bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4004: Targeting drug-resistant acute myeloid leukemia (AML) cells using novel casein kinase II (CK2) inhibitor
Authors: Duke Koby , Mercer Katherine , Rajaiah Rajesh , Daniyal Muhammad , Qiu Yi , Purandare Ashok , Uzun Yasin , Zhang Lijun , Klink Morgann , Gowda Chandrika 
Published: April 2023

Abstract
Introduction: Protein Kinase CK2 level and activity are high in Acute Myeloid Leukemia (AML) stem cells. Genetic inhibition of CK2 promotes apoptosis and shows synergistic cytotoxic activity with cytotoxic therapy. Here we report the anti-leukemia efficacy of a novel and potent small molecule inhibitor of CK2, BMS-135, in AML mouse models.
Methods: AML cell lines (n=8) and primary AML cells (n=3) representing various AML genetic subtypes (MLL rearranged, FLT3-ITD, TP53 mutation) were tested in vitro. Cells were treated with serial dilution of BMS-135 for 24 to 48hrs, and cell viability was measured using calorimetric cell viability (WST) assay. Similarly, treated cells were analyzed for cell cycle distribution, apoptosis, and colony formation. We measured the mRNA and protein levels of known CK2 targets. RNA sequencing and gene expression analysis was done to evaluate gene expression changes following treatment with BMS-135. Cell line-derived xenograft and patient-derived xenograft of AML were treated with BMS-135 at a dose of 7.5mg/kg oral gavage twice daily for 21 days or vehicle.
Results: Combined in vitro and in vivo experiments establish the efficacy of BMS-135. Cytotoxicity at inhibitory concentrations of 30-800nM, G0-G1 cell cycle arrest, increased apoptosis, and poor colony formation following treatment were noted consistently in all cells. Single-drug treatment with BMS-135 achieved 50-80% leukemia inhibition and significantly prolonged survival in treated mice after 3 weeks of therapy. Following in vivo treatment with BMS-135, we confirmed the inhibition of known CK2 targets (AKT, PI3K, Bcl-xL) in the bone marrow and spleen AML cells. No significant myelosuppression or organ toxicity was noted in tumor-bearing mice following 3 weeks of treatment when compared to vehicle-treated mice. BMS-135 shows synergistic cytotoxic activity with daunorubicin and cytarabine.
Conclusions: Selective inhibitor of CK2 is well tolerated and shows superior in vivo efficacy and target inhibition in a series of AML cells and xenografts. BMS-135 works synergistically with cytotoxic agents like daunorubicin and cytarabine. These results support further pre-clinical characterization and clinical development of BMS-135 for treating AML in combination with cytotoxic therapy.
Citation Format: Koby Duke, Katherine Mercer, Rajesh Rajaiah, Muhammad Daniyal, Yi Qiu, Ashok Purandare, Yasin Uzun, Lijun Zhang, Morgann Klink, Chandrika Gowda. Targeting drug-resistant acute myeloid leukemia (AML) cells using novel casein kinase II (CK2) inhibitor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4004.
Abstract 401: Developing KRAS G12C inhibitor-resistant tumor models for efficacy evaluation of next-generation anticancer therapies
Authors: Zhou Jun , Ye Zi , Bo Ning , Zhang Dan , Hua Li , Nie Chenpan , Wang Jingjing , Kumari Rajendra , Price Leo , Xu Xiaoxi 
Published: April 2023

Abstract
Background: AMG510, a novel KRAS G12C mutation-specific inhibitor approved in 2021 by FDA, was the first therapy to directly target the KRAS oncoprotein in KRAS-mutant cancers with other direct KRAS G12C inhibitors currently being investigated in multiple clinical trials. However, the emergence of resistance in patients who initially were responsive is a challenge. Uncovering the underlying mechanism of resistance would support the identification and development of novel therapies to overcome drug resistance. In this study, we generated a panel of KRAS G12C inhibitor-resistant tumor models by introducing a secondary KRAS mutation on top of G12C for use as in vitro and in vivo tools to develop possible strategies to overcome such resistance.
Methods: First, by using CRISPR/Cas9, we introduced a secondary KRAS mutation, including Y96C, Y96D and Y96S in MIA PaCa, which harbours a homozygous KRAS G12C mutation. Point mutation knock-in was validated by sanger sequencing and cell identity was confirmed by SNP. Then cell viability was measured by CellTiter-Glo after 5 days incubation with AMG510 and MRTX849. RAS-MAPK pathway activity was assessed in the parental and mutant cell lines Y96D by Western blot. Xenograft of MIA PaCa KRAS G12C/Y96D cells l was also established.
Results: Successful homozygous point mutation knock-in was achieved as confirmed by sanger sequencing. The double mutant cells displayed the similar growth rate as well as the morphology. In cell viability assays, relative to KRAS G12C parental cells, cells expressing the double-mutant alleles showed marked resistance to AMG510 and MRTX849. Consistent with the effects on cell viability, persistent phosphorylated ERK (pERK) and pRSK levels was also observed in KRAS G12C/Y96D expressing cells even at high concentrations of MRTX849, indicating sustained RAS-MAPK activity. In addition, MIA PaCa-KRAS G12C/Y96D was able to grow in vivo and will be used for pharmacological evaluation of KRAS inhibitors.
Conclusion: These double-mutant cells can be used to assess preclinical in vitro/in vivo efficacy of KRAS-targeted therapeutics. Crown Bioscience is in the process of developing a series of KRAS G12C inhibitor-resistant cell lines to better facilitate efficacy testing of KRAS-targeted therapeutics.
Citation Format: Jun Zhou, Zi Ye, Ning Bo, Dan Zhang, Li Hua, Chenpan Nie, Jingjing Wang, Rajendra Kumari, Leo Price, Xiaoxi Xu. Developing KRAS G12C inhibitor-resistant tumor models for efficacy evaluation of next-generation anticancer therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 401.
Abstract 4070: Engineering TRAIL-expressing immune cells to target GI malignancies
Authors: Srinivasan Praveen R. , Zhang Shengliang , El-Deiry Wafik S. 
Published: April 2023

Abstract
While adoptive cell therapies, such as chimeric antigen receptor (CAR) T cells, have had promising results in hematologic malignancies, their translation to solid tumors has been mostly unsuccessful. A significant limitation to use of adoptive cell therapy in solid tumors has been life-threatening off-target toxicities, including acute respiratory toxicity and cytokine release syndrome. The native T cell program releases a diverse range of toxic proteins upon activation, including interferons, interleukins, perforins, and granzymes. Rather than activate the native T-cell program, selective expression of tumor-targeting agents may be advantageous. TNF-related apoptosis-inducing ligand (TRAIL) is known to selectively target tumor cells with minimal toxicity to normal tissues. We therefore engineered Jurkat (a human CD4+ T cell leukemia cell line) and THP-1 (a human monocytic leukemia cell line) cells to constitutively express wild-type TRAIL using a third-generation lentivirus system. These cells killed multiple cell lines across colorectal and pancreatic cancer, thus representing a possible therapeutic strategy to target GI malignancies. Furthermore, the addition of the ferroptosis induced erastin enhanced cytotoxicity of TRAIL-engineered cells, suggesting that targeting ferroptosis in addition to apoptosis is a promising strategy for enhancing immune killing. Future work will focus on overcoming TRAIL resistance, tumor trafficking, and alteration of the tumor microenvironment.
Citation Format: Praveen R. Srinivasan, Shengliang Zhang, Wafik S. El-Deiry. Engineering TRAIL-expressing immune cells to target GI malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4070.
Abstract 4092: Development of nucleotide metabolic reprogrammed CAR T cell therapy suitable for solid tumors
Authors: Hu Yue , Sarkar Abhijit , Song Kevin , Hook Magnus , Heczey Andras , Song Xiaotong 
Published: April 2023

Abstract
CAR T cell therapy has represented an exciting breakthrough in the treatment of patients with hematologic malignancies. In contrast, the antitumor activity of CAR T cell therapy in solid tumors has been modest so far in clinical studies. The suboptimal clinical efficacy is a result of multiple factors including limited T cell trafficking, persistence, and the immunosuppressive tumor microenvironment (TME). While current strategies utilize costimulatory molecules and cytokines to activate CAR T cells, a key but largely overlooked problem of CAR T cell therapy is nutrient competition between tumor cells and T cells in the nutrient-poor TME. In our previous studies, a metabolic screen identified inosine as an alternative fuel for T cells which can support T cell growth and function in the absence of glucose. T cells could metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase. Moreover, we demonstrated that T cells have advantage over cancer cells in utilizing inosine, and supplementation with inosine enhances the antitumor efficacy of PD-1 mAb and adoptive T cell transfer in mouse models. In this study, we therefore engineered CAR T cells to express CD26 on the cell surface and a secreted adenosine deaminase (ADA) fused with an anchor. These metabolic reprogrammed CAR (designated as MRCAR) T cells exerts their activities through different mechanisms. ADA irreversibly converts adenosine to inosine, overcoming adenosine-mediated immunosuppression and providing inosine for CAR T cell growth, while CD26 induces a rich chemokine receptor profile enabling CAR T cells to traffic to solid tumors. We demonstrated that CD26-overexpressed CAR T cells displayed superior migration capacity and resisted TGF-beta suppression, while the CD26 expression on unmodified CAR T cells was significantly down-regulated by TGF-beta. We further proved that ADA is conditionally secreted in stress condition (i.e., low pH, lack of nutrient and oxygen) based on ADA’s biological characteristics, suggesting that ADA activates CAR T cells as a trans-signaling to the CAR construct in a tumor specific manner. Remarkably, we observed that the MRCAR T cells inhibit tumor growth more effectively than unmodified CAR T cells in both Huh7 human hepatocellular carcinoma (GPC3-MRCAR) and A549 human non-small cell lung cancer (HER2-MRCAR) mouse models. Thus, MR-CAR T cell therapy represents a promising approach to improve CAR T cell therapy against solid tumors.
Citation Format: Yue Hu, Abhijit Sarkar, Kevin Song, Magnus Hook, Andras Heczey, Xiaotong Song. Development of nucleotide metabolic reprogrammed CAR T cell therapy suitable for solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4092.
Abstract 4143: Enhancing adaptive immune responses with telomerase-mediated telomere targeting therapeutics in hepatocellular carcinoma
Authors: Flusche Ann Marie , Shay Jerry , Ogunrinde Ilgen Mender 
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and is the third leading cause of cancer-related deaths. In recent years, immune checkpoint inhibitors (ICIs) have improved treatment of solid tumors including HCC. However, due to low response rates with current standard of care immunotherapy and angiogenic inhibitors, there is an urgent need to develop new therapeutic strategies to improve the efficacy of immunotherapy against HCC. Our lab has shown that 6-thio-2’ deoxyguanosine (6-thio-dG), a telomerase-mediated telomere targeting agent, is incorporated into newly synthesized telomeres by telomerase and causes rapid telomere uncapping, thereby inducing telomere-associated DNA damage in cancer cells. These damaged DNA fragments can then lead to enhanced adaptive immune responses. In this study, we evaluated the therapeutic effects of 6-thio-dG in vitro and in vivo together with ICIs in liver tumors to determine whether combining immunotherapy with a telomere-targeting agent could serve as an effective strategy for HCC. To explore whether 6-thio-dG is effective in killing liver cancer cells, we ran cell viability and telomere dysfunction induced foci (TIF) assays to assess DNA damage on telomeres in vitro and compared tumor volumes of mice following 6-thio-dG monotherapy, immunotherapy, and sequential treatment of 6-thio-dG and immunotherapy in syngeneic mouse models. We observed that 6-thio-dG reduced cell viability and induced telomere dysfunction in a panel of human and mouse liver cancer cells. In addition, 6-thio-dG enhanced the therapeutic effect of immunotherapies in liver syngeneic mouse models. Overall, our findings show that the telomere-targeting anticancer agent 6-thio-dG inhibits HCC as a single monotherapy and/or sequential therapy together with immunotherapies. These results provide an experimental rationale for a potentially new immunochemotherapy strategy based on the administration of a telomere-targeting agent.
Citation Format: Ann Marie Flusche, Jerry Shay, Ilgen Mender Ogunrinde. Enhancing adaptive immune responses with telomerase-mediated telomere targeting therapeutics in hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4143.
Abstract 4204: Incidence of early-onset and average-onset colon cancer among Medicaid beneficiaries with and without HIV: a cohort study
Authors: Joshu Corinne , Calkins Keri , Rudolph Jacqueline E. , Xu Xiaoqiang , Wentz Eryka , Kaur Maneet , Pirsl Filip , Coburn Sally B. , Moore Richard D. , Lau Bryan 
Published: April 2023

Abstract
Background: Colorectal cancer has increased among people living with HIV (PLWH). Studies have reported either no difference or lower risk of colorectal cancer incidence among PLWH as compared to the general population. We evaluated the incidence of colon cancer, both average-onset (diagnosed at 50 or older) and early-onset (diagnosed at less than 50), among a diverse population of people with and without HIV who have comparable sociodemographic factors and access to care.
Methods: We obtained Medicaid Analytic eXtract (MAX) data from 2001-2015 for 14 states. We included 42,244,679 unique individuals with at least 7 months of continuous eligibility. HIV and colon cancer diagnoses were identified from inpatient and other non-drug claims. We used Cox proportional hazards regression models to assess the incidence of colon cancer, controlling for age, sex, race/ethnicity, calendar year of enrollment, state of enrollment, and number of comorbidities. Analyses were also adjusted for or stratified by age, sex, and race/ethnicity.
Findings: We identified 191 colon cancer cases among 523,969 person-years among PLWH and 15,098 colon cancer cases among 63,579,078 person-years among beneficiaries without HIV. Colon cancer incidence increased with age among beneficiaries with and without HIV. Overall, HIV was modestly, inversely associated with colon cancer incidence (HR:0.84, 95%CI: 0.73, 0.98). PLWH 18-39 years old had increased hazard of colon cancer as compared to those without HIV (HR:1.67, 95%CI: 1.06, 2.65); this association was attenuated after adjustment for co-morbidities. HRs were null when early-onset colon cancer was assessed among all beneficiaries less than 50 years. PLWH had lower hazard of average-onset colon cancer compared to those without HIV (HR:0.81, 95%CI: 0.68, 0.96); this association was statistically significant among male, but not female, beneficiaries.
Interpretation: Compared to beneficiaries without HIV, PLWH had a lower risk of average-onset colon cancer. PLWH had higher incidence of early-onset colon cancer, but this difference was attenuated after adjustment for comorbid conditions.
Citation Format: Corinne Joshu, Keri Calkins, Jacqueline E. Rudolph, Xiaoqiang Xu, Eryka Wentz, Maneet Kaur, Filip Pirsl, Sally B. Coburn, Richard D. Moore, Bryan Lau. Incidence of early-onset and average-onset colon cancer among Medicaid beneficiaries with and without HIV: a cohort study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4204.
Abstract 4214: Exposure to air pollution during pregnancy and risk of premenopausal breast cancer: A Swedish nation-wide cohort study including more than 1 million women
Authors: Edlund Jessica Lena , Gustafsson Malin , Linden Jenny , Wu Wendy Yi-Ying , Oudin Anna , Harlid Sophia 
Published: April 2023

Abstract
Background: Air pollution has been linked to an increased risk of breast cancer, but most previous studies have not considered if the exposure occurred during windows of susceptibility, such as pregnancy. Pregnancy is a period of rapid changes to both the breast tissue and the surrounding microenvironment. Exposures during this sensitive time-period could therefore result in erosion of the protective effect of pregnancy and make women more susceptible to external breast cancer risk factors. Aim: The aim of this study was to identify associations between air pollution exposure, occurring specifically during pregnancy, and risk of premenopausal breast cancer.
Method: Using nation-wide data from Swedish registers we constructed a cohort consisting of all women in Sweden who gave birth to their first child between January 1st 1991 and December 31st 2015. Women with a cancer diagnosis prior to pregnancy were excluded. Data on air pollution (yearly averages of PM10, PM2.5 and NO2), was collected from the residence of women during, and to some extent between, pregnancies. Associations between air pollution and premenopausal breast cancer is evaluated using Cox proportional hazards regression to estimate hazard ratios (HR), using age as the time scale and including appropriate confounders such as socioeconomic variables, comorbidities and family history of breast or ovarian cancer.
Results: The full cohort included 1 074 925 unique women and 2 302 256 pregnancies (the mean number of pregnancies for each woman was 1.75). During the study period, 13 292 (1.2 %) were diagnosed with breast cancer before they turned 50 years.
Conclusion: Our working hypothesis is that women exposed to higher levels of air pollution during pregnancy will have a higher risk of breast cancer. This large-scale study will have enough statistical power to detect the effect of air pollution on breast cancer risk, taking into account exposure both during and between pregnancies.
Citation Format: Jessica Lena Edlund, Malin Gustafsson, Jenny Linden, Wendy Yi-Ying Wu, Anna Oudin, Sophia Harlid. Exposure to air pollution during pregnancy and risk of premenopausal breast cancer: A Swedish nation-wide cohort study including more than 1 million women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4214.
Abstract 4215: Air pollution exposure during pregnancy and risk of premenopausal breast cancer among women with a family history of cancer
Authors: Hettinger Anna , Edlund Jessica , Gustafsson Malin , Lindén Jenny , Wu Wendy Yi-Ying , Oudin Anna , Harlid Sophia 
Published: April 2023

Abstract
Background: Having a family history of breast or ovarian cancer is an important risk factor for premenopausal breast cancer. One reason for this could be that women with an underlying genetic susceptibility are more sensitive to environmental exposures due to gene-environment interactions. This might be especially important if the exposure occur during windows of susceptibility, such as pregnancy. Aim: The aim of this project is to determine if exposure to air pollution during pregnancy is associated with premenopausal breast cancer in a population with a known family history of breast or ovarian cancer.
Methods: The project is based on nation-wide data from Sweden’s national registers and utilizes a cohort study design. The original cohort consists of women who gave birth to their first child between 1992 and 2015 (n=1 074 925), from this cohort we will select women with at least one first degree relative with breast or ovarian cancer (confirmed through register linkage). The primary outcome is primary breast cancer diagnosed before 50 years of age, and the exposure is levels of air pollution (PM10, PM2.5 and NO2) at the participant’s home address during each pregnancy. Cox proportional hazards regression will be used to determine hazard ratios using age as the time-scale.
Results: The registry based linkage makes it possible to distinguish between both relational context (mother or sister), number of afflicted first degree relatives and type of cancer (breast or ovarian). All included women also have at least one recorded pregnancy (prior to any cancer diagnosis).
Conclusion: This large scale study will be able to provide important information about the impact of air pollution exposure during pregnancy on breast cancer risk in a population with a documented family history of breast or ovarian cancer.
Citation Format: Anna Hettinger, Jessica Edlund, Malin Gustafsson, Jenny Lindén, Wendy Yi-Ying Wu, Anna Oudin, Sophia Harlid. Air pollution exposure during pregnancy and risk of premenopausal breast cancer among women with a family history of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4215.