bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Circulating Tumor Cell–Expressed Prostate-Specific Membrane Antigen and Prostate-Specific Antigen Transcripts in Different Stages of Prostate Cancer
Authors: Cho Hyungseok , Byun Seok-Soo , Son Nak-Hoon , Chung Jae Il , Seo Won Ik , Lee Chan Ho , Morgan Todd M. , Han Ki-Ho , Chung Jae-Seung 
Published: April 2024

Abstract

Purpose:
Prostate-specific membrane antigen (PSMA)–based images, which visually quantify PSMA expression, are used to determine prostate cancer micrometastases. This study evaluated whether a circulating tumor cell (CTC)–based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in prostate cancer.

Experimental Design:
We prospectively enrolled 21 healthy individuals and 247 patients with prostate cancer [localized prostate cancer (LPCa), n = 94; metastatic hormone–sensitive prostate cancer (mHSPC), n = 44; and metastatic castration-resistant prostate cancer (mCRPC), n = 109]. The mRNA expression of six transcripts [PSMA, prostate-specific antigen (PSA), AR, AR-V7, EpCAM, and KRT 19] from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC.

Results:
CTC detection rates were 75.5%, 95.3%, and 98.0% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA [hazard ratio (HR), 3.35; P = 0.028) and PSA mRNA (HR, 1.42; P = 0.047] expressions were associated with BCR. Patients with mHSPC with high PSMA (HR, 4.26; P = 0.020) and PSA mRNA (HR, 3.52; P = 0.042) expressions showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expressions were significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance.

Conclusions:
PSMA and PSA mRNA expressions are associated with BCR in LPCa. In advanced prostate cancer, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.
Abstract CT088: EVT801, a novel selective VEGFR-3 inhibitor targeting tumor angiogenesis, is pursuing dose escalation stage of phase I first-in-human study
Authors: Gomez-Roca Carlos , Cassier Philippe , Fitzgerald Michael , Davenne Lise , Costantin Cristina , Rochaix Philippe , Delord Jean-Pierre , Friend John , Nizzardo Andrea , Tagliavini Alessia , Pergher Marco , Fons Pierre , Mandron Marie 
Published: April 2024

Abstract
Background: EVT801 is a highly selective, orally available VEGFR3 inhibitor that modulates tumor angiogenesis without inducing hypoxia, one of the main causes of cancer-associated immunosuppression. EVT801 has shown compelling efficacy as single agent in multiple in vivo models. In addition, combination of EVT801 and Immune Checkpoint Therapy (ICT) agents shows additive effects and thus holds promises for combination treatment without induction of hypoxia-induced immunosuppression.
Clinical trial design: A phase I clinical study (NCT05114668) is underway to evaluate safety, tolerability, pharmacokinetics of EVT801 and explore patient characterization which is key for further development. The phase I trial consists in two sequential stages. During the first stage, currently ongoing, EVT801 is orally administered to patients with advanced solid tumors in a multiple ascending dose study using an accelerated 3+3 design (1 patient per dose until grade 2 toxicities are observed) in up to 48 patients in 8 dose levels. The primary objective is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Stage 2 will focus on validation of this RP2D in two 6-patient cohorts diagnosed with 2 indications. In addition to conventional measures of safety, tolerability, efficacy, and pharmacokinetics, the phase I study employs a rich suite of biomarkers analysis using histology, transcriptomics and immunomonitoring to provide early insights into the pharmacological activity of EVT801. At end of September 2023, 20 patients have been treated in five different cohorts for EVT801 doses ranging from 50mg QD to 400mg BID. At this date, only 1 dose limiting toxicity was declared at the higher dose.
Conclusion: Collection of safety data on these first enrolled patients showed no safety alert which allows further dose escalation and reinforces the good safety profile of EVT801 observed during the preclinical toxicology studies.
Citation Format: Carlos Gomez-Roca, Philippe Cassier, Michael Fitzgerald, Lise Davenne, Cristina Costantin, Philippe Rochaix, Jean-Pierre Delord, John Friend, Andrea Nizzardo, Alessia Tagliavini, Marco Pergher, Pierre Fons, Marie Mandron. EVT801, a novel selective VEGFR-3 inhibitor targeting tumor angiogenesis, is pursuing dose escalation stage of phase I first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT088.
Abstract CT214: Paricalcitol addition to chemotherapy in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PINBALL)
Authors: Propper David , Jameson Gayle , Roe Denise , Wertheim Betsy , Von Hoff Dan , Borazanci Erkut H. 
Published: April 2024

Abstract
Background Vitamin D agonism has been shown in preclinical studies to decrease the production of collagen, decrease myeloid derived suppressor cells, and decrease regulatory T cells in pancreatic ductal adenocarcinoma (PDAC). Paricalcitol is a vitamin D analog used for vitamin D replacement for those with secondary hyperparathyroidism. Two individuals with PDAC who had been developed resistance gemcitabine based combination therapy had shown clinical benefit with the addition of paricalcitol. This clinical study was done to study the effect of adding paricalcitol to individuals with metastatic PDAC receiving gemcitabine based combination therapy (NCT04054362, NCT03415854) .
Methods Adults with a histologically- or cytologically-confirmed diagnosis of metastatic PDAC and who were previously untreated were eligible. Individuals received gemcitabine based combination- either gemcitabine plus nab-paclitaxel or gemcitabine plus nab-paclitaxel and cisplatin and had to either demonstrate progressive or stable disease. Paricalcitol was given at a fixed dose of 25 mcg IV three days a week. The combination continued until either disease progression or poor tolerance. The primary objective was to determine the clinical benefit of adding paricalcitol to gemcitabine based combination therapy for metastatic PDAC. Secondary objectives included assessing safety and pharmacodynamic through patient biopsies.
Results A total of 34 patients were enrolled across two sites. 16 patients received paricalcitol. The overall response rate was 0% ( CR, PR). Disease control rate at 9 weeks was 21.4% (CR+PR+ SD). PFS upon addition of paricalcitol was 1.6 months. OS upon addition of paricalcitol was 4.8 months. Grade 3/4 AE's attributed to paricalcitol include 13% thrombocytopenia; 19% anemia; 6% transaminitis; 6% pleural effusion; 6% ascites- all grade 3.
Conclusions The addition of paricalcitol demonstrated evidence of limited clinical benefit in individuals with metastatic PDAC receiving front-line gemcitabine based therapy. Paricalcitol was generally well tolerated. Tumor analysis is ongoing. Addition studies utilizing prospective treatment of paricalcitol for front line treatment of mPDAC are ongoing (NCT03520790). Trial funding provided by SU2C, CRUK, Lustgarten Foundation, and AACR.
Citation Format: David Propper, Gayle Jameson, Denise Roe, Betsy Wertheim, Dan Von Hoff, Erkut H. Borazanci. Paricalcitol addition to chemotherapy in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PINBALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT214.
Abstract LB022: Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model
Authors: Humtsoe Joseph O. , Pothukuchi Anita , Kang Hyunseok , Ha Patrick 
Published: April 2024

Abstract
Adenoid cystic carcinoma (ACC) is a rare type of salivary gland cancer. Despite the many advances made in helping understand the disease behavior and characteristics, the prevailing challenge in managing patients with ACC is the lack of clinically approved systemic therapy drugs to successfully treat those with advanced recurrent or metastatic disease. There are multiple promising candidate agents being evaluated preclinically and in early phase clinical trials, yet an effective drug with consistent overall response remains to be identified. AXL is a member of the TAM family of tyrosine kinase receptors, and its overexpression and activation is generally associated with poor prognosis and chemoresistance in many cancer types. Previous reports show AXL is significantly upregulated in a subset of ACC tumors. Here, we evaluate the tumor growth inhibition effects of a newly developed antibody-drug-conjugate targeting AXL (ADCT-601) in a xenograft ACC cell line model. MDA-ACC-01 cells express high levels of cell surface AXL as confirmed by biochemical analysis. The tumor growth inhibition of MDA-ACC-01 cell xenograft was tested in a single-dose drug administration study. Immunodeficient mice bearing ACC tumors were either injected with vehicle (n=7) or with ADCT-601 at 0.5 (n=9) or 1.0 mg/kg (n=7). ADCT-601 treatment with either 0.5 mg/kg or 1.0 mg/kg resulted in complete response (CR) for all tumor implants. To reaffirm the drug’s efficacy, we challenged the vehicle-treated tumor, prior to exceeding the tumor volume endpoint, with a single-dose of ADCT-601 at 1.0 mg/kg. Strikingly, by day 6 post-treatment, tumor volume began to shrink and eventually resulted in CR except in all but one case. These results demonstrate ADCT-601 is an effective drug with significant anti-tumor activity in our preclinical models and is worthy of additional investigation to determine its translational potential.
Citation Format: Joseph O. Humtsoe, Anita Pothukuchi, Hyunseok Kang, Patrick Ha. Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB022.
Abstract LB026: Exploring MCT4 inhibitor Ful-23 and cytarabine synergy in acute myeloid leukemia therapeutics
Authors: Wu Yong , Wu Ke , Vadgama Jay 
Published: April 2024

Abstract
In the ongoing pursuit of addressing the formidable challenge presented by Acute Myeloid Leukemia (AML) treatment, this comprehensive study delves into the intricate antileukemic effects of Ful-23, our newly developed Monocarboxylate Transporter 4 (MCT4) inhibitor. Positioned as a promising candidate, Ful-23's unique mechanisms and potential synergies with established chemotherapeutic agents, such as Cytarabine, are elucidated in this research. Intracellular alkalinization stands as a crucial factor contributing to the evasion of chemotherapy by cancer cells. It serves as the primary determinant for the heightened resistance exhibited by cancer cells against chemotherapy interventions. The investigation reveals the multifaceted impact of Ful-23 on AML cells, showcasing its capacity to induce intracellular lactate accumulation and acidification. These metabolic alterations correlate with a substantial inhibition of proliferation, as evidenced by an IC50 of approximately 0.55 μM, and a marked induction of apoptosis, particularly notable in the MV411 AML cell line. These findings underscore Ful-23's potential as a potent antileukemic agent with distinct cellular effects. A collaborative approach involves the combination of low concentrations of Ful-23 (0.312 μM) with Cytarabine (0.312 μM), revealing a significant enhancement in cytarabine-induced proliferation inhibition and apoptosis when Ful-23 is introduced concurrently. Importantly, the translational impact of these findings extends to a zebrafish model, utilizing both MV411 cells and transplanted primary AML patient-derived bone marrow cells. In the zebrafish AML model, the combination treatment of Ful-23 and Cytarabine demonstrates a significant enhancement in their respective antitumor effects compared to monotherapy, indicating a pronounced synergistic effect. This additional validation strengthens the clinical relevance of the observed synergistic antileukemic interactions between Ful-23 and Cytarabine. Essentially, this investigation advances our understanding of AML treatment dynamics, emphasizing the crucial role of MCT4 inhibition and elucidating the mechanism by which it leads to intracellular acidification in synergistic therapeutic approaches for this intricate and formidable disease.
Citation Format: Yong Wu, Ke Wu, Jay Vadgama. Exploring MCT4 inhibitor Ful-23 and cytarabine synergy in acute myeloid leukemia therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB026.
Abstract LB050: BRAF V600E is associated with the upregulation of CLDN1 in thyroid cancer
Authors: Orozco Andrea Ross , Meraz Eliakym Arámbula , Quiroz Anette Roxana Gastelum , Ortega Fred Luque , Alvarez Edith Eunice García , Arrazola Marco Álvarez , Hernández Karla Lizbeth Morales , Magallanes Noemí García 
Published: April 2024

Abstract
Thyroid carcinoma is the most prevalent endocrine neoplasm. The most recurrent mutation in thyroid cancer (TC) is the V600E substitution in BRAF, which induces the over-activation of the MAPK pathway. The interaction between this pathway and the deregulation of genes that facilitate tumorigenesis such as CLDN1 could be useful for decision-making related to surgical removal and the degree of initial resection; however, there is a lack of information on the association of CLDN1 expression with BRAF V600E. Objective. Evaluate the gene expression of CLDN1 in BRAF-mutated and BRAF-unmutated thyroid nodules. Methods. RT-qPCR was performed to assess BRAF genotyping (rs113488022) and CLDN1 expression in 94 thyroid nodule biopsy samples (TC=48). Clinicopathological data was retrieved to establish further associations. Results. Mutated BRAF thyroid nodules were found to be 7.14 ± 0.293 times more expressed than those without the mutation (p &lt 0.001, N=94). BRAF V600E mutation was identified in patients with TC exclusively. CLDN1 expression was 41.315 ± 0.554 times greater in patients with TC than in those without TC (p &lt 0.001). Heterozygous patients had a change factor of 6.8, whereas mutated homozygotes had a change factor of 7.5 (p &lt 0.001, N=94). CLDN1 mean expression is significantly higher in A allele carriers compared to normal homozygotes (p &lt 0.001). When analyzing just within the TC group, the behavior is maintained, suggesting a potential association between the mutated allele and the expression of these genes. Conclusion. CLDN1 is significantly upregulated in TC patients carrying the BRAF V600E mutation. BRAF V600E is only observed in patients with TC, implying a biological connection between them, which can be explained via MAPK; subsequent studies are needed to confirm the correlations.
Citation Format: Andrea Ross Orozco, Eliakym Arámbula Meraz, Anette Roxana Gastelum Quiroz, Fred Luque Ortega, Edith Eunice García Alvarez, Marco Álvarez Arrazola, Karla Lizbeth Morales Hernández, Noemí García Magallanes. BRAF V600E is associated with the upregulation of CLDN1 in thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB050.
Abstract LB067: Tumor-reactive CD8 TIL with an exhausted phenotype can be expanded and regress human tumors
Authors: Weinberg Andrew , Curti Brendan , Montler Ryan , Thalhofer Colin , Ballinger Elaine , Cross Jessica , Tran Eric , Sanjuan Nelson , Taylor Matthew , Fountain Christopher , Payne Roxanne , Cardia James , Morris Nicholas 
Published: April 2024

Abstract
Tumor-reactive human CD8 T cells are found predominantly in the tumor microenvironment with an exhausted phenotype (extremely high levels of CD39, PD-1, CTLA-4, and TIM-3). The tumor-reactive cells can be enriched from patients’ tumors by sorting CD8+ TIL that express both CD39 and CD103. Our unique expansion method allowed these phenotypically exhausted cells to grow from thousands into billions. After expansion the CD39 and CD103 Double Positive (DP) CD8 TIL can recognize/kill autologous tumor cells in vitro. We tested whether the CD8 DP TIL could recognize/kill autologous tumor in vivo using a xenograft model with immune-compromised mice that constitutively secrete human IL-2 (NOG-hIL-2). The CD8 DP TIL were able to persist long-term, traffic to the tumor site, recognize autologous tumor, and facilitate tumor regression. Human IL-2 was necessary for their long-term survival in the periphery and for tumor regression. These preclinical data were the basis for a human clinical trial design for the adoptive transfer of CD8 DP TIL (product termed, AGX148). We recently opened a Phase 1 clinical trial using the CD39/103 DP CD8 TIL in a first-in-human protocol for adults with solid tumors (NCT05902520). The trial design has three cohorts based on giving IL-2 for 2 weeks, 3 weeks, or 4 weeks after adoptive transfer with six patients/cohort (3 receiving DP TIL alone and 3 receiving DP TIL combined with PD-1 siRNA knockdown with the INTASYLTM compound PH-762). The first 3 patients have been treated and received 27, 40, and 8 billion DP TIL, respectively. All 3 patients had failed standard therapy prior to their enrollment, including checkpoint blockade. No serious adverse events were observed in the first three patients. Two of three patients had partial responses 29 days after treatment and the third patient had stable disease for &gt;56 days. Blood draws and tumor biopsies were obtained prior to and after treatment and we are currently assessing the CD8 T cell repertoire (TCRseq) and phenotype from these patient samples. In conclusion, this is the first study showing that CD8 T cells with an exhausted phenotype isolated from human tumors can be expanded to billions and induce tumor regression in vivo.
Citation Format: Andrew Weinberg, Brendan Curti, Ryan Montler, Colin Thalhofer, Elaine Ballinger, Jessica Cross, Eric Tran, Nelson Sanjuan, Matthew Taylor, Christopher Fountain, Roxanne Payne, James Cardia, Nicholas Morris. Tumor-reactive CD8 TIL with an exhausted phenotype can be expanded and regress human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB067.
Abstract LB153: Spatial transcriptomics of mouse parathyroid gland cells expressing an activating variant of gcm2
Authors: Bolel Priyanka , Pina Jeremie O. , Faucz Fabio R. , Weinstein Lee S. , Agarwal Sunita K. 
Published: April 2024

Abstract
Tumors of one or multiple parathyroid glands and elevated serum calcium and parathyroid hormone (PTH) are the common characteristics of primary hyperparathyroidism (PHPT). Genes associated with familial PHPT (hereditary parathyroid tumors) include - MEN1, CDKN1B, CDC73, RET, MAX and GCM2. The glial cells missing 2 (GCM2) gene functions as a transcription factor that is essential for parathyroid gland development. Heterozygous germline missense variants located within the C-terminal conserved inhibitory domain (CCID) of GCM2 have been reported in a subset of patients with familial PHPT. In functional assays, these missense variants enhance the transcriptional activity of GCM2, suggesting that GCM2 could act as a proto-oncogene in parathyroid neoplasia. A recurrent germline activating missense variant of GCM2, p.Y394S in patients with familial PHPT has been reported in various publications. To study the direct contribution of this missense variant in parathyroid neoplasia, we used the CRISPR/Cas9 system to generate a heterozygous germline knock-in of p.Y392S in the mouse Gcm2 gene (which corresponds to the human variant p.Y394S in GCM2). In GCM2-binding site mediated luciferase reporter assays, the mouse Gcm2 variant p.Y392S also exhibited the transcription enhancing effect that was observed for the human GCM2 p.Y394S variant. However, mice with this variant (Gcm2 +/Y392S) did not show obvious parathyroid tumors. Because the mouse Gcm2 variant p.Y392S exhibited enhanced transcriptional activity, we performed spatial transcriptomics of parathyroid glands from wildtype (WT) and Gcm2 +/Y392S mice to examine differentially expressed transcripts in parathyroid cells with the p.Y392S variant of Gcm2. Using the 10X Genomics Visium platform, spatially resolved RNA-seq analysis was performed on parathyroid gland cells of WT and Gcm2 +/Y392S mice specifically marked by the expression of Pth and Gcm2. Spatial transcriptomics and Pathway analysis was performed to evaluate transcripts with more than 2-fold increased expression in parathyroid cells from the p.Y392S variant of Gcm2 compared to WT. Further investigation of these genes and pathways in mouse and human parathyroid cells can provide insights into the functional consequences of GCM2 activating variants and the pathophysiology of parathyroid tumorigenesis.
Citation Format: Priyanka Bolel, Jeremie O. Pina, Fabio R. Faucz, Lee S. Weinstein, Sunita K. Agarwal. Spatial transcriptomics of mouse parathyroid gland cells expressing an activating variant of gcm2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB153.