation-sensitizer doxorubicin specifically to tumors. Currently, studies are underway to evaluate the microscopic biodistribution of doxorubicin in tumor sections. Mass spectrometry analysis of various organs will be performed to determine the pharmacokinetics of liposomal doxorubicin delivered by GRP78 targeting peptides. In conclusion, our novel GRP78 targeting peptides specifically deliver liposomal doxorubicin to tumors. Doxorubicin encapsulated in GRP78 targeting peptide conjugated liposomes enhances the tumor growth inhibitory activity of radiation therapy. Specific delivery of radiation-sensitizing drugs encapsulated in a liposome by peptides that target radiation-inducible GRP78 is a promising therapeutic strategy for various cancers.
Citation Format: Abhay K. Singh, Chandresh Shyam, Calvin Lewis, Wendy Zhang, Sapna Deore, Vaishali Kapoor, Dennis E. Hallahan. GRP78 targeting peptides deliver liposomal doxorubicin specifically to cancer and enhance the efficacy of radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1446.