bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 914: Activity of SGN-B6A in patient-derived xenograft models of non-small cell lung cancer
Authors: Lyon Robert P. , Gosink John J. , Hale Christopher J. , Stilwell Jackie L. , Allred Sean , Hensley Kelly M. , Kumar Vineet , Patilea-Vrana Gabby , Nazarenko Natalya 
Published: July 2021

Abstract
The integrins are a large family of cell surface receptors with diverse roles in cellular adhesion, motility, and cytokinesis. Functional integrins exist as heterodimers consisting of single alpha and beta chains. Within this family, integrin beta-6, which dimerizes exclusively with isoform alpha-v, is expressed constitutively at low levels in numerous epithelial tissues and induced by tissue injury due to its role in tissue remodeling and wound repair. Numerous solid tumors, including non-small cell lung cancer (NSCLC), have been reported to overexpress integrin beta-6. Its role in tissue remodeling is believed to be the function that malignant cells exploit through its overexpression, allowing them to become more invasive into surrounding healthy tissue. Integrin beta-6 has also been reported to be among the integrins that can promote the epithelial to mesenchymal transition as well as provide resistance to anoikis, thus increasing the metastatic potential of malignant cells expressing it. SGN-B6A is an investigational antibody-drug conjugate (ADC) targeting integrin beta-6 to deliver the clinically validated payload monomethyl auristatin E (MMAE). We have previously presented data illustrating the antitumor activity of SGN-B6A in cell line-derived xenograft models originating from multiple carcinoma indications. Here we present results from a study of SGN-B6A activity dosed weekly at 3 mg/kg in patient-derived xenograft models of NSCLC, representing both squamous and adenocarcinoma histology. These results suggest that SGN-B6A is a promising ADC for the treatment of NSCLC and support further clinical investigation in the ongoing Phase I study (NCT04389632).
Citation Format: Robert P. Lyon, John J. Gosink, Christopher J. Hale, Jackie L. Stilwell, Sean Allred, Kelly M. Hensley, Vineet Kumar, Gabby Patilea-Vrana, Natalya Nazarenko. Activity of SGN-B6A in patient-derived xenograft models of non-small cell lung 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 914.
Abstract 929: A novel STAT3 inhibitor directly targeting STAT3 N-terminus simultaneously abrogates the nuclear and mitochondrial STAT3 activities leading to highly potent anti-cancer efficacy on the breast cancer
Authors: Kang Jinsuk 
Published: July 2021

Abstract
STAT3 functions are largely bifurcated: (1) STAT3 activated by Y705 phosphorylation (pY705) regulates target-gene expression in nucleus. (2) STAT3 activated by S727 phosphorylation (pS727) supports a electron transport complex (ETC) in mitochondria. Constitutive activation of STAT3 has long been considered to correlate with activation of diverse oncogenic pathways, which is a promising target for anti-cancer agents, but clinical therapeutic options are still unsatisfactory. Here we discovered a highly novel small-molecule inhibitor, JW-STAT3i directly binding to STAT3 N-terminal domain: 1) Through the cancer cell line panel screening, JW-STAT3i shows strong anti-cancer potency on various cancer cell lines including the breast cancer cell lines. 2) Anti-cancer mechanism of JW-STAT3i was elucidated: Firstly, the JW-STAT3i impairs pY705-STAT3 to abrogate pro-tumorigenic transcriptional programs mediated by STAT3. Secondly, JW-STAT3i also blocks pS727-STAT3 leading to mitochondrial dysfunction and AMPK activation. Consequently, JW-STAT3i treated cancer cells undergo growth arrest and apoptosis. 3) We further validated JW-STAT3i efficacy using cancer cell line- and patient-derived xenograft models whose response is well-correlated with the predictive biomarkers identified. Accuracy of in vivo efficacy in selected breast cancer PDX models based on predictive biomarker (estimated responders and non-responders) was very high. 4) We also demonstrated that JW-STAT3i shows a strong synergy with anti-PD-L1 antibody by induction of anti-tumorigenic immune environment. In conclusion, JW-STAT3i possesses both negative and positive effects on cancer cell proliferation and anti-immunity respectively. Currently, JW-STAT3i is under preclinical development and highly expected to be a promising anticancer therapeutic option in the near future.
Citation Format: Jinsuk Kang. A novel STAT3 inhibitor directly targeting STAT3 N-terminus simultaneously abrogates the nuclear and mitochondrial STAT3 activities leading to highly potent anti-cancer efficacy on the breast 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 929.
Abstract 941: TAM receptors as potential therapeutic targets in NF2-related schwannomas and meningiomas
Authors: Dave Foram , Ammoun Sylwia , Hanemann C Oliver 
Published: July 2021

Abstract
Background: Mutations in the NF2 gene, which codes for the tumor suppressor Merlin, is responsible for the development of all Neurofibromatosis Type 2 (NF2)-related tumors including schwannomas and meningiomas. These tumors can also occur spontaneously in non-NF2 patients. The only available treatments for this group of tumors are surgery and radiosurgery/radiotherapy. Therefore, in a search of effective drug-based treatments for NF2-mutated schwannomas and meningiomas, we are investigating TYRO3, AXL and MERTK (TAM) receptors as new therapeutic targets.
Methods: The expression and activation of TAM receptors were investigated using human Merlin-deficient meningioma and schwannoma tissues compared to control by Western blotting. Infiltration of tumor associated macrophages and their correlation to TAM family receptors were investigated using immunofluorescence double staining and flow cytometry. To understand the role of TAM receptors in the pathogenesis of schwannomas and meningiomas, in vitro shRNA knock-down and pharmacological inhibition analysis were conducted using patient-derived schwannoma and meningioma cells.
Results: The results revealed overexpression and hyper-activation of AXL, MERTK, TYRO3 in human Merlin-deficient meningiomas and schwannomas. Meningiomas and schwannomas show a varied level of infiltration by M2 macrophages (CD163+) and TAM receptors are expressed on these CD163+ macrophages in addition to the tumor cells. The expression of MERTK correlates to the level of infiltrated CD163+ macrophages. MERTK forms a complex with TYRO3 in both meningioma and schwannoma tissues, and its expression is mandatory to maintain AXL and TYRO3 levels in both cell types. MERTK and AXL contribute to the increased proliferation and survival of schwannoma and meningioma primary cells in vitro. Pathological proliferation and survival of both cell types were successfully reversed by AXL inhibitor BGB324 (BerGenBio, FDA approved for AML) and MERTK inhibitor UNC2025 (preclinical) in vitro, with UNC2025 being more effective. TYRO3 did not affect the proliferation of either schwannoma or meningioma primary cells.
Conclusion: Our findings suggest that TAM receptors are aberrantly expressed and activated in human Merlin-deficient meningiomas and schwannomas. Infiltration of M2 macrophages may contribute to an overall increase in the expression of TAM receptors in these tumors. AXL and MERTK are important in schwannoma and meningioma pathogenesis and are potentially good therapeutic targets. MERTK inhibitor UNC2025 has the potential to be used as a common candidate for the treatment of NF2-related tumors.
Citation Format: Foram Dave, Sylwia Ammoun, C Oliver Hanemann. TAM receptors as potential therapeutic targets in NF2-related schwannomas and meningiomas [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 941.
Abstract 970: Gender-specific stratification of survival following immune checkpoint inhibitor therapy based on intratumoral expression of a B cell gene signature
Authors: Aragaki Adam K. , Hoffman-Censits Jean , Hahn Noah M. , McConkey David J. , Johnson Burles Avner 
Published: July 2021

Abstract
Despite intensive efforts there is still a great need to identify biomarkers that can accurately identify patients who will obtain the most clinical benefit from immune checkpoint inhibitor (ICI) therapy. High intratumoral CD8+ T cell gene signature (CD8TGS) expression, tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1) expression all enrich for response to ICI treatment across multiple cancer subtypes. Although high intratumoral B cell gene expression also correlated with ICI response in melanoma, whether it adds predictive value in other cancers is unknown. We analyzed tumor RNA sequencing data from the IMvigor 210 phase 2 clinical trial of atezolizumab in patients with advanced urothelial carcinoma to examine potential relationships between B cell gene expression and clinical outcomes. Tumors with high levels of both signatures (BCGS/CD8TS or B8T high/high) had the highest overall survival (OS) of all B8T groups. Surprisingly, the subset of tumors with B8T high/low expression patterns were associated with the worst OS. Moreover, the B8T cell signature stratified patients with high TMB, or high PD-L1, into subsets with differential OS outcomes. Whereas the B8T high/high tumors were associated with the best clinical outcomes in ICI treated men, they were not associated with better OS in ICI treated women. Conversely, women with B8T high/high tumors had the best clinical outcomes in non-ICI treated muscle invasive bladder cancer. Collectively, these data suggest that the B8T signature can enhance OS stratification in patients with advanced urothelial carcinoma who were treated with ICI therapy, and that sex-specific differences in the tumor immune microenvironment may drive disparate outcomes.
Citation Format: Adam K. Aragaki, Jean Hoffman-Censits, Noah M. Hahn, David J. McConkey, Burles Avner Johnson. Gender-specific stratification of survival following immune checkpoint inhibitor therapy based on intratumoral expression of a B cell gene signature [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 970.
Abstract 987: Ovarian carcinoma cells are susceptible to ferroptosis
Authors: Li Jing , Wong Oscar Gee , Cheung Annie Nga 
Published: July 2021

Abstract
Ovarian carcinoma (OC) is a malignancy with grave prognosis owing to its high recurrence rate and broad resistance to a variety of apoptosis-inducing chemotherapeutic agents. Induction of alternative, non-apoptotic cell death represents a novel strategy for anti-cancer therapies worldwide. Ferroptosis is a recently defined type of non-apoptotic cell death driven by the accumulation of iron-dependent lipid reactive oxygen species (ROS), resulting in membrane damage and cell rupture. Lines of evidence suggested that OC may be susceptible to ferroptosis. However, the exact effects mediated by ferroptosis and the underlying regulatory mechanisms in OC are not fully characterized. Herein, we sought to explore the susceptibility of a number of OC cell line models towards ferroptosis and investigate the possibility of enhancing conventional platinum-based chemotherapy with ferroptosis inducers. Ferroptosis inducers Erastin and RSL3 dose-dependently induced ferroptotic cell death in ovarian cancer cell lines OVCAR3 and TUOC1, hallmarked by a significant decrease of GSH level and increase of ROS and lipid peroxidation levels after treatment. Treatment by a lipid ROS scavenger ferrostatin-1 (Fer-1), but not by the apoptosis inhibitor Z-VAD-FMK, significantly rescued OVCAR3 and TUOC1 cells from Erastin- and RSL3- induced cell death. Additionally, Erastin and RSL3 could significantly promote cytotoxicity of cisplatin in a cisplatin-resistant ovarian cancer cells OVCA420. Collectively, our results indicate a crucial role of ferroptosis in susceptibility of ovarian carcinomas, suggesting a potential anticancer strategy.
Citation Format: Jing Li, Oscar Gee Wong, Annie Nga Cheung. Ovarian carcinoma cells are susceptible to ferroptosis [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 987.
Abstract 998: Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of cancer
Authors: Phillips Caroline , Woodcock Simon , Eagle Catherine , Saunders Andrew , Tilston Craig , Bhamra Inder , Armer Richard 
Published: July 2021

Abstract
Background: RXC004 is a porcupine inhibitor, and thus a potent and selective inhibitor of Wnt ligand-dependent signalling. RXC004 is currently being investigated in a safety and tolerability study in cancer patients with solid tumours (NCT03447470). Certain Wnt pathway alterations, including loss-of-function RNF43 mutations and RSPO gene fusions, result in higher levels of the Wnt receptor Fzd on the cell surface increasing Wnt-ligand dependent signalling. These alterations are implicated in colorectal and pancreatic cancer. We present pre-clinical data on the effects of RXC004 in genetically defined models of cancer.
Methods: RXC004 in vitro effects on the metabolic activity of both sensitive (genetically selected RNF43 mutant or RSPO fusion models) and insensitive (beta-catenin mutant model) colorectal and pancreatic tumour cells lines were assessed. To test if these effects translated in vivo, RXC004 was also evaluated in an in vivo FDG-PET study in an RSPO fusion tumour cell line. In addition, as we had previously noted that RXC004 caused cell differentiation in an RSPO fusion model, we studied if pre-treatment with RXC004 would affect subsequent tumour growth post RXC004 induced cell differentiation in vivo.
Results: In tumour cell lines in vitro, RXC004 significantly reduced glucose uptake only in genetically selected tumour cell lines. In vivo FDG-PET studies also showed a reduction in FDG-PET signals post 7 days treatment of 5mg/kg QD RXC004. Imaging demonstrated that MaxSUV (maximum standardised uptake value) decreased by 31% in RXC004 treated versus vehicle treated tumours, furthermore biodistribution of PET ligand was significantly inhibited in tumours post 7 days RXC004 treatment. Pre-treatment of RXC004 in an in vivo mouse xenograft model for 7 days resulted in a significant reduction in tumour growth when tumour fragments from these pre-treated mice were re-implanted into naïve mice (P&lt;0.05).
Conclusion: These data demonstrate that RXC004 monotherapy results in tumour cell differentiation accompanied by reduced metabolic activity in genetically selected tumours. RXC004-induced cell differentiation may therefore continue to provide patient benefit even post dosing. Moreover, FDG-PET imaging in clinical studies may allow early detection of the positive effects of RXC004 in a non-invasive manner, and prior to any changes in tumour volume by conventional RECIST measurements.
Citation Format: Caroline Phillips, Simon Woodcock, Catherine Eagle, Andrew Saunders, Craig Tilston, Inder Bhamra, Richard Armer. Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of 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 998.
Abstract CT257: Phase 3 multicenter randomized trial of PSMA PET/CT prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer [PSMA dRT]: Study Protocol
Authors: Calais Jeremie , Zhu Shaojun , Hrimas Nader , Eiber Matthias , Hadaschik Boris , Stuschke Martin , Herrmann Ken , Czernin Johannes , Kishan Amar U. , Nickols Nicholas G. , Elashoff David , Fendler Wolfgang 
Published: July 2021

Abstract
Background: Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). PSMA PET/CT is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET/CT thus has the potential to guide patient selection and the planning for dRT and improve patient outcomes.
Methods: This is a multicenter randomized phase 3 trial (NCT04457245). We will randomize 312 patients to proceed with standard dRT (control Arm, n=150), or undergo a PSMA PET/CT scan at the study site (both 18F-DCFPyL and 68Ga-PSMA-11 can be used) prior to dRT planning (intervention arm, n = 162). dRT will be performed at the treating radiation oncologist facility. In the control arm, dRT will be performed as routinely planned. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET/CT findings into the RT planning. Androgen deprivation therapy (ADT) is administered per discretion of the treating radiation oncologist and may be modified as a result of the PSMA PET/CT results. We assume that approximately 8% of subjects randomized to the PSMA PET arm will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the primary endpoint analysis. The primary endpoint is the success rate of patients with unfavorable IR and HR PCa after standard dRT versus PSMA PET-based dRT. Secondary Endpoints (whole cohort) include progression free survival (PFS), metastasis-free survival after initiation of RT, overall survival (OS), % of change in initial treatment intent and Safety.
Discussion: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa who receive dRT. In this trial the incorporation of PSMA PET/CT may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection as a biomarker and to personalizes the radiotherapy plan.
Citation Format: Jeremie Calais, Shaojun Zhu, Nader Hrimas, Matthias Eiber, Boris Hadaschik, Martin Stuschke, Ken Herrmann, Johannes Czernin, Amar U. Kishan, Nicholas G. Nickols, David Elashoff, Wolfgang Fendler. Phase 3 multicenter randomized trial of PSMA PET/CT prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer [PSMA dRT]: Study Protocol [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 CT257.
Abstract LB050: Modulation of innate and adaptive immunity in blood and tumor of patients receiving the SHP2 inhibitor RMC-4630
Authors: Chen Ariel Yung-Chia , Haura Eric , Pacheco Jose , Koczywas Marianna , Gordon Michael , Ulahannan Susanna , Burris Howard A. , Ou Sai-Hong Ignatius , Wang Judy S. , Riess Jonathan W. , McCoach Caroline , Capasso Anna , Quintana Elsa , Hayes Josie , Dua Richa , Bitman Bojena , Guerra Martha , Wang Hongfang , Wang Xiaolin , Janne Pasi A. 
Published: July 2021

Abstract
RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node in the RAS signaling pathway. In preclinical models, SHP2 inhibition not only directly inhibited tumor growth through suppression of tumor-intrinsic RAS signaling, but also resulted in transformation of the tumor immune microenvironment, characterized by an increase in CD8+T cell infiltrates and selective depletion of pro-tumorigenic M2 macrophages.
In this study, we evaluated pharmacodynamic biomarkers in blood and tumors from patients in the RMC-4630 phase I monotherapy clinical trial (NCT 03634982) by using flow cytometry and immunohistochemistry (IHC). Safety, PK and efficacy data are reported in a separate abstract.
Longitudinal analysis of immune cell phenotyping in blood was conducted in 35 patients. There was a trend for lower pre-study monocytic myeloid-derived suppressor cell (mMDSC) to be associated with a better clinical outcome on RMC-4630 therapy. While the proportion of circulating T cell and B cell populations did not change, both blood mMDSC and total monocytes were significantly reduced during RMC-4630 administration. Furthermore, tumor volumes changes, and the proportion of patients with SD versus PD, positively correlated with the ratio of mMDSCs to total monocytes on RMC-4630 treatment.
Inhibition of pERK was observed in a subset of patients. Three paired tumor biopsies from efficacy-evaluable patients, including 1 PR, 1 SD and 1 PD, were available for tumor microenvironment analysis by multiplexed-IHC assays. Increase in tumor infiltrating T cells in the tumors of one patient with a PR and another with SD was observed on RMC-4630 therapy. Inhibition of tumor PD-L1 expression and a decrease in M2 macrophages was also observed on treatment in the tumor biopsy of the PR patient.
Collectively, the preliminary clinical biomarker data supports the preclinical observations that SHP2 inhibition with RMC-4630 modulates both innate and adaptive anti-tumor immunity.
Citation Format: Ariel Yung-Chia Chen, Eric Haura, Jose Pacheco, Marianna Koczywas, Michael Gordon, Susanna Ulahannan, Howard A. Burris, Sai-Hong Ignatius Ou, Judy S. Wang, Jonathan W. Riess, Caroline McCoach, Anna Capasso, Elsa Quintana, Josie Hayes, Richa Dua, Bojena Bitman, Martha Guerra, Hongfang Wang, Xiaolin Wang, Pasi A. Janne. Modulation of innate and adaptive immunity in blood and tumor of patients receiving the SHP2 inhibitor RMC-4630 [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 LB050.