bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B163: Discovery and characterization of OKI-219, an orally bioavailable H1047R-mutant-selective inhibitor of PI3Kα
Authors: Taylor Molly A , Zhao Qian , Mareska David , Hoh Maria , Izrayelit Yevgeniy , Litwiler Kevin , Boys Mark L , Woessner Rich , Walker Duncan , Diamond Jennifer , Winkler James D 
Published: December 2023

Abstract
Mutations in PI3Kα lead to constitutive activation of the PI3K/AKT/mTOR pathway and are found in approximately 13% of human cancers, with the PI3KαH1047R mutation being the most common. Targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies. However, treatment with non-mutant selective PI3Kα inhibitors, such as alpelisib, is associated with significant toxicities such as hyperglycemia due to on-target inhibition of the wild-type enzyme, which often leads to dose modification or discontinuation. Therefore, there is a significant need to develop new PI3Kα-targeted therapies that can avoid or minimize on-target toxicity and improve the safety and clinical benefit for patients.  OKI-219 is a PI3KαH1047R mutant-selective inhibitor, with ~100-fold cellular selectivity for the H1047R mutation over wild-type and biochemical selectivity across a 412 kinase panel, with no other kinases showing &gt;30% inhibition at 1 µM. In vitro, OKI-219 drives decreased phosphorylated AKT (pAKT) and decreased proliferation selectively in PI3KαH1047R mutant cell lines across several tumor types. In vivo, as a monotherapy, OKI-219 demonstrates dose-dependent antitumor activity in multiple human CDX and PDX tumor xenograft models, with regression rates up to 100% in PI3KαH1047R heterozygous (T47D) and homozygous (SUM185PE) CDX models, at doses that show no sign of the metabolic dysfunction (increased glucose or insulin) that is associated with wild-type protein inhibition. The in vivo antitumor activity correlates with pathway inhibition, measured by decreased pAKT in tumors. In addition to the monotherapy efficacy observed, OKI-219 in combination with the selective estrogen receptor degrader (SERD) fulvestrant showed significant combination benefit leading to tumor regressions in the H1047R-mutated ER+HER2- breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. These data support the hypothesis that OKI-219 will offer improved efficacy and a wider therapeutic window compared to non-mutant selective PI3Kα inhibitors. This hypothesis will be tested, as OKI-219 is moving into clinical investigation.
Citation Format: Molly A Taylor, Qian Zhao, David Mareska, Maria Hoh, Yevgeniy Izrayelit, Kevin Litwiler, Mark L Boys, Rich Woessner, Duncan Walker, Jennifer Diamond, James D Winkler. Discovery and characterization of OKI-219, an orally bioavailable H1047R-mutant-selective inhibitor of PI3Kα [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B163.
Abstract B175: In-vitro multicellular 3D-Spheroid model demonstrates the synergistic effect of 2-domain soluble FMS-like Tyrosine Kinase-1 (2d-sFlt-1) for breast cancer targeted therapies
Authors: Mutahar Adel Zaid I. 
Published: December 2023

Abstract
Using a conventional 2D-culture model, the anti-cancer drug failure rate was approximately 95%. Thus, incorporating in-vitro 3D models that better mimic in-vivo conditions became a central focus of drug discovery and regenerative medicine. Drug screening on triple-negative breast cancer (TNBC) with paclitaxel, doxorubicin alone or in combination with 2d-sFlt-1 revealed 28, 17, and 8-fold increase in the cytotoxicity effect using 2D-culture compared to 3D-spheroids. Tumor spheroids treated with 2d-sFlt-1 in combination with paclitaxel revealed a 13.5-fold higher response than paclitaxel alone. The targeted therapy was validated by a significant decrease in the formation of blood vessels either in tube formation or 3D-angiogenesis assays in endothelial-tumor cells co-cultured spheroids. The cytotoxicity effect of paclitaxel on 3D-tumor spheroids was enhanced with 2d-sFlt-1 (58% of dead cells) compared to (33% of dead cells) in paclitaxel alone. Furthermore, the antiproliferative effect of paclitaxel was significantly enhanced by combinatorial treatment with 2d-sFlt-1 (p&lt;0.0001) compared to bevacizumab (p&lt;0.05). Immunohistochemistry of 3D-tumor spheroids revealed inhibition in the expression of Ki-67 in combinatorial treatment. The increase in the migration rate of TNBC was significantly inhibited by combinatorial treatment as evidenced in 2D and 3D-invasion assays. Further, immunofluorescence of 3D-spheroids showed downregulation of EMT markers (E. Cadherin, vimentin, cortactin, and paxillin) in response to combinatorial treatment compared to paclitaxel alone. Moreover, inhibition of FAK expression upon 2d-sFlt-1 treatment was exhibited either in endothelial cells, MDA-MB231, or co-cultured spheroids. Expression of vascular endothelial growth factor (VEGF) was also decreased in combinatorial treatment as evidenced by ELISA. qPCR of 3D-spheroids revealed the downregulation of EMT genes (N-cadherin, SNAIL, and TWIST) and upregulation of E-cadherin in combinatorial treatment. These findings demonstrate the antiangiogenic and anti-metastatic properties of 2d-sFlt-1 on TNBC. We conclude that multicellular 3D spheroids for bioengineering tumor models are promising in vitro animal-free models for cancer therapies and regenerative medicine.
Citation Format: Adel Zaid I. Mutahar. In-vitro multicellular 3D-Spheroid model demonstrates the synergistic effect of 2-domain soluble FMS-like Tyrosine Kinase-1 (2d-sFlt-1) for breast cancer targeted therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B175.
Abstract C003: A quantitative mass spectrometry workflow for highly multiplexed measurement of immunomodulatory proteins to support immunotherapy clinical trials
Authors: Ousji Ons , Jang Anne , Genovesi Luca , Dupuis Nicholas , Geib Timon , Pottiez Gwenael , Schirm Michael 
Published: December 2023

Abstract
Background: Since the approval of the first immune checkpoint-directed immunotherapies, it has been well-known that the efficacy of these therapies has been limited to a subset of cancer patients. As the number of new potential immunotherapy targets has grown, including novel combination therapy strategies, improved immune-related biomarker measurement has played a key role in understanding novel mechanisms of action and response to drugs. To support these efforts, we have developed an analytically validated assay for the multiplexed quantitation of up to 113 immunomodulatory proteins in various matrices (e.g., human plasma, PBMC, cells, or tissue) based on anti-peptide immunoaffinity capture followed by LC-MRM mass spectrometry analysis.
Methods: Remnant samples from commercial biobanks were acquired in a variety of solid tumor indications. Briefly, matrices were denatured, reduced, alkylated, and digested using trypsin. Immunoaffinity capture of the peptide targets consisted of overnight incubation of the digested sample with anti-peptide antibodies coupled to protein G magnetic beads, followed by automated washing and elution of the peptides from the antibodies using the KingFisher platform. The peptides were analyzed in a multiplexed method by LC-MRM mass spectrometry. Endogenous levels for each target were measured relative to a stable isotopically labeled peptide standard.
Results: In panel experiments, we found that the targets can be quantified precisely and accurately over 3 orders of magnitude with an intra-/inter-assay precision and accuracy of less than 20%. In total, 107 peptide targets were detected endogenously in cell lines. We expand on these data with analysis of solid tumor FFPE specimens where the results will be compared to immunohistochemical staining for selected targets.
Conclusions: This study shows how multiplex immunoaffinity methods can complement classical methods of tissue-based protein expression for simultaneous and quantitative interpretation of protein levels.
Citation Format: Ons Ousji, Anne Jang, Luca Genovesi, Nicholas Dupuis, Timon Geib, Gwenael Pottiez, Michael Schirm. A quantitative mass spectrometry workflow for highly multiplexed measurement of immunomodulatory proteins to support immunotherapy clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C003.
Abstract C014: Pan-cancer analysis portrays NVL as a diagnostic and prognostic biomarker
Authors: Datta Mousumi , Nayak Dr. Aditi 
Published: December 2023

Abstract
NVL (also known as NVL2), an AAA+ ATPase, has recently been linked with various cancers. By systematic bioinformatics analyses, here we predict the prospect of NVL as a cancer biomarker. Our pan-cancer analyses reveal that NVL is overexpressed in cancers [GEPIA and UALCAN (TCGA) databases] and the top five cancers with elevated expression (more than twofold) of NVL are Breast Invasive Carcinoma, Testicular Germ Cell Tumors, Cholangiocarcinoma, Diffuse large B cell lymphoma, and Thymoma. NVL is also highly expressed in all stages of most cancers. Additionally, this high expression was found to be correlated to the poor survival of cancer patients (Kaplan-Meier Plotter and OncoDB databases). Since, genetic alteration is one of the major cause of cancer, we investigated mutation and copy number amplification status (cBioPortal and COSMIC databases) of NVL across the cancers. Many potential mutation sites were predicted (cBioPortal and COSMIC databases) and most strikingly, four mutation sites at the ATPase domain of NVL. This signifies that these are the mutations that might have role in carcinogenesis. The copy number amplification study also revealed the high amplification percentage of NVL across different cancers. We further focused on the functional characteristics of the protein NVL across cancers. The protein-protein interaction analyses found the proteins like SKIV2L2, WDR12, WDR74, UTP18, NAT10, TERT, DKC1, GTPBP4, BOP1, TEP1 directly interact with NVL. The top canonical pathways of NVL also indicate that NVL has crucial functions in cancer cell proliferation (DAVID). We, therefore, surmise that NVL could be considered as a potential diagnostic and prognostic marker for multiple cancers and a very promising biomarker and target for cancer.
Citation Format: Mousumi Datta, Dr. Aditi Nayak. Pan-cancer analysis portrays NVL as a diagnostic and prognostic biomarker [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C014.
Abstract C016: Evaluating clinical biomarkers of FHD-286, a potent and selective inhibitor of BRG1/BRM, in metastatic uveal melanoma
Authors: Wan Jessica , Horrigan Kim , Elliott GiNell , Johannessen Liv , Collins Mike , Lazar Alexander J. , Corrigan Dillon , Patriquin Caitlin , Agresta Sam , Piel Jessica , Hentemann Martin 
Published: December 2023

Abstract
The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates chromatin accessibility and gene expression through its ATP-dependent remodeling activity. FHD-286, a first-in-class compound that potently and selectively inhibits the ATPase components of the BAF complex, BRG1 and BRM, was evaluated in a Phase I dose escalation in subjects with metastatic uveal melanoma (mUM) (FHD-286-001). The pharmacodynamics of FHD-286 were assessed to demonstrate proof-of-mechanism and understand the downstream molecular and clinical impact of BRG1/BRM inhibition. In addition, circulating tumor DNA (ctDNA) was evaluated as an early predictor of overall survival benefit. Seventy-three subjects were on a daily dosing regimen ranging from 2.5 to 10 mg or an intermittent regimen of 1-week on/1-week-off ranging from 10 to 22.5 mg. Tumor biopsies were collected at screening and either Cycle 3, or end of treatment. Biomarker changes in the tumor were observed by histological assessment, by IHC/IF biomarker assays, and RNA sequencing. Observations were suggestive of a differentiation effect by FHD-286 on the tumor cells, including a decrease in stemness genes and an increase in mature melanocytic markers. Evidence of necrosis and a trend of decreasing tumor cell density were also seen. In addition, ctDNA was measured in serial plasma samples using a targeted NGS panel. A reduction in ctDNA was shown in approximately 50% of subjects, which correlated with an increased overall survival benefit. Lastly, serial blood samples collected in Paxgene RNA tubes were analyzed by RNA sequencing. A robust dose-dependent gene signature was identified as a peripheral readout of target engagement at steady-state in both dosing regimens and across dose cohorts. In summary, we observed changes in the tumor cells at the biopsy site and ctDNA that suggest FHD-286 has a biological impact on uveal melanoma that may lead to clinical benefit. Given the limitations and challenges to obtain tumor biopsies from every subject and at a frequent rate, the identified PD gene signature in the blood is a valuable tool to measure target engagement in this study, and other potential solid tumor indications.
Citation Format: Jessica Wan, Kim Horrigan, GiNell Elliott, Liv Johannessen, Mike Collins, Alexander J. Lazar, Dillon Corrigan, Caitlin Patriquin, Sam Agresta, Jessica Piel, Martin Hentemann. Evaluating clinical biomarkers of FHD-286, a potent and selective inhibitor of BRG1/BRM, in metastatic uveal melanoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C016.
Abstract C024: Trial in progress: Phase 1 study of BAL0891 as monotherapy and in combination with chemotherapy in patients with advanced solid tumors
Authors: Kummar Shivaani , Barve Minal , Feldman Eric , Ma Seunghyun , Merchan Jaime , Im Seock-Ah , Rha Sun Young 
Published: December 2023

Abstract
Background: BAL0891 is a first-in-class small-molecule mitotic checkpoint inhibitor (MCI) that targets threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) to disrupt spindle assembly checkpoint (SAC) regulation and induce tumor cell death. It has a more potent anti-tumor activity as compared to TTK-specific inhibitors due to its combined prolonged effect on TTK and transient effect on PLK1. In preclinical studies, BAL0891 demonstrated potent anti-tumor activity as a monotherapy and in combination with paclitaxel and carboplatin. In the first-in-human microdose study of TTK-CS-001 in healthy subjects, key BAL0891 pharmacokinetic (PK) parameters were investigated (i.e., clearance, half-life, exposure), and no safety signals were detected.
Trial design: This clinical trial is a multiple-cohort, open-label phase 1 study with 3 dose-escalation substudies, investigating intravenous (IV) BAL0891 as monotherapy, and in combination with carboplatin or paclitaxel, in patients with advanced solid tumors.
Primary objectives: 1) To evaluate safety/tolerability 2) To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BAL0891 monotherapy and in combination with carboplatin/paclitaxel.
Eligibility: Patients ages ≥18 years with advanced/metastatic solid tumors that are refractory to, or intolerant of existing therapy may participate in this study. Patients enrolled in dose level ≥4 of Substudy 1 and all patients in Substudies 2 and 3 must have measurable disease.
Substudy 1: Monotherapy BAL0891: IV doses of BAL0891 on Days 1 (D1) and 8 (D8) every 3 weeks (Q3W). A Bayesian logistic regression model (BLRM) will guide dose escalations, with 8 nominal DLs of 5/10/20/40/80/160/320/480 mg.
Substudy 2: Phase 1 BAL0891 D1, D8 + carboplatin AUC5-6 D1 Q3W.
Substudy 3: Phase 1 BAL0891 D1, D15 + paclitaxel 70-80 mg/m2 D1, D8, D15 Q4W. Substudies 2 and 3 may begin once the maximum tolerated dose (MTD) of BAL0891 monotherapy has been established or at the first signs of expected target toxicity and/or efficacy with monotherapy. Enrollment began in February 2023 and is ongoing in the United States and South Korea. Clinical trial information; NCT05768932
Citation Format: Shivaani Kummar, Minal Barve, Eric Feldman, Seunghyun Ma, Jaime Merchan, Seock-Ah Im, Sun Young Rha. Trial in progress: Phase 1 study of BAL0891 as monotherapy and in combination with chemotherapy in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C024.
Abstract C029: Phase Ib/II open label, multi-arm, parallel cohort dose finding and expansion study of NUC-3373 in combination with pembrolizumab in patients with advanced solid tumors or docetaxel in patients with lung cancer (NuTide:303)
Authors: Wilson Richard H , Thistlethwaite Fiona , McKissock Fiona G , Oelmann Elisabeth , Bloss Jeffrey D , Spicer James F , Middleton Gary 
Published: December 2023

Abstract
Background: NUC-3373 is a phosphoramidate transformation of fluorodeoxyuridine monophosphate (FUDR-MP) designed to replace fluoropyrimidines, such as 5-FU, which exert their activity via inhibition of thymidylate synthase (TS) and disruption of DNA synthesis and repair. Intracellular cleavage of NUC-3373 releases the anti-cancer metabolite FUDR-MP, thereby potentially improving the therapeutic ratio of 5-FU whilst reducing the practical barriers associated with 5-FU administration. In addition to generating high intracellular levels of FUDR-MP and being a potent inhibitor of TS, pre-clinical data have shown that NUC-3373 can enhance the activity of immunotherapy agents by promoting the release of damage associated molecular patterns, activating a natural killer cell response and reducing inhibitory signals on T-cells.
Methods: NuTide:303 is a Phase Ib/II open label, multi-arm, parallel cohort dose finding and expansion study to assess the safety, PK and efficacy of NUC-3373 given in combination with leucovorin (LV) and either (i) pembrolizumab in patients (pts) with solid tumors in Module 1 or (ii) docetaxel in pts with non-small cell lung cancer (NSCLC) or pleural mesothelioma in Module 2. Both modules consist of dose-validation (Phase Ib) and dose-expansion (Phase II). The Phase Ib part will determine the MTD, safety and tolerability along with preliminary efficacy of the combinations (in 6 - 20 pts). In the Phase II part, an additional 20-40 pts will be added. In both modules, pts with measurable disease and ECOG PS 0-1 are eligible. For Module 1, pts diagnosed with any solid tumor who have progressed on ≤2 prior lines of therapy for advanced/metastatic disease (including 1 prior line of an immunotherapy-containing regimen), and for whom pembrolizumab treatment would be appropriate, are eligible. For Module 2, pts with advanced/metastatic NSCLC or pleural mesothelioma who have progressed on, or were unable to tolerate, ≤2 prior lines of chemotherapy-containing regimens for advanced/metastatic disease are eligible. Additional modules combining other agents with NUC-3373 + LV are being planned. Clinical trial information: NCT05714553
Citation Format: Richard H Wilson, Fiona Thistlethwaite, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, James F Spicer, Gary Middleton. Phase Ib/II open label, multi-arm, parallel cohort dose finding and expansion study of NUC-3373 in combination with pembrolizumab in patients with advanced solid tumors or docetaxel in patients with lung cancer (NuTide:303) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C029.
Abstract C034: First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors
Authors: Simpkins Fiona , Schneider Reva , Mahipal Amit , LoRusso Patricia , Miller Crystal , Brown Eric , Carleton Mike , Gullbo Joachim , Mirza Nadeem Q 
Published: December 2023

Abstract
Background: ATRN-119 is an oral and highly selective nanomolar inhibitor of Ataxia Telangiectasia and Rad3- related (ATR) kinase, an enzyme that is activated by replication stress and DNA damage and prevents the collapse of DNA replication forks into double strand breaks. ATRN-119 is being studied in advanced solid tumors with dysregulated components of the DNA damage response (DDR) based on the hypothesis that these tumors will be more susceptible to ATR inhibition. Single agent ATRN-119 demonstrates increased cytotoxicity in vitro against a broad spectrum of human colon, breast, pancreatic, sarcoma, ovarian and prostate cancer cell lines that harbor genomic alterations of DDR genes. In vivo, ATRN-119 has demonstrated tumor growth inhibition in human castration-resistant prostate cancer and human colon cancer cell line-derived xenografts (CDX) mice models, and in BRCA mutant high grade serous ovarian cancer patient derived xenografts (PDXs).
Trial design: This is a first-in-human Phase 1/2a open-label study (NCT04905914) to evaluate safety, tolerability, pharmacokinetics (PK), and preliminary e!cacy of oral daily ATRN-119 in subjects with advanced solid tumors, conducted in 2 parts. Part 1 consists of a 3+3 dose escalation design at up to 6 dose levels to evaluate the tolerability, PK, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of repeated daily doses of ATRN-119. Enrollment in Part 1 is ongoing. Subjects must be ≥12 years old with advanced solid tumor, have documented DDR mutations, or advanced Merkel cell carcinoma, must have failed at least one prior standard treatment, have ECOG performance status of 0 or 1, with a life expectancy &gt; 3 months. Primary objective is safety/tolerability and secondary objective is efficacy. After determination of the MTD or maximum feasible dose (MFD) in Part 1, Part 2 will enroll up to 30 additional subjects. The trial is currently recruiting across 4 locations in the United States. Clinical trial identification: ClinicalTrials.gov Identifier: NCT04905914
Citation Format: Fiona Simpkins, Reva Schneider, Amit Mahipal, Patricia LoRusso, Crystal Miller, Eric Brown, Mike Carleton, Joachim Gullbo, Nadeem Q Mirza. First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C034.