bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LBA016: Androgen Receptor (AR) N-Terminus-Domain-Binding Small Molecule Degraders for the Treatment of AR Splice Variant-Positive Castration-Resistant Prostate Cancer
Authors: Narayanan Ramesh 
Published: December 2021

Abstract
Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. Over 30,000 men die of prostate cancer each year in the U.S. and the deaths predominantly occur due to late-stage castration-resistant prostate cancer (CRPC). Androgen receptor (AR) is the primary therapeutic target in castration-sensitive prostate cancer and CRPC, with over 85% of the cases expressing AR. About 30% of CRPC fail to respond to ligand-binding domain (LBD)-binding AR-signaling inhibitors, while the remaining develop resistance after an initial period of response of 12-24 months. Expression of AR splice variants (AR-SVs) that lack LBD has been identified as one of the primary causes for resistance development to AR-signaling inhibitors. AR-SVs also promote aggressive CRPC growth, resulting in shorter overall survival. We discovered novel AR N-terminus domain (NTD)-binding small molecule, GTx-534 that induce degradation of AR and AR-SV proteins, resulting in loss of AR signaling. Surface Plasmon Resonance (SPR), intrinsic fluorescence biophysical studies and thermal stability analysis with purified AR activation function-1 (AF-1) domain in the NTD showed GTX-534 binding. Notably, GTx-534 significantly inhibited AR and AR-V7-positive 22RV1 cell line xenograft in castrated immune compromised rodents with a tumor growth inhibition (TGI) of over 50% (p&lt;0.005), while enzalutamide failed to inhibit the 22RV1 tumor growth. Serum PSA concentrations of 22RV1-bearing animals were reduced to background levels by GTx-534 (p&lt;0.01), but not by enzalutamide. Genome-wide expression studies demonstrated a distinct mechanism of action for GTx-534 in AR-SV-positive tumors. The results from 22RV1 xenograft studies were validated in LuCaP 86.2 patient-derived xenograft (PDX) that express AR v567es, another AR variant that lacks the LBD widely expressed in CRPC. GTx-534 completely inhibited LuCaP 86.2 tumor growth with a TGI of greater than 90%, while enzalutamide failed to alter the tumor growth. These results provide preclinical proof-of-concept for the efficacy of GTx-534 in AR and AR-SV-positive CRPC. Disclosure. The work presented in here was funded by a Sponsored Research Agreement from Oncternal Therapeutics, Inc. to RN and DDM and by National Cancer Institute grant R01CA229164 to RN. RN is a consultant to Oncternal Therapeutics Inc. GFK and JBB are employees of Oncternal Therapeutics Inc.
Citation Format: Ramesh Narayanan. Androgen Receptor (AR) N-Terminus-Domain-Binding Small Molecule Degraders for the Treatment of AR Splice Variant-Positive Castration-Resistant Prostate Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA016.
Abstract LBA025: AXL-STAT3 targeting of lung tumor microenvironments
Authors: Taverna Josephine A. 
Published: December 2021

Abstract
The tumor microenvironment contains multiple cell types, each providing a unique functionality in support of malignant growth. To prepare a pro-metastatic niche, a tight signaling network may be present to coordinate delivery of co-stimulatory signals among different cell subpopulations. Here, we report that AXL signaling collaborates with STAT3 to create a symbiotic ecosystem that favors partial epithelial-mesenchymal transition of cancer cells, pro-tumorigenic remodeling of fibroblasts, and M2 polarization of macrophages. To facilitate intercellular communication, AXL-regulated IL-11 secreted from cancer cells and fibroblasts binds to surface GP130 on macrophages to activate STAT3 signaling for M2 polarization. Disruption of AXL-STAT3 circuit not only compromises this signaling co-dependency in lung cancer cells implanted in xenograft mice, but also limits their ability to conscript murine fibroblasts, macrophages, and other immune cells to form a shared habitat for tumor growth and invasion. Therefore, targeting AXL-STAT3 network is an attractive strategy to render inoperative tumor microenvironments that exploit this cellular synchronicity for tumor progression. Significance: Combined targeting of AXL and STAT3 signaling that facilitates co-dependency between malignant and non-malignant cells in tumor microenvironments is a promising strategy for the treatment of advanced lung adenocarcinomas.
Citation Format: Josephine A. Taverna. AXL-STAT3 targeting of lung tumor microenvironments [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA025.
Abstract LBA034: Necrostatin-1 Protects Ferroptosis by xCT Induction in a RIPK1- and IDO-independent manner
Authors: Abdullah Md , Yuk Hanna , Kim Do Hyung , Lee Haeseung , Lee Seung Jin 
Published: December 2021

Abstract
Ferroptosis is caused by the iron-mediated accumulation of lipid peroxidation, which is distinct from apoptosis and necroptosis. Necrostatin-1 inhibits receptor-interacting ser-ine/threonine-protein kinase 1 (RIPK1) to initiate necroptosis; it also inhibits indoleamine 2,3-dioxygenase (IDO) to regulate tumor immunity. However, few studies have examined the off-target effect of necrostatin-1 on the ferroptosis pathway. The present study examined wheth-er necrostatin-1 could interrupt ferroptosis induced by system xc- inhibitors (sulfasalazine and erastin) and a glutathione peroxidase 4 inhibitor (RSL3) in Huh7 and SK-HEP-1 cells. Necrostatin-1 completely prevented decreases in cell viability induced by sulfasalazine and erastin; it partially blunted decreases in cell viability induced by RSL3. Necrostatin-1, ferrostatin-1, and deferoxamine repressed sulfasalazine-provoked membrane permeabilization, as detected by 7-aminoactinomycin D staining and lipid peroxidation measured using a C11-BODIPY probe. However, other RIPK1 inhibitors (necrostatin-1s and GSK2982772) and an IDO inhibitor (1-methyl-D-tryptophan) did not recover the decrease in cell viability induced by sulfasalazine. Necrostatin-1 potentiated sulfasalazine-induced expression of xCT, a catalytic subunit of system xc- in these cells. These results demonstrated that necrostatin-1 blocked fer-roptosis through a mechanism independent from RIPK1 and IDO inhibition in Huh7 and SK-HEP-1 cells, indicating that its antioxidant activity should be considered when using necrostatin-1 as a RIPK1 inhibitor.
Citation Format: Md Abdullah, Hanna Yuk, Do Hyung Kim, Haeseung Lee, Seung Jin Lee. Necrostatin-1 Protects Ferroptosis by xCT Induction in a RIPK1- and IDO-independent manner [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA034.
Abstract LBA037: Reposition of the antibiotic nitroxoline as a novel STAT3 inhibitor for drug-resistant urothelial bladder cancer
Authors: LIN WENFENG , Sun Jingkai , Sadahira Takuya , Araki Motoo , Watanabe Masami , Nasu Yasutomo , Huang Peng 
Published: December 2021

Abstract
Background: Repeated cycles of first-line chemotherapy drugs such as doxorubicin (DOX) and cisplatin (CIS) trigger frequent chemoresistance in recurrent urothelial bladder cancer (UBC), posing a threat to the prognosis of patients. Nitroxoline (NTX), an antibiotic to treat urinary tract infections, has been recently repurposed for the treatment of multiple tumors. Here we aimed to investigate whether NTX suppresses the growth of drug-resistant UBC in vitro and in vivo and the underlying mechanism at the molecular level. Methods: The drug-resistant cell lines T24/DOX and T24/CIS were established by continual exposure of parental cell line T24 to DOX and CIS, respectively. The drug effects on cell proliferation were measured by XTT assay. Cell cycle distribution was analyzed by PI/RNase staining, while apoptosis was assessed by Hoechst 33342 and Annexin V-FITC/PI staining. The expressions of proteins related to STAT3 signaling, cell cycle, and apoptosis were detected by western blotting. Subcutaneous xenograft models of T24/DOX and T24/CIS were established to determine the in vivo anti-tumor effect of NTX. Results: T24/DOX and T24/CIS cells were resistant to DOX and CIS respectively, but they were sensitive to NTX in a time- and dose-dependent manner. Overexpressions of STAT3 and P-glycoprotein (P-gp) were identified in T24/DOX and T24/CIS, which could be reversed by NTX. Furthermore, western blotting showed that NTX downregulated the expressions of phosphorylated STAT3, c-Myc, Cyclin D1, CDK4, CDK6, Bcl-xL, Mcl-1, and Survivin, which were further confirmed by Stattic, a selective STAT3 inhibitor. In vivo, NTX exhibits the significant anti-tumor effect in T24/DOX and T24/CIS tumor-bearing mice. These results suggested that NTX-induced G0/G1 arrest, apoptosis, and P-gp reversal in drug-resistant UBC were mediated by inhibition of STAT3 signaling. Conclusion: Our findings repurpose NTX as a novel STAT3 inhibitor to induce P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC.
Citation Format: WENFENG LIN, Jingkai Sun, Takuya Sadahira, Motoo Araki, Masami Watanabe, Yasutomo Nasu, Peng Huang. Reposition of the antibiotic nitroxoline as a novel STAT3 inhibitor for drug-resistant urothelial bladder cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA037.
Abstract LBA048: Lymph node metastasis targeted intranodal delivery of docetaxel improves treatment outcome
Authors: Sukhbaatar Ariunbuyan , Sora Shouta , Shiro Mori , Kodama Tetsuya 
Published: December 2021

Abstract
Despite recent advances in diagnostic modalities and cancer treatment guidelines, systemic chemotherapy for the lymph node (LN) metastasis has poor treatment efficacy using conventional drugs. Therefore, a novel method, lymphatic drug delivery system (LDDS), has been proposed in a pre-clinical experiment that directly injects the anticancer drug into sentinel LNs to deliver into their downstream LNs, aiming to inhibit tumor cell growth in those LNs. The injection duration of chemotherapy drugs using the LDDS will be less than the intratumoral or intralesion methods used in the clinic, and systemic toxicity will be less than tumor-targeted therapy or systemic chemotherapy. Our previous results indicated that the treatment efficacy increased in LDDS treated groups than systemic delivery. Here, we show the improvement of treatment efficacy by increasing osmotic pressure and viscosity of the drug solvent delivered by LDDS using the metastatic LN mouse model. First, a metastatic LN mouse model was created by inoculating luciferase-expressing tumor cells into subiliac LN (SiLN) of MXH10/Mo/lpr mouse to induce metastasis into the proper axillary LN (PALN). Next, 10 mg/kg docetaxel (DTX) with increased osmotic pressure and viscosity were injected into tumor-inoculated SiLN with an injection rate of 2400 μL/min on day 7 post-inoculation to inhibit tumor cell growth in the inoculation and metastatic site. Luciferase activity decreases in PALNs and SiLNs were observed in groups between 1140 kPa, 1960 kPa, and 2780 kPa (4, 11, and 38 mPa·s) groups without inducing any side effects. By histology, no tumor cells were confirmed in those LNs of the 1960 kPa group. Then, DTX at 1960 kPa, 11 mPa·s was injected into tumor-inoculated SiLN on day 21 post-inoculation with different injection speeds and volumes. We found that DTX at 1960 kPa, 11 mPa·s injected at the injection rate of 200 μL/min with 400 μL volume, can inhibit tumor cell growth in the PALN and delay tumor growth SiLN. Furthermore, the antitumor effects depended on the tumor progression stage in the LNs, and the injection rates and volumes of administered drugs. We anticipate these optimal ranges as a starting point for developing more effective drug regimens to treat metastatic LNs with the LDDS. Moreover, administrable drugs in this novel method of ultrasound-guided LDDS or LDDS at intra-operative or image-guided surgery are not limited only to anticancer agents.
Citation Format: Ariunbuyan Sukhbaatar, Shouta Sora, Mori Shiro, Tetsuya Kodama. Lymph node metastasis targeted intranodal delivery of docetaxel improves treatment outcome [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA048.
Abstract P001: The anti-angiogenic antibody BD0801 demonstrates better anti-tumor activity than bevacizumab and synergize with chemotherapies in multiple tumor models
Authors: Xue Liting , Tang Jianxing , Ding Yuyin , Song Lei , Xu Shansen , Huang Yue , Wu Yan , Song Wenjie , Tang Renhong , Yang Wenqing 
Published: December 2021

Abstract
Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play a fundamental role in tumor growth and angiogenesis. An increasing number of evidences have suggested enhanced anti-tumor activity when combining anti-angiogenic agents with chemotherapies in the clinic. To support the clinical development of BD0801, a humanized rabbit anti-VEGF monoclonal antibody, we assessed anti-tumor activities of BD0801 using a series of preclinical tumor mouse models including human ovarian cancer OVCAR-8 and SK-OV-3, human non-small cell lung cancer (NSCLC) NCI-H460, and human renal cancer Caki-1 models, with bevacizumab being used as a benchmark. We also investigated the pharmacological kinetics (PK) of BD0801 in cynomolgus monkeys. BD0801 or bevacizumab were intravenously injected into tumor bearing mice at 0.8 mg/kg, 2.5 mg/kg or 7.5 mg/kg twice a week. Combinations of chemotherapy and BD0801 or bevacizumab were also investigated in some of the tumor models. BD0801 presented more potent anti-tumor activities than bevacizumab in ovarian cancer, NSCLC and renal cancer mouse models in a dose-dependent manner. The tumor growth inhibition of BD0801 was 2-20%, 34-66%, or 32-84% when dosed at 0.8 mg/kg, 2.5 mg/kg or 7.5 mg/kg, respectively. Besides, combination of 2.5 mg/kg BD0801 and 10 mg/kg paclitaxel presented a statistically stronger antitumor activity in human ovarian cancer models compared to both single treatments (P&lt;0.05). Combination of 2.5 mg/kg BD0801, 10 mg/kg paclitaxel, and 80 mg/kg carboplatin also presented a stronger antitumor activity than BD0801 or chemotherapy alone in the human NSCLC model. In cynomolgus monkeys received a single intravenous injection of BD0801 at 1.5, 5, and 15 mg/kg, the half-life (t1/2) of BD0801 was 39.4-142 h, the clearance (Cl) was 0.321-0.900 mL/h/kg, and the apparent volume of distribution (Vd) was 49.5-64.4 mL/kg. The peak concentrations (Cmax) of BD0801 were proportional to the doses administered. No difference on the PK parameters was observed between female and male monkeys. Taken together, this study has demonstrated BD0801 as a more potent molecule than bevacizumab in some preclinical tumor models, supporting further clinical development plans for BD0801, especially in combination with chemotherapeutics.
Citation Format: Liting Xue, Jianxing Tang, Yuyin Ding, Lei Song, Shansen Xu, Yue Huang, Yan Wu, Wenjie Song, Renhong Tang, Wenqing Yang. The anti-angiogenic antibody BD0801 demonstrates better anti-tumor activity than bevacizumab and synergize with chemotherapies in multiple tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P001.
Abstract P02-04: BDTX-1535, a CNS penetrant MasterKey inhibitor of common, uncommon and resistant EGFR mutations, demonstrates in vivo efficacy and has potential to treat osimertinib-resistant NSCLC with or without brain metastases
Authors: Lucas Matthew C. , Merchant Melinda S. , O'Connor Matthew , Cook Carl , Smith Sherri , Trombino Anthony , Zhang Wu-Yan , Visiers Irache , Tith Kate , Foroughi Reza , Waters Nigel , Wrona Iwona , Pickard Michael , Eathiraj Sudharshan , Witt Karsten , Roberts Christopher , Humphrey Rachel , Buck Elizabeth 
Published: December 2021

Abstract
NSCLC accounts for approximately 85% of lung cancer cases worldwide. NSCLC harboring EGFR mutations constitutes 10-20% of all lung cancer cases in Europe and North America, and up to 50% of those in Asia. The majority (80-90%) of these mutations are either Exon19del or L858R. Uncommon EGFR mutations, of which G719X, S768I and L861Q are amongst the most frequent, account for 10-20% of EGFR mutations in NSCLC. Additionally, secondary EGFR mutations such as C797S that emerge during treatment with osimertinib occur in ~10% of patients. Current generation EGFR inhibitors with efficacy against common, uncommon and/or resistance mutations are either poorly brain penetrant or do not have broad spectrum activity against multiple mutations. BDTX-1535 is an irreversible, spectrum selective MasterKey inhibitor of common, uncommon and resistance EGFR mutations such as G719X and C797S that occur in NSCLC (IC50&lt;10nM). BDTX-1535 is differentiated from many EGFR inhibitors by its CNS-penetrating properties. BDTX-1535 has a Kpuu, defined as the ratio of the unbound brain tissue concentration over the unbound plasma concentration, of 0.8 in rat. In studies of EGFR Exon19del+C797S, BDTX-1535 achieved pEGFR suppression exceeding 24 hours in vitro and following a single dose in vivo. BDTX-1535 has demonstrated robust tumor growth inhibition and regressions in multiple pre-clinical models, including PDX intracranial models. Thus, BDTX-1535 has potential to treat patients with NSCLC harboring a broad range of mutations, both common and uncommon, as well as those associated with resistance to the current standard of care TKIs. The CNS penetrating properties may help to treat CNS metastases or to prevent them from occurring. BDTX-1535 is currently being evaluated in IND-enabling studies.
Citation Format: Matthew C. Lucas, Melinda S. Merchant, Matthew O'Connor, Carl Cook, Sherri Smith, Anthony Trombino, Wu-Yan Zhang, Irache Visiers, Kate Tith, Reza Foroughi, Nigel Waters, Iwona Wrona, Michael Pickard, Sudharshan Eathiraj, Karsten Witt, Christopher Roberts, Rachel Humphrey, Elizabeth Buck. BDTX-1535, a CNS penetrant MasterKey inhibitor of common, uncommon and resistant EGFR mutations, demonstrates in vivo efficacy and has potential to treat osimertinib-resistant NSCLC with or without brain metastases [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-04.
Abstract P057: The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin
Authors: Krastev Dragomir , Li Shudong , Sun Yilun , Pommier Yves , Ramadan Kristijan , Lord Christopher J. 
Published: December 2021

Abstract
Poly-(ADP-ribose) polymerase inhibitors (PARPi) elicit anti-tumour activity in homologous recombination defective cancers by promoting cytotoxic, chromatin-bound, “trapped” PARP1. How cells process trapped PARP1 remains unclear. By exploiting wild-type or trapping-resistant PARP1 transgenes combined with either a rapid immunoprecipitation mass-spectrometry of endogenous proteins (RIME)-based approach or PARP1 Apex2-proximity labelling linked to mass-spectrometry, we generated proteomic profiles of trapped and non-trapped PARP1 complexes. This combined approach identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase (aka VCP). Subsequent experiments demonstrated that upon trapping, PARP1 is SUMOylated by the SUMO-ligase PIAS4 and subsequently ubiquitinated by the SUMO-targeted E3-ubiquitin ligase, RNF4, events that promote p97 recruitment and p97 ATPase-mediated removal of trapped-PARP1 from chromatin. Consistent with this, small molecule p97 complex inhibitors, including a metabolite of the clinically-used drug disulfiram, CuET that acts as a p97 sequestration agent, prolong PARP1 trapping and thus enhance PARPi-induced cytotoxicity in homologous recombination defective tumour cells and patient-derived tumour organoids. Taken together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 from chromatin and the response of homologous recombination defective tumour cells to PARPi.
Citation Format: Dragomir Krastev, Shudong Li, Yilun Sun, Yves Pommier, Kristijan Ramadan, Christopher J. Lord. The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P057.
Abstract P083: Metastatic NSCLC -Re-challenging with first generation TKI after a drug free holiday after resistance to 3rd generation TKI
Authors: Acharya Suryakanta 
Published: December 2021

Abstract
BACKGROUND Lung cancer is the most common cancer worldwide in males & a good number of patients present with metastatic disease. Though EGFR mutated patients respond to EGFR TKIs, resistance develops ultimately. Overcoming 3rd generation EGFR TKI resistance is a big challenge. METHOD 20 patients of metastatic adenocarcinoma, confirmed with core biopsy & IHC (EGFR positive) were offered Erlotinib initially. Osimertinib was offered to those who developed EGFR TKI resistance due to T790M mutation (10 cases). All 10 patients eventually developed resistance to Osimertinib. All patients were given 3 months drug free holiday & then re-challenged with Erlotinib. RESULT 4 out of 10 (40%) patients responded to the therapy. 6 patients had progression & were managed by systemic chemotherapy & radiation. CONCLUSION Literature shows up to 50% metastatic adenocarcinoma, EGFR positive patients who had developed EGFR TKI resistance to 1st & 3rd generation TKIs, responds to re-challenge with first generation TKI after a drug free holiday. In this series 40% patients responded. This approach should be tried & non-responders can be offered systemic chemotherapy & radiation.
Citation Format: Suryakanta Acharya. Metastatic NSCLC -Re-challenging with first generation TKI after a drug free holiday after resistance to 3rd generation TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P083.