tbuckley/cabot-search huggingface dataset:
Abstract 928: Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC)
Authors: Omid Yazdanpanah, Sami Dwabe, Garrett Harada, Steven Seyedin, Nataliya Mar
Journal: Cancer Research (2024)

Abstract Multiple regimens are available for management of mccRCC including either immuno-oncology doublet (IO/IO) or combinations of IO and tyrosine kinase inhibitors (TKI). Clinical trials have compared these regimens to sunitinib, with no direct comparison between them. As such, there is ambiguity among physicians about preferred first-line for mccRCC. We performed a single-institution retrospective study of adults treated in first-line for mccRCC between 1/1/2017 and 1/1/2023. Regimens included IO/IO (ipilimumab/nivolumab [I/N]) or IO/TKI (pembrolizumab/axitinib [P/A], nivolumab/cabozantinib [N/C], or pembrolizumab/lenvatinib [P/L]). We compared efficacy and toxicity endpoints, using Kruskal-Wallis test for medians and Chi-square for categorical variables. 42 patients with median age of 61 (range: 36-95) were included. Patient distribution in IO/IO vs IO/TKI group was 20.0% vs 30.8% in International Metastatic Database Consortium (IMDC) favorable risk, 46.7% vs 38.5% in intermediate-risk, and 33.3% vs 30.8% in poor-risk group. 78.6% vs 66.6% of patients had WHO grade 3/4 ccRCC, 18.8% vs 15.4% had sarcomatoid features in the IO/IO vs IO/TKI, respectively. 38% (16/42) received I/N, 7% (3/42) N/C, 52% (22/42) P/A, and 2% (1/42) P/L. Median follow-up was 109 weeks. Table-1 compares the efficacy of IO/IO vs IO/TKI. IO-related toxicity, TKI-related toxicity, treatment interruptions, dose reductions, and need for steroids were not significantly different between IO/IO and IO/TKI (p= 0.240, p=0.372, p=0.923, p=1.00, and p=0.248, respectively). Genomic characteristics will be reported in poster. Despite small sample size, our real-world data showed that patients treated with IO/IO had significantly worse outcomes compared to those treated with IO/TKI. While this difference may stem from a more aggressive disease in IO/IO group but further insights needs to be obtained through future prospective studies comparing IO/IO and IO/TKI regimens. Variable IO/IO IO/TKI p-value Median treatment duration (weeks) 8.3 59.4 &amp;lt;0.001 Disease control rate (complete response + partial response + stable disease) (%) 50.0 91.7 0.024 Time from 1st line to 2nd line therapy (weeks) 14.6 57.1 0.001 Median overall survival (weeks) 63.6 Not reached 0.001 Citation Format: Omid Yazdanpanah, Sami Dwabe, Garrett Harada, Steven Seyedin, Nataliya Mar. Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC) [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 928.
Abstract 5091: Response to neoadjuvant chemoimmunotherapy in resectable locally advanced oral squamous cell carcinoma: a single-center retrospective observational study
Authors: Jinsong Li, Bowen Li, Shule Xie, Haotian Cao, Zhaoyu Lin, Qunxing Li, Song Fan
Journal: Cancer Research (2024)

Abstract Background: This study aims to investigate the effectiveness of neoadjuvant chemoimmunotherapy (NACI) regimens in treating advanced oral squamous cell carcinoma (OSCC). Methods: We analyzed clinicopathologic features of advanced OSCC patients who received PD-1 inhibitors in combination with carboplatin and paclitaxel before surgical tumor resection between 2020 and 2022. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and pathologic response were used to evaluate the efficacy of the NACI treatment. Adverse events apparently related to NACI treatment were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier survival curves and compared using the log rank test. Additionally, we calculated the area under curve (AUC) to compare the predictive value of PD-L1 expression with baseline serum lipid biomarkers for patient response. Results: Our analysis involved 104 advanced OSCC patients who received NACI. Notably, the top three grade 1-2 treatment-related adverse events (TRAEs) were Alopecia (104; 100%), Anemia (81; 77.9%) and Pruritus (62; 59.6%). Only one patient developed grade 3-4 TRAEs due to increased aminotransferases. The pathological complete response (PCR) rate was 47.1%, and the major pathological response (MPR) rate was 65.4%. Importantly, patients achieving MPR exhibited higher CPS. The diagnostic value of CPS as a biomarker for NACI efficacy was enhanced when combined total cholesterol (TC) level. Our findings from DFS and OS suggested that patients who underwent NACI before surgery experienced improved survival compared to those who accepted the surgery alone. Conclusions: The data from this study proved evidence that NACI treatment is safe and encouragingly efficacious in treating advanced OSCC patients. Citation Format: Jinsong Li, Bowen Li, Shule Xie, Haotian Cao, Zhaoyu Lin, Qunxing Li, Song Fan. Response to neoadjuvant chemoimmunotherapy in resectable locally advanced oral squamous cell carcinoma: a single-center retrospective observational study [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 5091.
Abstract 6629: Cancer-associated nerves regulate anti-tumor immunity in pancreatic cancer
Authors: Ruiyuan Xu, Jianlu Song, Yuan Chen, Xinpeng Yin, Chengcheng Wang, Yupei Zhao
Journal: Cancer Research (2024)

Abstract Nerves serve an emerging component of the tumor microenvironment (TME), contributing to tumorigenesis and cancer progression. Neural invasion (NI) is a common feature of pancreatic ductal adenocarcinoma (PDAC), accounting for distant metastasis and local recurrence. However, the mechanism by which tumor associated nerves (TANs) regulate anti-tumor immunity remains largely elusive. Here, we investigated the association between TANs and immunosuppressive TME to develop more effective therapeutic strategies for PDAC. Using tumor samples of PDAC patients, we identified that the nerves invaded by cancer cells showed increased adrenergic activation accompanied with no parasympathetic or sensory innervation changes. Patients with severe NI were associated with increased catecholamine levels. Additionally, single-cell RNA-sequencing and spatial transcriptome analysis of tumors from patients with PDAC revealed that peri-neural niches of severe NI patients were characterized by decreased CD8+ T cells and increased activity of M2 polarization of tumor-associated macrophages (TAMs), and regulatory T (Treg) cells, which was validated by multiplexed immunofluorescence staining. We further identified that CD8+ T cells expressing β-adrenaline receptors (β-ARs) reduced proliferation and cytokine production when exposure to catecholamines in a dose-dependent manner or co-cultured with dorsal root ganglia pretreated with cancer cells. KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) mice treated with catecholamines accelerated tumor progression by inhibiting T cell-mediated antitumor responses, which was abrogated by surgical sympathectomy of KPC mice. Especially, in an orthotopic PDAC model, nonselective β-blocker propranolol in combination with immune checkpoint blockade (ICB) significantly enhanced active CD8+ T cells with concurrent reduced tumor growth. We suggest a novel regulatory mechanism of inhibiting anti-tumor immunity that can promote cancer progression mediated by TANs invasion. These data establish a close connection between the nerves, cancer cells, and immune cells and provide the potential novel targets of therapeutic approaches in PDAC. Citation Format: Ruiyuan Xu, Jianlu Song, Yuan Chen, Xinpeng Yin, Chengcheng Wang, Yupei Zhao. Cancer-associated nerves regulate anti-tumor immunity in 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 6629.
Abstract 7145: Identification of Debio 0432 as a potent and selective USP1 inhibitor for cancer therapy
Authors: Noemie Luong, Annett Kunze, Nicolas Quesnot, Erin R. Aho, Loren Berry, Scott Boiko, Alex J. Buckmelter, Sebastien Lofek, Selena Vigano, Christophe Chardonnens
Journal: Cancer Research (2024)

Abstract Introduction: Debio 0432 is a Ubiquitin Specific Protease 1 (USP1) inhibitor at preclinical stage. This study presents the first data on this small molecule and its activity as an anti-cancer therapy in multiple preclinical models. USP1 is a deubiquitinase, member of the deubiquitinating enzyme (DUB) family that plays an important role at the replication fork during DNA replication. Its prominent role in DNA repair, targeting Proliferating Cell Nuclear Antigen (PCNA) that regulates polymerase recruitment in the translesion synthesis (TLS), makes it an emergent target in the DNA damage repair (DDR) field. Methods: In silico docking has been used to identify a likely binding site of Debio 0432. Biochemical and cellular assays have been performed to show its activity on the target and in cell lines of different cancer types. In vivo models in cell line derived xenograft (CDX) and patient derived xenograft (PDX) were then used to confirm the activity of the compound and to study PK/PD relationship. Results: Debio 0432 likely binds USP1 in an allosteric pocket and is very selective across the 58 members of the USP family. Furthermore, it does not affect any kinase. Its biochemical activity on USP1 is in the low nanomolar range and cellular activity ranges between from single digit nM to above 1uM. In vivo, Debio 0432 shows antitumor activity in the BRCA mutant breast cancer model MDA-MB-436. The downstream target Ub-PCNA, selected as pharmacodynamic marker, is modulated in a dose and plasma exposure-dependent manner. Further in vivo experiments in PDX models showed dose-dependent activity in different cancer types, in both BRCA wild type and mutant models. Treatments in all in vivo studies were well tolerated. Conclusion: Overall, we show that Debio 0432 is a selective and potent small molecule targeting USP1, an emerging target in the DDR field. It shows good activity in different preclinical models and is well tolerated at active doses. Debio 0432 is currently undergoing IND-enabling studies and in preparation for entry into clinical development. Citation Format: Noemie Luong, Annett Kunze, Nicolas Quesnot, Erin R. Aho, Loren Berry, Scott Boiko, Alex J. Buckmelter, Sebastien Lofek, Selena Vigano, Christophe Chardonnens. Identification of Debio 0432 as a potent and selective USP1 inhibitor for cancer therapy [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 7145.
Abstract 6969: Determining the role of obesity in breast cancer progression
Authors: Alexandra Perlman, Alisa Piekny, Elena Kuzmin, Sylvia Santosa
Journal: Cancer Research (2024)

Abstract Breast cancer, especially triple negative breast cancer, impacts a large proportion of the female population. Approximately ten to fifteen percent of all breast cancer diagnoses will be triple negative. Triple negative breast cancer lacks receptors that are used as therapeutic targets for other forms of breast cancer and has the poorest prognosis. Notably, the age of onset has also decreased, which correlates with the rise in prevalence of obesity. In addition, past studies revealed that maintaining a high BMI from childhood correlates with higher cancer mortality in adulthood. However, the mechanisms by which obesity contributes to cancer progression are not clear. Adipose tissue from different locations (visceral vs. subcutaneous, abdominal vs. femoral) and from patients with obesity from childhood rather than as adults could have different molecular characteristics. Further, depending on the genetic background, different profiles may be more susceptible to environmental cues that could drive their progression. To address this, we are using conditioned media collected from tissues that reflect these differences and determining how they affect TNBC cell lines with distinct genetic profiles. Preliminary data revealed that adipose tissue from both the abdominal and femoral regions of high BMI individuals caused an increase in the proliferation rate of TNBC cell lines. To determine if the adipocytes vs. other cell types in the adipose tissue drive this growth, we are co-culturing mature adipocytes from these tissues with the TNBC cell lines. Recent studies by other groups showed that adipocyte-derived extracellular vesicles could drive the expression of EMT genes in cancer cells. We will purify EVs from the adipocytes and characterize differences in their molecular signatures for different patients to determine which factors cause the change in TNBC progression and correlate this with different fat depots and/or age of onset. We will also measure the effect of adipose tissue and/or adipocytes on other cancer hallmarks including metastasis (migration and invasion) and changes in metabolism. These studies should reveal how adipocytes confer changes in TNBC progression, and how to consider obesity in different treatment regimes. Citation Format: Alexandra Perlman, Alisa Piekny, Elena Kuzmin, Sylvia Santosa. Determining the role of obesity in breast cancer progression [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 6969.
Abstract 6952: The role of interleukin-11 (IL11) in cancer-associated cachexia (CAC)
Authors: Kimberly Drinkwater, Ashlyn Meyers, Samin Kargari, Natalie Crisan, Aaron Mody, Minsub Shim
Journal: Cancer Research (2024)

Abstract Cancer-associated cachexia (CAC), characterized by loss of skeletal muscle and involuntary body weight loss, is responsible for increased chemotherapy toxicity, reduced quality of life, and impaired survival in cancer patients. While interleukin-11 (IL11), one of the IL6 family cytokines, was originally thought to be involved in hematopoiesis, studies increasingly suggest its involvement in tumorigenesis including chemoresistance, metastasis, and survival of cancer cells. However, the precise role of IL11 in CAC has not been determined. Our lab has previously shown that IL11 treatment suppressed the myogenic differentiation of C2C12 myoblasts, suggesting that IL11 may interfere with differentiation and subsequent regeneration of muscle. In this study, we investigated the role of IL11 in cancer-induced muscle wasting using cell culture and mouse models. The mRNA expression of IL11 was highly up-regulated in C26 and Lewis lung carcinoma (LLC) cells, two well-known cachectic mouse cancer cell lines, while its expression was low in a non-cachectic MC38 mouse colon cancer cell line. Knockdown of IL11 in C26 cells using two independent lentiviral shRNAs significantly reduced the mRNA levels of the cytokines involved in CAC including GDF15, LIF, and VEGFA, while the mRNA level of IL6 was not significantly altered. Additionally, IL11 knockdown significantly reduced the mRNA and protein levels of ATF4, CHOP, and TRIB3, suggesting that IL11 may be responsible for the activation of unfolded protein response, an adaptive mechanism for growth, survival, and angiogenesis of cancer. Knockdown of IL11 in C26 and LLC cell lines also significantly reduced the volume of tumors in syngeneic mouse models, while over-expression of IL11 in MC38 cells increased tumor size. Moreover, the knockdown of IL11 in cachectic cancer cells partially prevented the loss of muscle and body weight in tumor-bearing mice, although the amelioration of muscle loss by IL11 knockdown may be associated with the decreased tumor burden. Together, these results indicate that IL11 may contribute to muscle wasting and provide novel insight into the previously unestablished role of IL11 in CAC. Citation Format: Kimberly Drinkwater, Ashlyn Meyers, Samin Kargari, Natalie Crisan, Aaron Mody, Minsub Shim. The role of interleukin-11 (IL11) in cancer-associated cachexia (CAC) [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 6952.
Abstract 5464: Galectin-3 expression in Ewing sarcoma: Modulation of the immune microenvironment in an immunocompetent model
Authors: Yunash Maharjan, Sreya Dey, Elina Mukherjee, Jessica Daley, Kelly M. Bailey
Journal: Cancer Research (2024)

Abstract Objective: Ewing sarcoma is an aggressive cancer of adolescents. Patients with metastatic Ewing sarcoma often receive radiation as part of their treatment protocol. We have demonstrated that both Ewing tumor cells and T cells infiltrating Ewing tumors express Galectin-3 (Gal3), an immunosuppressive protein in the tumor microenvironment. Here, we utilize an immunocompetent, humanized mouse model of Ewing sarcoma to investigate the role of Galectin-3 in the Ewing tumor immune microenvironment both at baseline and following radiation. Specifically, we sought to determine the influence of Galectin-3 on post-radiation inflammation in Ewing sarcoma. Methods: Human Ewing cells -/+ Gal3 expression were generated using CRISPR/Cas 9 technology. Cells -/+ Gal3 were orthotopically injected into humanized mice and allowed to established tumors over ~3 weeks. Tumors were then treated with radiation (or no radiation controls). To also address immune cell expression of Gal3, galectin inhibitors were utilized. Tumors were analyzed by bulk RNA sequencing and flow cytometry analysis (Cytek Aurora) for human CD45, CD3, CD4, CD20, CD8, CD56, CD14, CD16, etc. Peripheral blood controls were also collected and analyzed to ensure consistent baseline immune reconstitution. Results: CHLA10 and TC32 Ewing sarcoma cell lines both demonstrate Gal3 expression at baseline by western blot. CRISPR/Cas 9 knock-out of Gal3 in both cell lines showed successful knock down. Impact on growth and sensitivity to radiation in vitro was assessed by live cell Incucyte assays. Tumors in humanized mice were established utilizing these cells (or Gal3 expressing non-targeting controls) and changes in the post-radiation transcriptional profiles were assessed. Immune cells infiltrating these tumors were also quantified. Ongoing work focuses on additional characterization of these tumor infiltrating immune cell populations following radiation therapy and the impact of broader galectin inhibition on this effect. Conclusion: This work contributes to the understanding of radiation-induced tumor inflammatory responses in Ewing sarcoma by defining the role of tumor and T cell galectin-3 expression inn Ewing immunobiology. Next steps will explore translational opportunities based on these findings. Citation Format: Yunash Maharjan, Sreya Dey, Elina Mukherjee, Jessica Daley, Kelly M. Bailey. Galectin-3 expression in Ewing sarcoma: Modulation of the immune microenvironment in an immunocompetent model [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 5464.
Abstract 5288: Soy isoflavone genistein reboosts targeted therapy sensitivity in triple negative breast cancer
Authors: Taiwo Bankole, Zhenhai Li, Yuanyuan Li
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) is a very aggressive type of breast cancer that does not expression important proteins called estrogen, progesterone and HER2. This makes TNBC hard to treat because it does not respond to common targeted treatments. However, recent treatments using the immune system to target key immune proteins such as PD-1 and PD-L1 have been successful in many types of cancer. This form of immunotherapy works by blocking PD-1/PD-L1 pathway and leads to stimulating the body's own immune system to recognize and attack cancer cells, thus providing a potential new treatment option for TNBC patients. Nevertheless, only approximately 30% of TNBC patients may respond to these drugs, suggesting the majority of TNBC patients would not benefit from these innovative immunotherapies. It is believed that low levels of immune cells and PD-L1 expression in tumors are the primary reasons for the lack of response or resistance to anti-PD-1/PD-L1 treatments. The use of nontoxic and healthy food and nutrition to increase treatment response is an emerging field of cancer research. Our studies showed that adding genistein (GE), a bioactive dietary component found in soybean products such as soy milk, soy protein and tofu, could significantly enhance the efficacy of anti-PD-1 immunotherapy in a TNBC mouse model that was previously not responsive to the treatment. Our research also found that soybean GE can increase tumor immune response by significantly recruiting active immune cells into the tumor and increasing PD-L1 expression. Our studies will help to establish a novel nutrition-based intervention targeting TNBC patients who might not qualify for this treatment initially. Eventually, we will develop a novel strategy of administering a tailored dietary plan to resensitize these patients to emerging anti-PD-1/PD-L1 immunotherapies. Citation Format: Taiwo Bankole, Zhenhai Li, Yuanyuan Li. Soy isoflavone genistein reboosts targeted therapy sensitivity in triple negative breast 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 5288.
Abstract 270: Dissecting the effects of p53 mutation and p53 loss on pancreatic tumor microenvironment
Authors: Yang Chen
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignant disease with a dismal prognosis. In the past decades, a plethora of genetically engineered mouse models (GEMMs) with autochthonous pancreatic tumor development have greatly facilitated the studies of pancreatic cancer. Commonly used GEMMs of PDAC often harbor the oncogenic KRAS driver mutation (KrasG12D), in combination with either p53 mutation by knock-in strategy (Trp53R172H) or p53 loss by conditional knockout (Trp53cKO) strategy, in pancreatic cell lineages. However, the systematic comparison of the tumor microenvironment between KrasG12D; Trp53R172H (KPmut) mouse models and KrasG12D; Trp53cKO (KPloss) mouse models is still lacking. In this study, we conducted cross-dataset single-cell RNA-sequencing (scRNA-seq) analyses to compare the pancreatic tumor microenvironment from KPmut mouse models and KPloss mouse models, especially focusing on the cell compositions and transcriptomic phenotypes of major cell types including cancer cells, B cells, T cells, granulocytes, myeloid cells, cancer-associated fibroblasts, and endothelial cells. We identified the similarities and differences between KPmut and KPloss mouse models, revealing the effects of p53 mutation and p53 loss on oncogenic KRAS-driven pancreatic tumor progression. Citation Format: Yang Chen. Dissecting the effects of p53 mutation and p53 loss on pancreatic tumor microenvironment [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 270.