tbuckley/cabot-search huggingface dataset:
Abstract 7326: <i>TP53</i> p.Pro47Ser polymorphism in breast cancer susceptibility in Mali
Authors: Brehima Diakite, Yaya Kassogue, Mamoudou Maiga, Oumar Kassogue, Kadidiatou Cisse, Fousseyni Diarra, Cheick Traore B. Traore, Bakarou Kamate, Jane L. Holl, Lifang Hou
Journal: Cancer Research (2024)

Abstract Background: The aim of this study was to assess the potential association of p.Pro47Ser polymorphisms of TP53 with the risk of developing breast cancer in the Malian population. Methods: We analyzed DNA samples from 72 breast cancer patients and 121 unrelated healthy, age-matched individuals to examine the presence of the polymorphisms. The genotyping of TP53 polymorphism was performed using PCR-RFLP and HRM (high-resolution melting) methods. Results: The genotypic frequencies of PP, PS, and SS were found to be 63.9% PP, 30.6% PS, and 5.6% SS in breast cancer patients, compared to 70.2% PP, 22.3% PS, and 7.4% SS in the control group. The frequencies of P and S alleles of TP53 p.P47S polymorphism were 79.2% vs 81.4%, 20.8% vs 18.6%, and 5% vs 4.5% in patients and controls, respectively. In this study, no significant correlation was observed between TP53 p.Pro47Ser polymorphism and breast cancer in the Malian population (Pro/Ser vs Pro/Pro: OR = 1.55, 95% CI = 0.80-3.05, P = 0.19; Ser/Ser vs Pro/Pro: OR = 1.27, 95% CI = 0.34-4.74, P = 0.71; and Ser vs Pro allele: OR = 1.39, 95% CI = 0.80-2.32, P = 0.24). Conclusion: Despite the absence of a genetic association between TP53 p.Pro47Ser and the risk of breast cancer in Malian patients, our findings suggest that individuals carrying at least one minor Ser allele are not protected against the disease. Citation Format: Brehima Diakite, Yaya Kassogue, Mamoudou Maiga, Oumar Kassogue, Kadidiatou Cisse, Fousseyni Diarra, Cheick Traore B. Traore, Bakarou Kamate, Jane L. Holl, Lifang Hou. TP53 p.Pro47Ser polymorphism in breast cancer susceptibility in Mali [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7326.
Abstract 6071: Identification of a molecular glue degrader targeting the full-length AR and AR-V7 splice variant
Authors: Yuan Liu, Mads B. Larsen, Bo Lin, Irene A. Cardenal, Jason Kennerdell, Toren Finkel, Bill B. Chen
Journal: Cancer Research (2024)

Abstract Prostate cancer is the most common cancer in males and the fifth leading cause of cancer mortality worldwide. A variety of therapeutic approaches exist including steroid synthesis inhibitors and next-generation ligand binding domain (LBD) antagonists [e.g., enzalutamide (Enza)]. However, these approaches are only effective against tumors bearing the full-length androgen receptor (AR-FL). In the course of their disease, many patients acquire androgen receptor splice variant 7 (AR-V7), a mutant form of the receptor which lacks the LBD and is constitutively activated. To date, no effective therapy has been demonstrated for patients with metastatic prostate cancer bearing the AR-V7 signature. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to a wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that are bound to AR-V7. One such molecule, AR-600, directly bound to AR-V7 and moreover, induced proteasomal-mediated targeted protein degradation of both AR-V7 and AR-FL. In prostate cancer cell lines expressing AR-FL, AR-600 induced a gene expression profile similar to cells treated with Enza including a marked reduction in KLK3 (PSA) expression. Moreover, AR-600 inhibited the growth of 22RV1 cells (IC50=23 nM), a cell line that predominantly expresses AR-V7, as well as C4-2 cells that express predominantly full-length AR (IC50=51 nM). In contrast, the compound did not affect the growth of a wide variety of non-tumorigenic cells, non-prostate tumor cell lines or PC3 cells, a prostate cell line that exhibits AR-independent cell growth (IC50&amp;gt;100uM). Preliminary exploration of the mechanism of action of AR-600 (M.W. ~300 Daltons) demonstrates the compound works as a molecular glue. These results thereby identify a small molecule glue degrader that can specifically induce the targeted protein degradation of the AR-V7 splice variant. Given the strong association of this isoform with treatment resistance, this approach would appear to provide an attractive strategy for patients with metastatic castration resistant prostate cancer. Citation Format: Yuan Liu, Mads B. Larsen, Bo Lin, Irene A. Cardenal, Jason Kennerdell, Toren Finkel, Bill B. Chen. Identification of a molecular glue degrader targeting the full-length AR and AR-V7 splice variant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6071.
Abstract 3050: Evaluating the role of ∆Np63α in driving growth and metastasis of pancreatic ductal adenocarcinoma
Authors: Daniel H. Ryan, Chin-Hsien (Emily) Tai, Xianyu Zhang, Mayrel Palestino Dominguez, Christine Alewine
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the US and is rising in incidence. PDAC tumors may be either classical or basal in transcriptomic subtype, and PDAC patients with basal tumors have worse prognosis and may have increased resistance to chemotherapy. Previous studies have shown that ∆Np63α drives basal program expression. The goal of this project is to investigate whether ∆Np63α expression is sufficient to increase pancreatic cancer cell growth, metastasis and chemoresistance and whether these cells can outcompete ∆Np63α non-expressers in mixed tumors. Non-∆Np63α expressing human PDAC cell lines AsPC1 and HPAFII were stably transduced to express either ∆Np63α or mCherry (control). For both AsPC1 and HPAFII, ∆Np63α-expressing and control cells had similar proliferation rates and susceptibility to chemotherapy agents oxaliplatin and SN38 when grown in culture. When control or ∆Np63α-expressing AsPC1 cells were implanted orthotopically into the pancreas of athymic nude mice, there was no significant difference in primary tumor mass and pathological analysis of lungs and livers did not reveal any significant difference in metastatic burden. Bulk RNA sequencing of primary tumors confirmed that tumors in mice inoculated with AsPC1-∆Np63α had significantly upregulated expression of genes associated with the basal subtype. Collectively, these data suggest that while ∆Np63α drives the basal program in PDAC, its expression is insufficient to cause resistance to these chemotherapies or a growth or metastatic advantage in an immunodeficient setting. Further work is needed to elucidate the mechanism by which ∆Np63α contributes to more aggressive PDAC tumors. Citation Format: Daniel H. Ryan, Chin-Hsien (Emily) Tai, Xianyu Zhang, Mayrel Palestino Dominguez, Christine Alewine. Evaluating the role of ∆Np63α in driving growth and metastasis of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3050.
Abstract 4086: ABN202 (anti-Trop-2-interferon-beta mutein): A potent antibody-cytokine fusion protein for the treatment of Trop-2 positive solid tumors
Authors: Hee Geon Park, Hyun Kyung Lee, Myeung Ryun Seo, Daa Eun Kim, Sang Beom Bang, Ji Yang Lee, Sung Youl Hong, Kyoung Song, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Jun Young Choi, Young Kee Shin
Journal: Cancer Research (2024)

Abstract Trop-2, trophoblast cell-surface antigen 2, is a type 1 transmembrane glycoprotein overexpressed in many solid cancers, including breast, lung, pancreatic, bile duct and bladder cancer. Overexpression of Trop-2 in cancer patients is associated with disease progression and poor prognosis. The antibody-drug conjugate (ADC) targeting Trop-2, Sacituzumab-govitecan (Trodelvy®), is approved for patients with triple-negative breast cancer (TNBC) and bladder cancer. However, Trop-2 targeting ADCs exhibit a high frequency of grade 3/4 adverse events and a short duration of response. Therefore, there is an unmet medical need for new treatment strategies beyond ADCs. In a previous study, we designed ABN202 (αTrop-2) to comprise a Trop-2 targeting antibody (Sacituzumab) and IFN-β mutein (ABN102) for the Trop2-positive tumor-specific delivery of ABN102. We confirmed anti-cancer activities of ABN202 against Trop-2 positive bladder cancer. In this study, we evaluated in vitro and in vivo anti-cancer efficacy of ABN202 (αTrop-2) in Trop-2 positive TNBC, bile duct cancer and bladder cancer cell lines. To identify response biomarkers for ABN202 (αTrop-2), we analyzed cell lines exhibiting both response and non-response to ABN202 (αTrop-2). In conclusion, ABN202 (αTrop-2) demonstrated potent anti-cancer efficacy compared to Trodelvy®. Our results support ABN202 (αTrop-2) as a promising drug candidate against Trop2-positive solid tumors. Citation Format: Hee Geon Park, Hyun Kyung Lee, Myeung Ryun Seo, Daa Eun Kim, Sang Beom Bang, Ji Yang Lee, Sung Youl Hong, Kyoung Song, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Jun Young Choi, Young Kee Shin. ABN202 (anti-Trop-2-interferon-beta mutein): A potent antibody-cytokine fusion protein for the treatment of Trop-2 positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4086.
Abstract 7147: ASN-3186 is a potent and selective inhibitor of USP1 for the treatment of BRCA1/2 mut and HRD+ cancers
Authors: Qiaoling Sun, Yunfei Chen, Maojiang Wu, Jing Lv, Hongyue Jin, Peng Zeng, Xia Song, Wenfeng Hou, Qi Huang, Wei Niu, Mengyao Zhang, Tie-Lin Wang, Alice Chen
Journal: Cancer Research (2024)

Abstract Ubiquitin-specific protease 1 (USP1), a well-characterized member of the deubiquitinating enzyme family, selectively cleaves ubiquitin from various target proteins, including DNA repair protein PCNA. USP1 contributes to oncogenesis by playing critical roles in DNA damage repair processes including translesion synthesis and the Fanconi anemia pathway. Despite the clinical benefit achieved with PARP inhibitors (PARPi) in BRCA-mutated (BRCAm) or homologous recombination deficient (HRD+) populations, some patients either do not respond to therapy or develop resistance. USP1 inhibitors may have the potential to address this unmet clinical need as USP1 functions in distinct DNA damage repair pathway as compared to PARP. ASN-3186 is a novel, potent, and selective USP1 inhibitor with enzyme IC50 value of single digit nanomolar and selectivity &amp;gt;1000-fold against other family members. ASN-3186 demonstrated potent anti-proliferative activity in the BRCA1m triple negative breast cancer (TNBC) cell line, MDA-MB-436 (IC50 &amp;lt;30 nM). MDA-MB-436 CDX mouse model confirmed dose-dependent, single-agent inhibitory activity of ASN-3186 in vivo with higher potency than KSQ4279, possibly due to ASN-3186’s higher oral bioavailability. Efficacy is consistent with increase of pharmacodynamic biomarker ub-PCNA. The combination of ASN-3186 and PARPi Olaparib yielded a more robust and durable anti-tumor response, with near-complete tumor regression demonstrated at higher combination dose. Moreover, addition of ASN-3186 significantly sensitized Olaparib’s minimal anti-tumor activity in CAOV3 (ovarian, HRD high) and MX-1 (TNBC, BCRA1/2 mut) models, which are resistant to PAPRi, indicating that it has the potential to overcome PARPi resistance. Synthetic lethal activity was also observed when ASN-3186 was combined with DNA damage drug Gemcitabine. Furthermore, ASN-3186 displayed desirable ADME and PK profiles with high oral bioavailabilities (&amp;gt;75%) across species. These data support further clinical development of ASN-3186 as a potential best-in-class USP1 inhibitor, both as a single agent as well as in combination with PARPi, for treatment of BRCA1/2 mut and HRD+ cancers. Citation Format: Qiaoling Sun, Yunfei Chen, Maojiang Wu, Jing Lv, Hongyue Jin, Peng Zeng, Xia Song, Wenfeng Hou, Qi Huang, Wei Niu, Mengyao Zhang, Tie-Lin Wang, Alice Chen. ASN-3186 is a potent and selective inhibitor of USP1 for the treatment of BRCA1/2 mut and HRD+ cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7147.
Abstract 1592: Single-cell transcriptomics reveals unique stromal and metabolic heterogeneity in liver metastatic pancreatic cancer
Authors: Rima Singh, Christopher Halbrook
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer related death in the US. This mortality is strongly linked to the complex PDA tumor microenvironment that drives resistance to chemotherapy and immune suppression. Most patients succumb to metastatic disease, with liver being the most frequently colonized organ. Despite this, most pre-clinical studies have focused on primary PDA models to study the disease. Accordingly, the extent that the liver metastatic niche promotes immune evasion and resistance to treatment remains unclear.To directly compare primary vs. metastatic tumors in PDA tumors, we have optimized a syngeneic experimental model to contrast primary vs. metastatic lesions. To define the similarities and differences between cell types present in these tumors, we employed a single-cell transcriptomics approach. Our analysis has identified shared populations of malignant epithelial, stromal, and immune cells between lesions, allowing for a direct comparison of programming. Here, we have observed that the dominant populations of PDA cells in pancreas vs. liver tumors engage in distinct metabolic programs that suggest different actionable vulnerabilities.Beyond these, we also observed fibroblasts and myeloid sub-populations that are exclusive to liver tumors. These data further support our hypothesis that alternative mechanisms of metabolic, immune, and stromal interactions take place in the metastatic tumor microenvironment. To define these crosstalk networks, we employed the interactome tool CellChat, which has uncovered unique signaling interactions between the CAF and cancer cell populations in pancreatic or liver tumors. Overall, these data have the potential to lead to new avenues to directly target cancer cells or engage an effective immune response that can be designed to treat metastatic pancreatic cancer- an urgent clinical need. Citation Format: Rima Singh, Christopher Halbrook. Single-cell transcriptomics reveals unique stromal and metabolic heterogeneity in liver metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1592.
Abstract 1491: The enhanced formation of neutrophil extracellular traps (NETs) may contribute to the exacerbation of peritoneal metastasis in a diabetic host
Authors: Rei Takahashi, Hideyuki Ohzawa, Yuki Kaneko, Misaki Matsumiya, Yurie Futoh, Kohei Tamura, Kazuya Takahashi, Yuki Kimura, Akira Saito, Hideyo Miyato, Naohiro Sata, Joji Kitayama
Journal: Cancer Research (2024)

Abstract Background: Diabetes is associated with increased risk of cancer development and progression. Recent studies have shown that neutrophils in diabetic patients are prone to forming neutrophil extracellular traps (NETs) which have been reported to capture circulating cancer cells, leading to the promotion of liver and lung metastasis. This study aims to clarify the causative relationship between NETs and the peritoneal metastasis (PM) in diabetic condition. Methods: Outcome of the diabetic patients who received curative gastrectomy for gastric cancer from 2010 to 2021 in our institute was comparatively investigated with those without diabetes. Neutrophils were isolated from the bone marrow from C57BL/JHamSlc-ob/ob mouse (type 2 diabetes model) and wild type mouse using Ly6G-based positive immunomagnetic selection. The neutrophils were stimulated with 100nM of PMA for 4 hours and NETs formation was evaluated by the addition of Sytox Green under fluorescent microscope. A mouse gastric cancer cell, YTN16P (5 × 105 cells) was intraperitoneally (IP) injected, the number of metastatic nodules on mesentery was comparatively evaluated two weeks later. Results: Disease-free survival (p=0.004, HR=1.65) and overall survival (p=0.035, HR=1.46) of 203 diabetic patients were significantly worse those of 975 non-diabetic patients. Neutrophils isolated from ob/ob mice produced markedly increased NETs than that from wild-type mice. NETs produced by neutrophils obtained from the peritoneal cavity of ob/ob mice after IP injection of a 9% casein solution effectively captured many YTN16P in vitro. The concentration of double strand DNA (dsDNA) in plasma in ob/ob mice compared with their counterparts (676ng/mL vs 590ng/mL, p=0.036, n=3). The number of PM in ob/ob mice was significantly more than that in wild-type controls (39.1 vs 15.5, p=0.027, n=10). Conclusion: Enhanced NETs formation in diabetic conditions may be associated with an increased risk of PM in gastric cancer. Citation Format: Rei Takahashi, Hideyuki Ohzawa, Yuki Kaneko, Misaki Matsumiya, Yurie Futoh, Kohei Tamura, Kazuya Takahashi, Yuki Kimura, Akira Saito, Hideyo Miyato, Naohiro Sata, Joji Kitayama. The enhanced formation of neutrophil extracellular traps (NETs) may contribute to the exacerbation of peritoneal metastasis in a diabetic host [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1491.
Abstract 7246: Enhancing PDAC therapy through <i>in vivo</i> correction of <i>KRAS</i> G12D using enIscB-directed base editor combined with ICB
Authors: Chao Yang, Qingxiao Fang, Tianxing Zhou, Yongjie Xie, Jun Yu, Jihui Hao
Journal: Cancer Research (2024)

Abstract In this study, we aim to investigate the therapeutic potential of in vivo genetic therapy using AAV-mediated adenine base editor (ABE) delivery for pancreatic ductal adenocarcinoma (PDAC) carrying the KRASG12D mutation (PDACG12D), and further explore its potential when combined with immune checkpoint blockade (ICB). The KRASG12D mutation is a dominant genetic alteration representing a highly sought-after and effective therapeutic target in PDAC. However, the in vivo genetic therapy for KRASG12D in PDAC has been rarely explored. Programmable base editors have been shown to install genetic mutations precisely and have significant therapeutic value, providing a promising strategy for genetic therapy of PDACG12D. Here, we engineered ABEs derived from various programmable nucleases, considering the protospacer adjacent motif (PAM) or target adjacent motif (TAM) sequence. The hypercompact A8e-enIscB demonstrated the highest editing efficiency in HEK293TG12D and PANC-1 cell lines. Subsequently, A8e-enIscB was packaged into a single-AAV system and delivered to humanized mice subcutaneously transplanted with patient-derived organoidG12D (PDOG12D). We found the delayed tumor progression with BE-based genetic therapy. Additionally, a substantial editing efficiency in tumor tissues and lower off-target editing in normal tissues was observed. By comparing single-cell transcriptome sequencing data between BE-treated and non-treated samples, we observed a reprogrammed immune microenvironment characterized by elevated infiltration of cytotoxic CD8+ T cells and NK cells, as well as decreased recruitment of suppressive PMN-MDSCs, Tregs and TAMs upon correction of KRASG12D. Furthermore, AAV-directed ABE genetic therapy could significantly sensitize PDAC to ICB therapy (anti-PD-1, anti-CTLA4) in humanized PDAC PDO/PDX mouse models. Accordingly, an ongoing work in which the genetic therapy combined with ICB phase IA investigator-initialized trial will be designed to evaluate the safety of this regimen. In summary, our study demonstrates the efficiency and safety of innovative genetic therapy for correcting the KRASG12D mutation in PDAC. Furthermore, we demonstrated the therapeutic potential of combining this genetic therapy with ICB. Citation Format: Chao Yang, Qingxiao Fang, Tianxing Zhou, Yongjie Xie, Jun Yu, Jihui Hao. Enhancing PDAC therapy through in vivo correction of KRAS G12D using enIscB-directed base editor combined with ICB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7246.