tbuckley/cabot-search huggingface dataset:
Abstract 3382: The predictive effect of gBRCAs mutations on rates of pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in Chinese breast cancer (BC) patients: a single-center study in Xijing Hospital, Northwest China
Authors: Jing Fan, Ting Wang, Jiajun Ding, Yidi Wang, Mengxuan Li, Huimin Meng, Jing Kong, Haoyi Zi, Qingxia Li, Shuai Wang, Fei Yao, Changbing Zhu
Journal: Cancer Research (2025)

Abstract Background and Objective: The link between germline BRCA (gBRCA) mutations and the effectiveness of neoadjuvant therapy (NAC) in early-stage breast cancer (BC) is debated. It prompted us to conduct this retrospective study to determine NAC efficacies according to gBRCA variant status overall or further by BC molecular subtypes. Methods: A cohort of 452 female patients receiving standard NAC and following surgery with gBRCAs mutational signatures were enrolled in this study. Pearson Chi-square test, continuous correction chi-square test and fisher's exact test were used to explored the association between gBRCA1/2 mutation and the response to NAC. Results: Overall, 131 patients with triple negative breast cancer (TNBC), 215 patients with Luminal B (HER2- or HER2+) BC as well as 57 HER2+ patients were included. All enrolled patients classified as stageII-III. 60.6% (20/33) of gBRCA1 mutation (gBRCA1mut) patients, 28.6% (8/28) of gBRCA2 mutation (gBRCA2mut) patients and 39.6% (155/391) of noncarriers patients achieved pathological complete response (pCR) (p=0.049). For achieving RCB 0/I, the rates were 69.7% (23/33), 39.3% (11/28) and 50.4% (197/391) respectively (p=0.045). Among HER2- patients, gBRCA1mut patients were more likely to be pCR compared to non-gBRCA1mut carriers (53.8% vs. 25.2%, p=0.005), so as in gBRCA1/2mut patients compared to non-gBRCA1/2mut carriers (42.9% vs. 25.7%, p=0.023). In Luminal B (HER2-) patients, only gBRCA1mut was associated with better pCR rate (57.1% in gBRCA1mut patients compared to 13.9% in non-gBRCA1mut patients, p=0.013). While in TNBC patients, pCR was more frequent in gBRCA1/2mut patients compared to noncarriers (60.7% vs. 37.9%, p=0.034). Additionally, in clinically node-positive patients, in spite of the difference was not statistically significant, gBRCA2mut patients tended to be worse response to NAC compared to non-gBRCA2mut patients (0.0% vs. 29.3%, p=0.077). Conclusion: Though the outcome of a single-center study with small sample size was restricted, it could be found that BRCA1mut patients had better response to NAC, while BRCA2mut patients achieved less from NAC. Citation Format: Jing Fan, Ting Wang, Jiajun Ding, Yidi Wang, Mengxuan Li, Huimin Meng, Jing Kong, Haoyi Zi, Qingxia Li, Shuai Wang, Fei Yao, Changbing Zhu. The predictive effect of gBRCAs mutations on rates of pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in Chinese breast cancer (BC) patients: a single-center study in Xijing Hospital, Northwest China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3382.
Abstract 5747: Assessment of neuro-pharmacokinetic behavior of BDTX-1535 in brain tumor patients by a validated LC-MS/MS method
Authors: Vahuni Karapetyan, Tigran Margaryan, Nader Sanai, Artak Tovmasyan
Journal: Cancer Research (2025)

Abstract BDTX-1535 is an orally available, highly potent, irreversible inhibitor of epidermal growth factor receptor (EGFR), targeting a range of EGFR mutations, including extracellular variants and amplifications commonly expressed in glioblastoma. To assess CNS penetration of BDTX-1535 in glioblastoma patients, a novel bioanalytical method was developed to measure total and unbound BDTX-1535 levels in human brain tumor tissue, plasma, whole blood and cerebrospinal fluid (CSF). The method was validated using plasma as a surrogate matrix over the concentration range of 0.2-500 nM on an LC-MS/MS system. The MS/MS detection was conducted in positive electrospray ionization mode, while chromatography was performed using a Kinetex™ F5 column (50 × 2.1 mm, 1.7 µm) with a total 3.8-minute gradient elution time. The maximum coefficient of variation for both intra- and inter-day precision was 16.3%, with accuracy ranging from 91.5% – 107.2% across all matrices. BDTX-1535 was stable in human whole blood, plasma and brain homogenate for at least 4 hours at room temperature (RT) and 105 days at -20°C, as well as in stock and working solutions for at least 9 hours (RT) and 52 days (4°C). Equilibrium dialysis experiments revealed the unbound fractions of 0.01 and 0.08 for BDTX-1535 in human brain and plasma, respectively. The validated method is currently employed to assess BDTX-1535 levels in human brain tumor tissue, CSF, blood and plasma in an ongoing trial on recurrent high-grade glioma patients (NCT06072586). Initial results of measured total and unbound drug levels in the gadolinium-enhancing and non-enhancing brain tumor regions indicate significant brain penetration ability of BDTX-1535 in high-grade glioma patients. Citation Format: Vahuni Karapetyan, Tigran Margaryan, Nader Sanai, Artak Tovmasyan. Assessment of neuro-pharmacokinetic behavior of BDTX-1535 in brain tumor patients by a validated LC-MS/MS method [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5747.
Abstract 7329: Overcoming systemic toxicity of IL-12-based immunotherapy by tumor-targeting and IL-12 attenuation
Authors: Jihoon Chang, Byoung Chul Lee
Journal: Cancer Research (2025)

Abstract With the recent success of immune checkpoint inhibitors, there is a renewed interest in cytokines as promising agents for cancer immunotherapy. Cytokines are well-established immunomodulators, and several inflammatory cytokines, including IL-12, have demonstrated potent anti-tumor activity. However, systemic administration of IL-12 has been associated with severe immune related adverse events, significantly limiting its therapeutic application. To overcome such narrow therapeutic window, we developed KNP-101, a bispecific Fc-fusion protein consisting of anti-FAP and attenuated IL-12. KNP-101 accumulates in the tumor microenvironment via anti-FAP and thus induces IL-12 activity at the tumor site. In addition, additional mutations were introduced into IL-12 to further mitigate systemic toxicity. Although the IL-12 activity was attenuated, KNP-101 mouse surrogate maintained significant anti-tumor potency in various mouse syngeneic models with a single intravenous injection. In combination therapies with anti-PD-L1, KNP-101 mouse surrogate demonstrated a synergistic anti-tumor effect. Analysis of tumor infiltrated lymphocytes via FACS demonstrated that the effects were mediated by immune cell infiltration. In naïve mouse toxicity test, KNP-101 mouse surrogate was tolerable up to 150 ug/head and no survival issue was observed. Similar toxicity studies were performed in tumor-bearing mice and, KNP-101 mouse surrogate showed safe profiles being tolerable up to 500 ug/head with no survival issues. Noticeably, KNP-101 mouse surrogate induced far less IFNg in serum compared to null/IL-12 suggesting that systemic toxicity was greatly reduced. Furthermore, KNP-101 was tolerable at doses up to 2.4 mg/kg in repeat-dose non-GLP studies conducted in cynomolgus monkey. Notably, KNP-101demonstrated that systemic toxicity of IL-12 therapy can be overcome by tumor-targeting and IL-12 attenuation strategies. KNP-101 exhibited a wide therapeutic window, by showing potent anti-tumor activities and significantly improved safety profiles. These attributes position KNP-101 as a promising therapeutic option for patients facing resistance to current cancer therapies. Citation Format: Jihoon Chang, Byoung Chul Lee. Overcoming systemic toxicity of IL-12-based immunotherapy by tumor-targeting and IL-12 attenuation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7329.
Abstract 7327: Harnessing FcγR glycoengineering to enhance anti-tumor monoclonal antibody efficacy
Authors: Bowie Yik-Ling Cheng, Raquel M. Centeio, David Kung-Chun Chiu, Taia T. Wang
Journal: Cancer Research (2025)

Abstract New strategies to enhance the activity of anti-tumor monoclonal antibodies (mAbs) that mediate cytotoxicity are needed. Glycoengineering of certain anti-tumor mAbs has been employed to increase their cytotoxic activity; however, the benefits of this approach are limited to specific patient groups. Beyond mAb engineering, an additional strategy involves modifying Fc gamma receptors (FcγRs), the receptors for IgG antibodies on effector cells, to augment specific antibody effector functions including cytotoxicity. One method for improving FcγR binding to mAbs is through glycoengineering, though the potential to modulate anti-tumor mAb activity via in vivo FcR glycoform engineering remains unexplored. We investigated the impact of FcγR glycosylation on therapeutic mAb activity and demonstrated that modifying FcγR glycoforms can enhance antibody-mediated anti-cancer responses. Underprocessed N-linked glycoforms were associated with improved binding affinity of Rituximab and Trastuzumab to FcRs, which enhanced the antibody-dependent cellular cytotoxicity activity of human peripheral blood mononuclear cells against target cells expressing CD20 or HER2, respectively. In vivo, glycoengineering of FcγRs improved the therapeutic efficacy of both a wild-type and an afucosylated anti-tumor mAb, demonstrating that this approach can further potentiate the activity of mAbs that have already been engineered for increased cytotoxicity. These findings underscore the potential of FcγR glycoengineering as a strategy to optimize mAb-based cancer immunotherapy. Citation Format: Bowie Yik-Ling Cheng, Raquel M. Centeio, David Kung-Chun Chiu, Taia T. Wang. Harnessing FcγR glycoengineering to enhance anti-tumor monoclonal antibody efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7327.
Abstract 5735: Design of a peptide-targeted radiotherapy for treatment of bone cancers
Authors: Losha D. Jung, Philip S. Low
Journal: Cancer Research (2025)

Abstract According to the American Cancer Society, ∼400, 000 new cases of malignant bone metastases are diagnosed each year in the United States, with prostate and breast cancers accounting for the largest fractions. Unfortunately, progression of these metastases can lead to bone fractures, spinal cord compressions, hypercalcemia, and severe pain, resulting in a decrement in quality and duration of life. Given the limited effectiveness of existing clinical interventions in alleviating these symptoms, there is a critical need for therapies capable of selectively eradicating bone metastases without harming healthy tissues. To address this problem, we have developed a novel bone cancer-targeted radiotherapy comprised of an acidic oligopeptide that homes specifically to exposed hydroxyapatites (i.e. the mineral component of bone that becomes exposed in bone metastases) linked to a universal chelating agent (e.g. DOTA) that can bind to various cytotoxic radionuclides such as 177Lu, 225Ac, or 90Y. Tail vein administration of the 177Lu-labeled form of the above conjugate into nu/nu mice bearing intratibial C4-2 human prostate cancer revealed pronounced accumulation and retention of the conjugates in the tumor-induced bone lesions, with associated radioactivity decreasing modestly from 38% to 23% injected dose per gram (ID/g) from 4 hours to 240 hours. As the uptake in healthy tissues, aside from the kidneys, was minimal, and renal accumulation declined significantly from 2.8% to 0.13% ID/g over the same 240-hour period, it was concluded that bone metastases could be effectively irradiated without inducing measurable toxicity to healthy tissues. Subsequent therapeutic efficacy studies validated this prediction, demonstrating that serum PSA levels, a biomarker of C4-2 tumor growth, were significantly reduced in mice treated with the targeted radiotherapy, whereas untreated mice experienced disease progression necessitating euthanasia. Comparison of microCT scans between treated and untreated cohorts revealed a substantial reduction in bone lesions in the treated groups. Additionally, pathological examinations showed no detectable harm to kidney, blood, and bone marrow. These findings conclusively suggest that our bone cancer-targeted radiotherapy has the potential to improve survival and quality of life in this challenging patient population while minimizing toxicity. Citation Format: Losha D. Jung, Philip S. Low. Design of a peptide-targeted radiotherapy for treatment of bone cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5735.
Abstract 3934: Establishing a non-invasive direct injection method to achieve an orthotopic murine model of cervical cancer in immunocompetent mice
Authors: Marlene L. Campos Guerrero, Liyun Chen, Lori Strong, Stephanie Markovina
Journal: Cancer Research (2025)

Abstract Current cervical cancer murine models consist of transgenic genetically engineered mouse models (GEMMS) that require multiple genetic mutations and/or hormone induction for spontaneous cervical cancer development. Other techniques used for studying cervical cancer in mice consist of subcutaneous injection of tumor cells and surgical implantation of tumor cells into the lower portion of the uterus. These approaches are useful for studying tumor cell behavior - growth and progression but are limited to their location and the use of immune-compromised mice models, and/or survival surgery. Attempts for tumor cell deposit into mice cervix have consisted of pretreating mice with hormones and irritating the cervix and vaginal canal prior to depositing tumor cells. Here, we focused on establishing a reproducible, reliable, non-surgical approach to orthotopic establishment of tumors directly into cervix of the immunocompetent mice. We hypothesized that this technique will not require hormone pre-treatment of mice and reliably establishes tumor cells within the cervix epithelium in mice. To test this hypothesis, we used TC1 murine cell line expressing E6 and E7 oncogenes and engineered to express luciferase to inject the cervix of mice through the urovaginal opening. We confirmed establishment of tumor cells in the cervix 3-hours post injection through bioluminescence imaging (BLI) and monitored tumor growth with BLI imaging every 3 days. Additionally, we confirmed tumor growth through micro-CT imaging every 7 days post injection. We identified that mice with cervix injection can be monitored up to 24-31 days post injection. Tumor histologic images confirm tumor establishment in cervix submucosa with local-regional spread, and lung metastasis, similar to the pattern of spread seen in human cervical cancers. While existing methods of orthotopic tumor establishment achieve a similar model of spread, this approach is minimally invasive and does not require breeding. Additional studies are ongoing to determine the success rate of desired cervical tumor establishment using this method and to discern molecular mechanisms of invasion and metastasis in cervical cancer. Citation Format: Marlene L. Campos Guerrero, Liyun Chen, Lori Strong, Stephanie Markovina. Establishing a non-invasive direct injection method to achieve an orthotopic murine model of cervical cancer in immunocompetent mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3934.
Abstract 4717: Glycosylation inhibition in multiple myeloma and its impact on treatment
Authors: Heni Patel, Sharnett Riley, Hiral Kapadia, Robert B. Campbell
Journal: Cancer Research (2025)

Abstract Background: Multiple myeloma (MM) is a rare and incurable blood cancer that predominantly affects older adults. It is characterized by the uncontrolled proliferation of malignant plasma cells within the bone marrow, which often exhibit abnormal glycosylation patterns that may influence their interactions with chemotherapy. Notably, MUC1-C is aberrantly expressed in MM cells, playing a pivotal role in their growth and survival, making it a promising target for therapeutic intervention. Research has demonstrated that the inhibition of MUC1-C with benzyl-α-GalNAc enhanced the susceptibility of these cells to CTL-mediated immune responses and the effects of cytotoxic drugs. Modifying the glycosylation of MUC1-C has the potential to increase the susceptibility of MM cells to clinically relevant treatment approaches. Building on this, the current study investigated the use of glycosylation inhibitors as a strategy to improve drug efficacy in MM. We hypothesized that the glycosylation levels normally observed in MM cells functions as a cellular barrier to therapeutic agents. Method: The RPMI-8226 human plasmacytoma cell line (ATCC CCL-155) was cultured aseptically in RPMI-1640 growth medium supplemented with 10% fetal bovine serum (FBS). The cells were subsequently seeded into 24-well plates and pre-exposed to the glycosylation inhibitor, benzyl-α-GalNAc. Following a 48-hour incubation, the plates were next exposed to various agents for an additional 24-hr period. To assess the extent to which glycosylation influences drug uptake, one study involved the use of a fluorescently tagged anti-MUC1 antibody. To examine the influence of glycosylation on drug effects, the clinical agents imatinib and cyclophosphamide were also employed. Results: The pre-exposure of RPMI-8226 to glycosylation inhibitor cells resulted in greater uptake of the anti-MUC1 antibody compared to the untreated cells (P = 0.0008). Furthermore, the combination of glycosylation inhibitor and imatinib improved the drug effects when compared to imatinib alone (P = 0.0012). A similar observation was observed with cyclophosphamide (P = 0.0329). These findings emphasize the promising potential of combining therapeutic agents with glycosylation inhibitors to improve the effectiveness and precision of drug therapy. Conclusion: The application of a glycosylation inhibitor significantly enhanced drug uptake and subsequent drug effects. The promising findings suggest that the alteration of glycosylation patterns in MM may improve drug treatment efforts. Citation Format: Heni Patel, Sharnett Riley, Hiral Kapadia, Robert B. Campbell. Glycosylation inhibition in multiple myeloma and its impact on treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4717.
Abstract 4714: Elucidating mechanisms of acquired resistance to mobocertinib in non-small cell lung cancer harboring EGFR exon 20 insertion mutations
Authors: Gaku Yamamoto, Yu Tanaka, Yoshitaka Zenke, Jie Liu, Tetsuya Sakai, Hiroki Izumi, Eri Sugiyama, Shigeki Umemura, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Susumu S. Kobayashi, Hibiki Udagawa
Journal: Cancer Research (2025)

Mobocertinib (TAK-788) is an oral irreversible tyrosine kinase inhibitor specifically developed to target EGFR exon 20 insertion (ex20ins) mutant non-small cell lung cancer (NSCLC); however, acquired resistance inevitably develops, limiting its clinical efficacy. This study aims to elucidate mechanisms of mobocertinib resistance through multiple clinical and preclinical approaches. Through targeted Next-Generation Sequencing on tumor samples from a patient with EGFR ex20ins (A767_S768insSVD) mutant NSCLC treated with mobocertinib, we identified secondary KRAS Q61H mutation as a potential resistance mechanism. To recapitulate clinical resistance, we successfully established a cell line (TH937) derived from this patient's pre-treatment tumor. In vivo mobocertinib-resistant tumors (mobo-R) were generated by continuous oral administration of mobocertinib to TH937 xenograft nude mice. Although no actionable secondary EGFR or KRAS mutations were identified in whole exome sequencing, transcriptomic analyses revealed upregulation of MAPK and RAS-related signaling in mobo-R tumors. In vitro analyses also showed reactivation of ERK signaling after mobocertinib treatment, while phosphorylation of 49 major receptor tyrosine kinases (RTKs), including EGFR and other ErbB family members, was not observed. These finding indicates that RTK-independent MAPK reactivation, potentially driven by RAS signaling, may serve as a resistance mechanism. In conclusion, we found that genomic or transcriptomic alterations of MAPK/RAS signaling mediate mobocertinib resistance. Further validation and exploration are needed to improve the therapy of EGFR ex20insmutant NSCLC. Citation Format: Gaku Yamamoto, Yu Tanaka, Yoshitaka Zenke, Jie Liu, Tetsuya Sakai, Hiroki Izumi, Eri Sugiyama, Shigeki Umemura, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Susumu S. Kobayashi, Hibiki Udagawa. Elucidating mechanisms of acquired resistance to mobocertinib in non-small cell lung cancer harboring EGFR exon 20 insertion mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4714.