bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6206: The xl313 cryptic collagen epitope regulates ovarian tumor growth by a yap dependent mechanism
Authors: Han Xianghua , Caron Jennifer M. , Brooks Peter C. 
Published: September 2020

Abstract
Structural changes in the extra cellular matrix (ECM) can lead to the exposure of cryptic regulatory sites that play important roles in angiogenesis, inflammation, tumor growth, and tumor metastasis. Previously, we discovered that a unique cryptic regulatory site (XL313 cryptic epitope) containing the amino acid sequence RGDKGE, is generated during tumor development, and we found that this collagen epitope promotes angiogenesis and inflammation in vivo. Here, we provide the first evidence that ovarian carcinoma cells can bind the XL313 collagen epitope through integrin alpha-V beta-3 and that selectively blocking cellular interactions with the XL313 epitope significantly inhibits ovarian tumor growth and the formation of ascites fluid in vivo. To understand the cellular mechanism(s) by which antagonists of the XL313 epitope inhibit these pathological processes, we examined down-stream signaling events that were altered following blocking ovarian tumor cell interaction with the XL313 collagen epitope. Importantly, selectively targeting the XL313 epitope significantly reduced nuclear accumulation of the transcriptional co-activator YAP. In addition, blocking cellular interaction with the XL313 epitope resulted in enhanced YAP phosphorylation at serine-127. Interestingly, specific targeting of the XL313 epitope also enhanced LATS1 phosphorylation, which is a key effector molecule in the hippo- signaling pathway. Taken together, our data provide new cellular and molecular insight for understanding the role of the XL313 cryptic collagen epitope in controlling ovarian tumor growth, and suggest that selectively targeting the XL313 epitope-integrin-signaling cascade may represent a novel strategy to inhibit ovarian cancer progression.
Citation Format: Xianghua Han, Jennifer M. Caron, Peter C. Brooks. The xl313 cryptic collagen epitope regulates ovarian tumor growth by a yap dependent mechanism [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 6206.
Abstract 6216: Therapeutic potential of IAP inhibitor APG-1387 in combination with PARP- or MEK-targeted therapy, or chemotherapy in pancreatic cancer
Authors: Li Qiang , Fang Douglas D. , Gu Shoulai , Yang Dajun , Zhai Yifan 
Published: September 2020

Abstract
APG-1387 is a small molecule antagonist of the inhibitor of apoptosis proteins (IAPs) which blocks the activity of IAPs family proteins (XIAP, cIAP-1, cIAP-2, and ML-IAP) and consequently induces apoptosis. It is currently in phase I clinical development in patients with solid tumors, including pancreatic cancer. Targeting IAPs has been reported to effectively inhibit tumor growth in the preclinical models of pancreatic cancer. Currently, PARP and MEK inhibitors are also in clinical development for pancreatic cancer with BRCA1/2 or KRAS mutations. To further explore the therapeutic potential of APG-1387 in combination with PARP or MEK inhibitors, a genomic biomarker guided avatar mouse trial (n=2) using pancreatic cancer patient-derived xenografts (PDX) was conducted to evaluate antitumor activity of APG-1387 in combination with (i) the PARP inhibitor, olaparib, in PDXs carrying BRCA1/2 mutations, and (ii) the MEK inhibitor, trametinib, in PDXs carrying KRAS mutations.
The results revealed that APG-1387 improved the antitumor activity of olaparib in 4 out of 6 (67%) BRCA1/2 mutant PDXs with a 44% reduction of T/C (%) value (T, treatment group, C, vehicle control), including one partial tumor regression (PR). In combination with trametinib, the antitumor activity was improved in 4 out of 9 (44%) KRAS mutant PDXs, showing a 34% reduction in the T/C value. Furthermore, synergy of the combinations of APG-1387 with PARP or MEK inhibitor was confirmed in a follow-up efficacy study (n=5) using a PDX model carrying both BRCA2 and KRAS mutations. The molecular mechanisms underlying the synergy are currently being investigated.
In summary, our results suggest that APG-1387 is a potential agent for pancreatic cancer treatment, ascribing to its potential synergistic antitumor effect by combining with either PARP inhibitors in BRCA1/2 mutant or MEK inhibitors in KRAS mutant pancreatic cancers. Overall, our data provide the scientific rationale for the future clinical development of these combinations in pancreatic cancer patients with distinct genomic alterations.
Citation Format: Qiang Li, Douglas D. Fang, Shoulai Gu, Dajun Yang, Yifan Zhai. Therapeutic potential of IAP inhibitor APG-1387 in combination with PARP- or MEK-targeted therapy, or chemotherapy in pancreatic 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 6216.
Abstract 622: Rapid non-uniform adaptation to conformation-specific KRAS G12Cinhibition
Authors: Xue Jenny Y. , Zhao Yulei , Aronowitz Jordan , Mai Trang T. , Vides Alberto , Qeriqi Besnik , Kim Dongsung , Li Chuanchuan , de Stanchina Elisa , Mazutis Linas , Risso Davide , Lito Piro 
Published: September 2020

Abstract
KRAS GTPases are activated in one-third of cancers and KRAS G12C is the most common activating alteration in lung adenocarcinoma. KRAS G12C-specific inhibitors (G12Ci) are in Phase-I clinical trials and early data show only partial responses in lung cancer patients. How cancer cells bypass inhibition, to prevent maximal responses to therapy, is not understood. Because KRAS G12C cycles between an active and inactive conformation, and the covalent G12Ci only bind to the latter, we tested whether isogenic cell populations respond non-uniformly by studying the effect of treatment at a single-cell resolution. Using single-cell RNA sequencing and a fluorescent quiescence biosensor, we show that shortly after treatment, most cancer cells are sequestered in a quiescent state with low KRAS activity, while a small population reactivates KRAS to resume proliferation. This rapid divergent response is due to synthesis of new, drug-free KRAS protein, resulting from increased KRAS transcription in response to suppressed MAPK signaling. Combining cell fate-specific gene expressions and results from a CRISPR-Cas9 screen, we identified that adaptive signals such as epidermal growth-factor receptor and aurora kinase A signaling modulate the heterogeneous response to treatment with G12Ci. These upstream signals help to maintain new KRAS G12C protein in its active, drug-insensitive state, which restores KRAS signaling and transcriptional output in a subset of cells to allow escape from G12Ci-induced quiescence. Cells without these adaptive changes (or cells where they are pharmacologically inhibited) remain sensitive to G12Ci treatment, because new KRAS G12C is either not available, or it exists in its inactive, drug-sensitive state. Combined inhibition of these adaptive signals along with KRAS G12C produced more potent antitumor effects in xenograft models. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome to maximize the therapeutic potential of conformation-specific KRAS G12C inhibitors in the clinic.
Citation Format: Jenny Y. Xue, Yulei Zhao, Jordan Aronowitz, Trang T. Mai, Alberto Vides, Besnik Qeriqi, Dongsung Kim, Chuanchuan Li, Elisa de Stanchina, Linas Mazutis, Davide Risso, Piro Lito. Rapid non-uniform adaptation to conformation-specific KRAS G12Cinhibition [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 622.
Abstract 6225: Addition of TRAIL receptor agonists after treatment with ONC201 or ONC212 converts pancreatic cancer cells from anti-proliferative to apoptotic in vitro
Authors: Jhaveri Aakash V. , Zhou Lanlan , Ferarrini Isacco , Lee Young , El-Deiry Wafik S. 
Published: September 2020

Abstract
The 7% five-year survival rate for pancreatic cancer patients has remained unchanged for decades; the need for novel therapeutic interventions is imminent. ONC201 is the founding member of the impridone class, a class of orally bioavailable small molecules which show efficacy in multiple tumor types. ONC201 and ONC212, a fluorinated imipridone, have been shown to be potent inducers of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. Both compounds are currently in clinical trials. In the context of pancreatic cancer, ONC201 and ONC212 induce either apoptotic or anti-proliferative effects. Additionally, both compounds activate the integrated stress response leading to DR5 upregulation in various cell types. We hypothesized that exogenous addition of TRAIL receptor agonists after pre-treatment with ONC201 or ONC212 could convert cells from anti-proliferative to apoptotic. Here, we examined both rhTRAIL and TLY012, a novel TRAIL receptor agonist with a substantially improved half-life. Pancreatic cancer cell lines were screened for synergy when treated with ONC201 or ONC212 for 72 hours followed by either rhTRAIL or TLY012 for 4 hours. Four cell lines (AsPC-1, BxPC3, Capan-1, and PANC-1) showed potent synergy with both rhTRAIL and TLY012. Growth inhibition was assessed through both Cell-Titer Glo and colony assays. Apoptotic synergy was determined using Cell-Titer Glo, western blots for PARP cleavage, and sub-G1 flow cytometric assays. Further analysis showed that ONC201 activates the integrated stress response and primes pancreatic cancer cells for TRAIL-induced apoptosis through regulation of key proteins. Upregulation of the integrated stress response and downregulation of XIAP, c-FLIP, and Bcl-XL was observed after treatment with ONC201 in BxPC3 and PANC-1 cell lines. The combination of ONC201 and TRAIL receptor agonists was non-toxic to human foreskin fibroblasts. Future experiments aim to examine G1 arrest after treatment with ONC201 and ONC212 via western blot and flow cytometry, to confirm surface expression of TRAIL and DR5 via flow cytometry, and to determine efficacy in pancreatic cancer xenografts. Taken together, these data indicate a novel therapeutic strategy for treatment of patients with ONC201 and ONC212 resistant pancreatic tumors.
Citation Format: Aakash V. Jhaveri, Lanlan Zhou, Isacco Ferarrini, Young Lee, Wafik S. El-Deiry. Addition of TRAIL receptor agonists after treatment with ONC201 or ONC212 converts pancreatic cancer cells from anti-proliferative to apoptotic in vitro [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 6225.
Abstract 6226: Sapanisertib interferes with the NRF2-mediated stress response to synergize with Obatoclax and extend AT/RT survival
Authors: Parkhurst Ashlyn , Wang Sabrina , Kaur Harpreet , Arnold Antje , Eberhart Charles , Raabe Eric , Rubens Jeffrey 
Published: September 2020

Abstract
Atypical teratoid rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy, highly resistant to all therapies, and responsible for one of the greatest numbers of life years lost due to cancer. We have previously demonstrated that Sapanisertib combines synergistically with cisplatin to extend survival in AT/RT. To understand the mechanisms underlying this synergy and to identify further novel combination therapies to improve AT/RT survival, we performed RNASeq on AT/RT cell models 4 hours after Sapanisertib treatment. Pathway analysis revealed that Sapanisertib disrupts the NRF2-mediated stress response and apoptotic signaling pathway leading to a pro-death phenotype. Activating mutations in the NRF2 coding gene, NFE2L2, have been identified as a possible biomarker predicting Sapanisertib efficacy in lung cancer clinical trials. Short hairpin knockdown of NRF2 led to decreased expression of the anti-apoptotic proteins MCL-1, BCL-2, and BCL-xL suggesting that interfering with NRF2 may drive this pro-death phenotype in AT/RT. Obatoclax is a synthetic small molecule inhibitor of the BCL-2 family of proteins that was well tolerated in phase II clinical trials and readily crosses the blood brain barrier. Obatoclax treatment of NRF2 knockdown AT/RT cell models slows cell growth, induces high rates of apoptosis, and leads to increased oxidative stress compared to short hairpin scramble controls (cell viability assay, t-test p&lt;0.05; ANNEXIN V cell sorting assay t-test p&lt;0.05, MUSE oxidative stress assay t-test p&lt;0.05). We treated AT/RT cell models with Sapanisertib and showed that treatment decreases expression of NRF2 and MCL-1 (western blot). Sapanisertib combines synergistically with Obatoclax to increase oxidative stress, slow cell growth, and increase apoptosis (MUSE oxidative stress assay ANOVA p&lt;0.05; cell viability assay, ANOVA p&lt;0.05; ANNEXIN V cell sorting assay ANOVA p&lt;0.05, Compusyn model of synergy, CI&lt;1.0). We next developed orthotopic mouse models of AT/RT using our luciferase-labeled CHLA06 and BT37 AT/RT cell models. We administered Sapinisertib and Obatoclax using mouse equivalent dosing to human clinical trials (Sapinisertib 6mg/kg oral weekly, Obatoclax 10mg/kg oral twice a week). Combination treatment was well tolerated and more than doubled median survival. Our data supports a new clinical trial combining Sapinisertib with Obatoclax to extend survival in AT/RT.
Citation Format: Ashlyn Parkhurst, Sabrina Wang, Harpreet Kaur, Antje Arnold, Charles Eberhart, Eric Raabe, Jeffrey Rubens. Sapanisertib interferes with the NRF2-mediated stress response to synergize with Obatoclax and extend AT/RT survival [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 6226.
Abstract 6237: Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis
Authors: Niu Yimin , Gao Cuicui , Yang Hongbin , Huo Qiang , Wang Andrew , Xu Ming , Liu Yang 
Published: September 2020

Abstract
Background: Protein drugs are one of the most promising new areas in drug research and development, however, great challenges are still faced in the drug delivery in vivo. Previously, we constructed bone targeted micelles for bone metastases. In order to address the issues of protein delivery in vivo and enhanced cancer bone metastasis treatment, we engineered and evaluated a bone-targeting nanoparticles by using metal organic framework nanoparticles (MOFs), bone-targeting agents (Alendronate) and hyaluronic acid (HA) as materials and a protein toxin as therapeutic.
Methods: Alendronate (ALN) were conjugated to HA through PEG as linker and ALN-PEG-HA were obtained. Cytochrome C, as modle proteins, were caged in the MOFs (ZIF-8) by selfassembly of Zn2+ and organic ligands (2-methylimidazole) to form protein-encapsulated nanoparticles (ZIF8-CC). And ALN-PEG-HA were further decorated on the surface of ZIF8-CC nanoparticles via the coordination effect between its carboxyls and metal ions in ZIF-8 to result in active-targeting ALN-HA@ZIF8-CC nanopartilces. The materials and nanoparticles were synthesized and characterized by NMR, FT-IR, TEM, DLS, XRD, TGA and N2 adsorption−desorption isotherms analysis. The in vitro release profiles, stability and cytocompatibility were also studied.
Results: The synthesis of ALN-PEG-HA was confirmed by 1H-NMR and FT-IR. TEM, XRD and DLS showed that ALN-HA@ZIF8-CC nanopartilces had been prepared, and the experiment of washing nanoparticles with SDS confirmed that protein was encapsulated in ZIF-8 instead of adsorbed on its surface. TGA and N2 absorption-degradation isotherms analysis also confirmed the formation of the crystal structure and porous structure, respectively. HA coated nanoparticles have good stability while ZIF8-CC were easy to aggregate. The results of in vitro release showed that the nanoparticles have acid sensitive release properties and excellent cell compatibility. In addition, In vitro bone fragment targeting experiment confirmed that nanoparticles have strong bone affinity.
Conclusions: Our data demonstrated that bone-targeted protein drug-encapsulated MOFs were constructed.
Citation Format: Yimin Niu, Cuicui Gao, Hongbin Yang, Qiang Huo, Andrew Wang, Ming Xu, Yang Liu. Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis [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 6237.
Abstract 6247: Drug delivery with real time customizable micro-scaled continuous liquid interface printed 3D devices
Authors: Hagan C. Tilden , Bloomquist Cameron J. , DeSimone Joseph M. , Wang Andrew Z. 
Published: September 2020

Abstract
Background: Surgery is a key treatment for cancer. However, local recurrence after surgery is common and can lead to significant morbidity and mortality. Current strategies to prevent recurrence include intraoperative radiation or systemic chemotherapy. We hypothesize that local chemotherapy delivery can prevent recurrence while reducing toxicity. To accomplish this, we propose to engineer 3D printed devices that can deliver chemotherapy in a localized and prolonged fashion.
Methods: Paclitaxel and a cisplatin prodrug were dissolved into a liquid resin mixture of PEG550-DMA and HEMA. Custom 3D patches were printed on a Carbon 3D continuous liquid interface printer with microneedles protruding from one side of a flat surface substrate. A non-drug loaded flat backing was also printed from the same resin, and adhered to back side of the microneedle patch. Tumor growth recurrence inhibition post surgical resection was assessed in NU/NU mice in both 344SQ/Luc and A431 tumor models. Tumors were inoculated subcutaneously (106 344SQ/Luc, 5 × 105 A431) and allowed to grow until they reached 5-7mm in length. Tumors were then surgically resected and mice were either given an IV drug treatment, or had a 3D printed patch implanted in the surgical pocket. Tumor recurrence was evaluated with both luciferase bioluminescence imaging and physical measurement of tumor size. Toxicity parameters were analyzed with enzyme and CBC tests.
Results: All drug loaded patches showed significant tumor growth inhibition compared to their corresponding IV drug treatment groups. While single drug loaded patches were significant in their inhibition of tumor growth compared to IV delivery of the same drug, dual drug loaded patches showed the most significant tumor inhibition compared to either single IV drug treatment or a dual IV drug treatment. There were no significant differences in measured toxicity parameters between groups.
Conclusions: Our data demonstrated that local drug delivery through a customizable 3D continuous liquid interface printed drug loaded patch can improve tumor growth recurrence inhibition post surgical resection.
Citation Format: C. Tilden Hagan, Cameron J. Bloomquist, Joseph M. DeSimone, Andrew Z. Wang. Drug delivery with real time customizable micro-scaled continuous liquid interface printed 3D devices [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 6247.
Abstract 6265: Combining arsenic and topoisomerase inhibitors synergistically inhibit gastric cancer
Authors: Kang Ting , Ge Maolin , Lu Shumin , Wang Qing , Zhu Shouhai , Zhu Chuanying , Zheng Leizhen , Liu Han , Chen Siyu 
Published: September 2020

Abstract
Objectives: Arsenic compounds have cytotoxic activities in gastric cancer cells, however, the underlying mechanism is unclear and the clinical potential need to be explored. This study was aimed to investigate the mechanism of arsenic on gastric cancer and find a novel regimen for the treatment of gastric cancer.
Methods: Gastric cancer cell lines were treated with arsenics and/or chemotherapeutic drugs. MTT assay, FACS, Western blotting, q-RT-PCR and CHIP were used to detect proliferation, modulation of proteins and genes.
Results: We previously showed that NFATc3 was a target of Arsenic sulfide and its inhibition blocks gastric cancer growth. Here we show that the NFATc3 expression is critically important for the growth and survival of gastric cancer cells because knockdown of NFATc3 resulted in DNA damage and cell cycle arrest. Arsenic sulfide can target NFATc3 in gastric cancer cells and cause cell double-strand DNA breaks (DSB). However, overexpression of NFATc3 can block the DNA damage. Abolishing NFATc3 expression, whether by shRNA-induced silencing or Arsenic sulfide treatment, directly upregulated recombination activating gene 1 (RAG1, an endonuclease which is essential for immunoglobulin V(D)J recombination), leading to fatal DSB. NFATc3 targets the promoter of RAG1 for transcriptional inhibition. Moreover, we find that Arsenic sulfide and topoisomerase inhibitors (Irinotecan and Epirubicin, Doxorubicin, Etoposide and SN38) synergistically inhibit gastric cancer. Arsenic sulfide, as well as Arsenic Trioxide, enhanced the cytotoxic effect of Irinotecan and they synergistically induced NFATc3 degradation, resulted in disability of DNA repair system, as reflected by the decrease in the phosphorylated ATM/CHK2/CHK1 protein level and the dramatic increase in the phosphorylated H2AX protein level. More inspiring, a patient with advanced gastric cancer with liver and lymph-node metastasis who failed in first-line treatment achieved PR with 2 months treatment of Irinotecan combined with Realgar-Indigo Naturalis Formula, the main component of which is Arsenic sulfide. The progression-free survival was 4 months with no additional adverse event.
Conclusions: Our research links arsenic compounds to the regulation of DNA damage repair and RAG1 expression as a mechanism for the cytotoxic effect. The combination of arsenic with topoisomerase inhibitors may represent a novel regimen for the treatment of gastric cancer and warrants further studies.
Citation Format: Ting Kang, Maolin Ge, Shumin Lu, Qing Wang, Shouhai Zhu, Chuanying Zhu, Leizhen Zheng, Han Liu, Siyu Chen. Combining arsenic and topoisomerase inhibitors synergistically inhibit gastric 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 6265.