bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB093: Low IGFBP7 expression identifies a subset of breast cancers with favorable prognosis and sensitivity to IGF-1 receptor targeting with ganitumab: Data from I-SPY2 and SCAN-B
Authors: Godina Christopher , Pollak Michael N. , Jernström Helena 
Published: April 2024

Abstract
Background and Hypothesis: To date, no IGF-1R targeting agent has shown clinical benefit in patients despite promising preclinical data. We hypothesized that Insulin-like growth factor binding protein-7 (IGFBP7) expression predicts response to Insulin-like growth factor-1 receptor (IGF-1R) targeting agents, for which there are no biomarkers predictive of efficacy. High IGFBP7 expression was previously associated with breast cancer progression.
Materials and Methods: The predictive value of IGFBP7 expression was interrogated in I-SPY2 (NCT01042379) for pathological complete response (pCR) to neoadjuvant treatment and in SCAN-B (NCT02306096) for clinical outcome. In I-SPY2, IGFBP7 expression was examined as a predictor of pCR to neoadjuvant chemotherapy alone and separately to the combination of chemotherapy plus ganitumab (anti-IGF-1R antibody) and metformin. Odds ratios (OR) and hazard ratios (HR) with 95% confidence interval (CI) were calculated with logistic and Cox regression, respectively.
Results: Higher IGFBP7 expression conferred lower odds of achieving pCR in the ganitumab/metformin plus chemotherapy arm, ORadj 0.38 (95% CI 0.17-0.80) but not in the chemotherapy-alone arm, adjusted OR 1.23 (95% CI 0.63-2.45; P interaction=0.016). In the ganitumab/metformin plus chemotherapy arm, 46.9% of patients with tumors in the lowest quartile of IGFBP7 expression achieved pCR compared to compared to only 5.6% in the highest quartile. In SCAN-B, higher IGFBP7 expression was associated with distant metastasis risk HRadj 1.41 (95% CI 1.16-1.73).
Conclusion: Low IGFBP7 gene expression identifies a subset of breast cancer patients for whom the addition of ganitumab and metformin to chemotherapy results in a significantly improved pCR rate compared to neoadjuvant chemotherapy alone. Furthermore, we add to prior evidence that high IGFBP7 expression is predictive of poor outcome.
Citation Format: Christopher Godina, Michael N. Pollak, Helena Jernström. Low IGFBP7 expression identifies a subset of breast cancers with favorable prognosis and sensitivity to IGF-1 receptor targeting with ganitumab: Data from I-SPY2 and SCAN-B [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 LB093.
Abstract LB096: Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma
Authors: Tomasova Kristyna , Seborova Karolina , Kroupa Michal , Horak Josef , Vodickova Ludmila , Rob Lukas , Hruda Martin , Mrhalova Marcela , Bartakova Alena , Bouda Jiri , Fleischer Thomas , Kristensen Vessela , Vodicka Pavel , Vaclavikova Radka 
Published: April 2024

Abstract
Impaired telomere length (TL) maintenance in ovarian tissue may play a pivotal role in epithelial ovarian carcinoma (OvC) onset. TL in either target or surrogate tissue (blood) is currently being investigated as a predictor in anti-OvC therapy or as a biomarker of the disease progression, respectively. There is presently an urgent need for an appropriate approach to chemotherapy response prediction. We performed a monochrome multiplex qPCR measurement of TL in peripheral blood and tumor tissues of 209 OvC patients. Methylation status and gene expression of shelterin complex and telomerase catalytic subunit (hTERT) were determined within tumor tissues by High-Throughput DNA methylation profiling and RNA sequencing (RNA-Seq) analysis, respectively. The patients sensitive to cancer treatment (n=46) had shorter telomeres in peripheral blood cells compared to those treatment-resistant (n=93; P=0.037). Cancer tissue TL lower than the median predisposed to better overall survival (P=0.002). Gene expression of TPP1, which recruits telomerase to telomeres, was positively associated with TL in tumor tissue (P=0.026). TL measured in peripheral blood cells could serve as a marker of platinum therapy response in OvC patients. Additionally, TL determined in tumor tissue provides information on OvC patients' overall survival. The study was financed by the project NPO (LX22NPO05102), the Czech Health Research Council (NU21-03-00145), and the Czech Science Foundation (21-27902S).
Citation Format: Kristyna Tomasova, Karolina Seborova, Michal Kroupa, Josef Horak, Ludmila Vodickova, Lukas Rob, Martin Hruda, Marcela Mrhalova, Alena Bartakova, Jiri Bouda, Thomas Fleischer, Vessela Kristensen, Pavel Vodicka, Radka Vaclavikova. Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma [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 LB096.
Abstract LB108: Specific plasma DNA end-motifs distinguish patients with lung adenocarcinoma versus benign nodules
Authors: Hyun Jason C. , Yip Shun H. , Swarup Neeti , Ramamurthy Raghuraman , Cheng Jordan C. , Choi Irene , Wong Edmund , Arora Akanksha , Aberle Denise , Wong David T. , Tang Cheuk Y. 
Published: April 2024

Abstract
Background: Recent studies have identified blood plasma DNA as a rich source of biomarkers for non-invasive cancer detection. In particular, analysis of shorter DNA fragments or “fragmentomics” have shown promising results with numerous competing approaches such as those based on mutation calls, length distributions, or preferred fragmentation patterns. In this study, we assessed the potential of fragment end motif distributions in discriminating patients with lung adenocarcinoma versus benign tumors.
Methods: Plasma samples from 37 patients (20 benign, 17 malignant) were subject to whole genome sequencing. For each sample, DNA fragments were grouped as short (30-99bp) and long (100-269bp) and end motif distributions were calculated by counting occurrences of 4-9bp sequences at either the 5’ or 3’ end of each fragment. A proprietary machine learning algorithm was employed to identify a minimal set of motifs capable of accurately distinguishing benign from malignant samples.
Results: Just two 5’ end motifs in long fragments, CCAT and GACA, were sufficient for distinguishing malignant from benign samples in a two-step decision tree (89% accuracy with all samples, 86% accuracy in leave-one-out cross validation). Accuracy was significantly higher when compared to random guessing by shuffling labels (p=1.6*10−6, FWER &lt; 0.05, Bonferroni correction, 351 tests). CCAT motif frequency was also significantly associated with cancer stage (p=0.04, Kruskal-Wallis test) and specifically elevated in early stage samples (I, II).
Conclusions: These results suggest that plasma DNA end motif distributions are informative in discriminating patients with lung adenocarcinoma versus benign tumors. The two-motif model suggests that specific, rather than systemic changes in end motif distributions are more strongly associated with lung cancer patients and may point to specific mechanisms linked to cancer progression.
Citation Format: Jason C. Hyun, Shun H. Yip, Neeti Swarup, Raghuraman Ramamurthy, Jordan C. Cheng, Irene Choi, Edmund Wong, Akanksha Arora, Denise Aberle, David T. Wong, Cheuk Y. Tang. Specific plasma DNA end-motifs distinguish patients with lung adenocarcinoma versus benign nodules [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 LB108.
Abstract LB109: Detection of high grade intraepithelial neoplasia in colorectal cancer using a new blood-based multiplex septin9 methylation assay
Authors: Wu Youming , Tong Yongqin Tong , Zhang Haitao , Li Yun , Li Ming , Qiu Lili , Liu Wenlan , Mei Siqing , Mao Yu , Cao Yanhua , Su Caiyan , Yu Wentao , Wang Junli , Wang Taizhong , Zhu Zhongyuan , Yu Dehua Derek 
Published: April 2024

Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, and regular screening is effective in reducing its mortality. Epi proColon was the first blood-based Septin9 gene methylation assay approved by the US FDA for CRC screening. However, the broader application of this assay has been hindered by its relatively lower sensitivity in detecting early-stage CRC and precancerous lesions. In this study, we developed a new multiplex Septin9 methylation assay, named ColonUSK, which simultaneously detects two CpG-rich subregions in the promoter of the Septin9 gene and an internal control in a single reaction. In comparison with the Sepin9 assay targeting only one CpG-rich subregion, this new assay demonstrated improved sensitivity, with a detection limit as low as 12pg of the positive DNA. To assess its value in CRC screening, we conducted an opportunistic screening study involving a total of 1366 subjects. Blind testing was performed to evaluate ColonUSK in comparison with clinical diagnosis using colonoscopy and pathological examination (the clinical gold standard). The clinical sensitivities of ColonUSK for detecting CRC and advanced adenoma were 77.34% (95% CI: 72.89%-81.26%) and 25.26% (95% CI: 17.16%-35.41%), respectively. The clinical specificity of the assay for non-CRC cases was 95.95% (95% CI: 94.36%-97.13%). Notably, ColonUSK was able to detect 54.29% of cases with high-grade intraepithelial neoplasia. The Kappa test value for this experiment was 0.76, indicating a high degree of consistency between ColonUSK and pathological diagnosis. Our results suggest that ColonUSK holds potential as a non-invasive screening tool for colorectal cancer.
Citation Format: Youming Wu, Yongqin Tong Tong, Haitao Zhang, Yun Li, Ming Li, Lili Qiu, Wenlan Liu, Siqing Mei, Yu Mao, Yanhua Cao, Caiyan Su, Wentao Yu, Junli Wang, Taizhong Wang, Zhongyuan Zhu, Dehua Derek Yu. Detection of high grade intraepithelial neoplasia in colorectal cancer using a new blood-based multiplex septin9 methylation assay [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 LB109.
Abstract LB110: Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various 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
PurposeProstate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer (PCa) micrometastases. This study evaluated whether a circulating tumor cell (CTCs-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in PCa.
Experimental design We prospectively enrolled 21 healthy individuals and 247 patients with PCa (localized PCa [LPCa]: 94; metastatic hormone-sensitive PCa [mHSPC]: 44; and metastatic castration-resistant PCa [mCRPC]: 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% 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) expression was associated with BCR. mHSPC patients with high PSMA (HR: 4.26; P=0.020) and PSA mRNA (HR: 3.52; P=0.042) expression showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expression was significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance.
Conclusion PSMA and PSA mRNA expression is associated with BCR in LPCa. In advanced PCa, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.
Citation Format: Hyungseok Cho, Seok-Soo Byun, Nak-Hoon Son, Jae Il Chung, Won Ik Seo, Chan Ho Lee, Todd M Morgan, Ki-Ho Han, Jae-Seung Chung. Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate 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 LB110.
Abstract LB115: Strong antitumor effect elicited by inhibition of AKT or FOXP3 in combination with anti-PD-L1 in Pten mutant lung squamous cell carcinoma
Authors: Houry Maeva , Redrado Miriam , Carnevalli Larissa , Barry Simon , Galan Nuria , Otegui Nerea , Leon Sergio , Montuenga Luis , Exposito Francisco , Calvo Alfonso 
Published: April 2024

Abstract
PTEN is mutated in ~10% lung squamous cell carcinoma (LUSC) patients, which results in hyperactivation of PI3K-AKT-mTOR signaling pathways. Mutations in the PI3K-AKT-mTOR pathway influence the configuration the tumor microenvironment (TME). We have recently reported that PTEN mutations in LUSC are associated with increased tumor infiltration of T regulatory immunosuppressive cells (Tregs) and fibrogenesis (PMID: 37311042). Moreover, we have demonstrated that PTEN mutations in LUSC induces resistance to anti-PD-1 therapy. Based on these findings, we have investigated whether blockade of AKT signaling with capivasertib (AZD5363) and/or inhibition of Treg-associated FOXP3 transcription factor, using the FOXP3 targeting antisense oligonucleotide (ASO) AZD8701 (FOXP3i), would cause tumor growth inhibition in the PTEN mutant context. In in vitro assays we found that Pten-null LUSC UN680 murine cells were highly sensitive to capivasertib, with inhibition of the AKT-mediated signaling cascade, reduction in cyclin D1 levels, cytoplasmic translocation of FOXO1 and increase in apoptosis and autophagy. In in vivo studies using Pten-null UN680 cells subcutaneously injected in AJ immunocompetent mice, treatment with either capivasertib or the FOXP3i induced &gt;90% tumor regression and increased survival. Moreover, on average 3/8 (~37%) animals were cured in each treatment group. In a re-challenge experiment performed in animals cured by the FOXP3i, tumors were not developed upon injection of Pten-null UN680 cells, demonstrating immunological memory. Combination of capivasertib+FOXP3i at the same doses did not cause further tumor growth inhibition, but combination of capivasertib+anti-PD-L1 or FOXP3i+anti-PD-L1 increased antitumor benefit compared to monotherapy treatment, and further increased survival. In summary, we demonstrate that immunotherapy resistant tumors with hyperactivation of AKT due to Pten mutation are highly sensitive to AKT or FOXP3 inhibition and that combinatorial strategies using these targets and anti-PD-L1 can be appropriate strategies to treat these tumors.
Citation Format: Maeva Houry, Miriam Redrado, Larissa Carnevalli, Simon Barry, Nuria Galan, Nerea Otegui, Sergio Leon, Luis Montuenga, Francisco Exposito, Alfonso Calvo. Strong antitumor effect elicited by inhibition of AKT or FOXP3 in combination with anti-PD-L1 in Pten mutant lung squamous cell carcinoma [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 LB115.
Abstract LB159: Discovery of HP560, a novel BET inhibitor for the treatment of myelofibrosis
Authors: Li Jing , Fan Lei , Yuan Hongwei , Huo Yongxu , Yu Hua , Wang Fei , Li Xinghai 
Published: April 2024

Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by defective clonal hematopoiesis, bone marrow fibrosis, splenomegaly, severe anemia, and the propensity for transformation to acute myeloid leukemia (AML). Inhibitors targeting JAKs (Janus kinases) have revolutionized the treatment of MF, but are limited by modest efficacy or acquired resistance after prolonged treatment. Here, we report a novel inhibitor, HP560 that targets BET (bromodomain and extra-terminal) proteins and shows promising therapeutic activities against MF and AML. Through engaging the bromodomain pocket of BET proteins in a competitive manner with acetylated histones, HP560 causes the disruption of BET proteins from chromatin. HP560 has high binding affinities for all BET proteins and strong anti-proliferative activity as well as synergistic anti-proliferative effect in combination with ruxolitinib, a JAK1/2 inhibitor. In an MF cell line derived tumor xenograft (CDX) mouse model, HP560 prolongs survival and improves splenomegaly and anemia, and these effects are enhanced when combined with ruxolitinib. HP560 also significantly and dose-dependently inhibits tumor growth in an AML CDX mouse model. Together, HP560 is a potent pan-BET inhibitor and can be developed as a monotherapy or in combination with a JAK inhibitor for the treatment of MF. HP560 structure will not be disclosed.
Citation Format: Jing Li, Lei Fan, Hongwei Yuan, Yongxu Huo, Hua Yu, Fei Wang, Xinghai Li. Discovery of HP560, a novel BET inhibitor for the treatment of myelofibrosis [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 LB159.
Abstract LB169: Using a global reporter on transcript abundance to identify a selective inhibitor of Nrf2 signaling in KEAP1-mutant non small cell lung cancer
Authors: Read Timothy J. , Damon Leah , Yoo Reo , Grochala Carter , Liechty Cole , Rhine Christy , Rimel Jenna , Simpson David , Lundblad Riley , Pham Casey , Steel Richard , Azofeifa Joey 
Published: April 2024

Abstract
Loss-of-function mutations in Kelch-like ECH-associated protein 1 (KEAP1) are common in non-small cell lung cancer (NSLC) and result in particularly poor prognosis. Such mutations activate the transcription factor Nrf2, leading to aberrant expression of chemoprotective genes and rendering cells resistant to chemotherapy. We used our chemo-transcriptomic platform, termed GRETA, for Global Reporter on Transcript Abundance, to identify compounds that inhibit Nrf2 transcription factor activity in KEAP1-mutant NSCLC cell lines. After defining the transcriptomic signature imparted by constitutive activation of Nrf2 in a KEAP1 KO NCI-H1975 cell line, we generated over 10,000 transcriptomes to identify compounds that dampen the Nrf2-overactive transcriptional signature. One such compound, ARP-4316, displays selectivity for KEAP1-mutant cell lines, reduces nuclear Nrf2 protein levels, and reduces Nrf2 transcriptional activity in an ARE reporter assay. Furthermore, ARP-4316 synergizes with 5-fluorouracil in two KEAP1-mutant cell models, A549 and NCI-H2122, suggesting that ARP-4316 may sensitize KEAP1 mutant cell lines to chemotherapy by inhibiting Nrf2 transcriptional activity. Efforts to identify the cellular target and mechanism of action of ARP-4316 are underway.
Citation Format: Timothy J. Read, Leah Damon, Reo Yoo, Carter Grochala, Cole Liechty, Christy Rhine, Jenna Rimel, David Simpson, Riley Lundblad, Casey Pham, Richard Steel, Joey Azofeifa. Using a global reporter on transcript abundance to identify a selective inhibitor of Nrf2 signaling in KEAP1-mutant non small cell lung 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 LB169.
Abstract LB177: Discovery of HC-4955, a novel AR-V7-targeting PROTAC for the treatment of mCRPC
Authors: Li Jing , Tu Zhilin , Du Wu , Xiang Xi , Wen Zeyu , You Yang , Zhao Lijuan , Chen Yin , Yang Chengcheng , Yuan Hongwei , Li Xinghai 
Published: April 2024

Abstract
Prostate cancer is the second most commonly diagnosed cancer and the second leading cause of cancer death among men worldwide. Androgens play an important role in the development and progression of prostate cancers and targeting androgen receptor (AR) signaling axis over decades has remained a mainstay of prostate cancer therapy. Next generation hormonal agents (NHAs) enzalutamide and abiraterone have brought clinical benefits for metastatic castrate-resistant prostate cancer (mCRPC) patients, AR axis-targeted therapy resistance is inevitable due to AR gene amplification or mutations. AR-V7 is the most clinically relevant AR splice variant associated with endocrine resistance and poor prognosis. AR-V7 constitutively activates AR signaling and lacks the ligand binding domain (LBD) where hormones and AR antagonists interact, resulting in resistance to AR signaling inhibitors (ARSi). Thus, AR-V7 is a promising therapeutic target to address ARSi resistance in mCRPC. We have discovered a highly potent AR-V7 proteolysis targeting chimera (PROTAC), HC-4955 that degrades both the wild-type AR (WT-AR) and AR-V7 mutant. HC-4955 degrades AR-V7 with DC50 &lt; 5 nM. In silico molecular docking analysis predicts the binding of HC-4955 to the N-terminal domain of AR and then the essential amino acids contributed to HC-4955 binding are validated by mutational analysis studies. HC-4955 also potently degrades mutants of AR-LBD mutations including L702H and T878A and these mutations are also associated with ARSi resistance. HC-4955 strongly inhibits proliferation of ARSi-resistant prostate cancer cell lines with IC50 &lt; 10 nM. HC-4955 shows a robust anti-tumor activity in the AR-V7-bearing 22Rv1 cell line derived tumor xenograft (CDX) and patient-derived xenograft (PDX) mouse models, with majority of the tumors completely regressed and &gt; 90% AR-V7 expression decreased at 1-5 mg/kg (QD, PO) in these models. The pre-clinical results support the clinical development of HC-4955 for the treatment of mCRPC. Selected pre-clinical data along with the chemical structure of HC-4955 will be presented.
Citation Format: Jing Li, Zhilin Tu, Wu Du, Xi Xiang, Zeyu Wen, Yang You, Lijuan Zhao, Yin Chen, Chengcheng Yang, Hongwei Yuan, Xinghai Li. Discovery of HC-4955, a novel AR-V7-targeting PROTAC for the treatment of mCRPC [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 LB177.