tbuckley/cabot-search huggingface dataset:
Abstract 4508: Defining PIM kinase protein regulation and PROTAC for pre-clinical testing
Authors: Hope Liou, John Brognard, Rolf Swenson, Pedro Torres-Ayuso, Noel Warfel
Journal: Cancer Research (2024)

Abstract The PIM kinase family are serine/threonine kinases known to be overexpressed in castration-resistant prostate cancer (CRPC). PIM1, an isoform of PIM, is known to regulate cell survival, migration, and proliferation. Uniquely, PIM kinases are constitutively active due to the lack of a regulatory domain. Therefore, PIM protein levels are reflected in PIM activity and are regulated by protein degradation and synthesis. PIM inhibitors have been developed, targeting the PIM kinase activity and inhibiting phosphorylation of downstream targets, but have had limited efficacy. Our lab and others demonstrate that PIM inhibitor treatment increases total PIM protein levels, suggesting that PIM kinases control protein stability via autophosphorylation. To elucidate the mechanism of autophosphorylation dependent regulation of PIM1, we used phospho-proteomics to identify potential autophosphorylation sites on PIM1. We have identified overexpression of deubiquitinase USP28 inhibiting degradation of PIM1, leading to the investigation of the role of F-box protein Fbw7 in regulating PIM1. Dominant-negative expression of Fbw7 results in increased PIM1 total protein. Additionally, coimmunoprecipitation of Fbw7 knockdown cells resulted in decreased PM1 ubiquitination compared to control. Therefore, we have identified Fbw7 as a putative E3 ligase responsible for PIM1 degradation. To address the limited efficacy of PIM inhibitors, we have developed the first PIM-PROTAC (PIMTAC) with our collaborators. Proteolysis targeting chimera (PROTAC) is a promising approach to eliminating the pro-tumorigenic effects of PIM. The PIMTAC selectively targets PIM kinases for degradation and we have demonstrated in vitro efficacy. PIMTAC successfully maintains degradation of all isoforms of PIM for over 72 hours. In vitro assessment of anti-tumor efficacy demonstrated increased apoptotic death with PIMTAC alone compared to PIM inhibitor or docetaxel. Furthermore, dual treatment of PIMTAC and docetaxel had more apoptotic death compared to PIM inhibitor with docetaxel. We aim to develop the PIMTAC for pre-clinical testing. Citation Format: Hope Liou, John Brognard, Rolf Swenson, Pedro Torres-Ayuso, Noel Warfel. Defining PIM kinase protein regulation and PROTAC for pre-clinical testing [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 4508.
Abstract 1858: Discovery of AT86474, a highly efficacious anti-ROR1 ADC utilizing a proprietary payload
Authors: Ban Xiong Tan, Xi Yun Zhang, You Xue Wu, Yin Wen Cheng, Shao Jun Liu, Ping Du, Chen Zhong, Bin Zou
Journal: Cancer Research (2024)

Abstract ROR1 is a pseudo kinase that is involved in the non-canonical Wnt signaling pathway and is highly expressed during early embryonic development. In adult tissues, ROR1 is expressed at very low levels but its increased expression is observed in hematological cancers and a broad range of solid tumors. AT86474 is a highly homogeneous antibody drug conjugate incorporating AxcynCYSTM technology that allows reproducible site-specific conjugation with DAR4 composition greater than 97%. AT86474 utilizes a proprietary payload derived from an FDA approved drug that was optimized in-house for increased potency and with altered PK properties to limit systemic exposure. In vitro, the payload displays broad sub-nanomolar activity across multiple cancer cell lines, including those resistant to paclitaxel, DM1, MMAE and DXd. The payload is conjugated via an enzyme-cleavable linker optimized for solubility, stability, and high drug to antibody ratios. AT86474 uses a humanized and optimized monoclonal antibody that demonstrates selective binding to ROR1-positive cells and subsequent internalization, sub-nanomolar potency in vitro and strong bystander effects. AT86474 was evaluated in a preclinical CDX mouse model of ovarian cancer, where substantial tumor growth inhibition was observed with two weekly doses at as low as 1 mg/kg. As ROR1 over-expression is also observed in many solid tumors, such as pancreatic, gastric, breast and lung cancers, the use of AT86474 can be expanded to benefit a large patient population. Citation Format: Ban Xiong Tan, Xi Yun Zhang, You Xue Wu, Yin Wen Cheng, Shao Jun Liu, Ping Du, Chen Zhong, Bin Zou. Discovery of AT86474, a highly efficacious anti-ROR1 ADC utilizing a proprietary payload [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 1858.
Abstract 4861: Incidence rates of bladder and kidney cancers among U.S. military servicemen: Comparison with the rates in the general U.S. population
Authors: Julie A. Bytnar, Katherine A. McGlynn, Sean Q. Kern, Craig D. Shriver, Kangmin Zhu
Journal: Cancer Research (2024)

Abstract Background: The military population may differ from the general population in factors related to the incidence of bladder and kidney cancers. However, incidence rates of these cancers have not been systematically compared between the two populations. This study compared incidence rates of bladder and kidney cancers and their trends between active-duty servicemen and men in the general U.S. population. Methods: Data were obtained from the Department of Defense’s (DoD) Automated Central Tumor Registry (ACTUR) and the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database. Patients were active-duty servicemen in ACTUR and men in SEER who were diagnosed with malignant bladder and kidney cancers and 18-59 years at diagnosis from 1990-2013. Age-adjusted rates, incidence rate ratios (IRR), and their 95% confidence intervals (95% CI) were compared between the two populations by age, race, and cancer stage. Trends in the incidence were also compared. Results: Incidence rates were lower in ACTUR than SEER for bladder cancer overall (IRR=0.55, 95% CI=0.48-0.62) and by age, race, or tumor stage. However, for 50-59-year-old men, the rates did not differ between the populations. Trend analysis showed bladder cancer incidence decreased more in ACTUR than SEER over the study period. Kidney cancer incidence rates were marginally lower overall (IRR=0.92, 95% CI=0.84-1.00) and significantly lower for 30-49-year-old Black men in the military than the general population. For kidney cancer, the trends were similar between the two populations with increased incidence from 1999 to 2013. Conclusion: Lower bladder and kidney cancer incidence in ACTUR, notably in younger individuals, may be primarily associated with healthier status and better health care. The lack of differences in bladder or kidney cancer incidence among 50-59-year-old men between the populations might result from more cumulative military-related exposures in this age group, which effects were offset by healthier status and better medical care. Disclaimer: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of NCI, USUHS, HJF, the DoD or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products or organizations does not imply endorsement by the US Government. Citation Format: Julie A. Bytnar, Katherine A. McGlynn, Sean Q. Kern, Craig D. Shriver, Kangmin Zhu. Incidence rates of bladder and kidney cancers among U.S. military servicemen: Comparison with the rates in the general U.S. population [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 4861.
Abstract 3980: Investigating the role of host obesity in promoting immunotherapy resistance
Authors: Henry Nnaemeka Ogbonna, Zachary Roberts, Haley Kvarnberg, Francesca Dempsey, Patrick N. Song, Anna G. Sorace, Lyse Norian
Journal: Cancer Research (2024)

Abstract Obesity is linked to an increased risk of various cancers, including renal cell carcinoma (RCC). Many RCC patients have obesity at diagnosis and treatment initiation, and our lab has found that this significantly impairs immunotherapy outcomes. Both preclinical and clinical reports, from our lab and others, have demonstrated that obesity reduces the efficacy of CD8+ T cell-dependent immunotherapy by increasing pro-tumorigenic IL-1β. Combining anti-PD-1 based therapy with anti-IL-1β triggers the recruitment of CD8+ T cells and improves the efficacy of anti-PD-1 based immunotherapy. However, the mechanistic links between obesity and increased IL-1β production remains unknown. Our objective is to identify mechanisms promoting IL-1 β-driven immunosuppression within renal tumors of obese mice. In our in vivo studies, we utilized a BALB/c mouse model of diet-induced obesity (DIO) and lean controls in combination with the Renca-Luc RCC cell line. Using flow cytometry and western blot, we respectively assessed leukocyte populations producing IL-1β and tumor energetics. Flow cytometry revealed that intra-tumoral IL-1β is produced primarily by tumor associated macrophages (TAMS). Immunoblotting demonstrated that increased IL-1β production is linked to altered mitochondrial function and ATP production. These early findings support the hypothesis that obesity driven IL-1β expression is mediated by tumor-associated macrophages and that mitochondrial dysfunction drives immune suppression. Understanding these molecular and immune-related mechanisms may pave the way for novel strategies to reduce immunosuppression in obese RCC patients, thus improving immunotherapeutic efficacy and overall clinical outcomes. Citation Format: Henry Nnaemeka Ogbonna, Zachary Roberts, Haley Kvarnberg, Francesca Dempsey, Patrick N. Song, Anna G. Sorace, Lyse Norian. Investigating the role of host obesity in promoting immunotherapy resistance [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 3980.
Abstract 359: The Hippo pathway on breast tumor recurrence &amp;lt;and&amp;gt; collateral vulnerability to ferroptosis
Authors: Chao-Chieh Lin, Jen-Tsan Chi
Journal: Cancer Research (2024)

Abstract Comparing with primary breast tumors, recurrent breast cancers are generally considered more aggressive and incurable. Therefore, novel molecular strategies are urgently needed to target these type of cancers. Here, we report that murine recurrent breast tumor cells are highly susceptible to ferroptosis, a novel form of cell death. Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), the receptor for collagen I, is upregulated in ferroptosis-sensitive recurrent tumor cells. Ferroptosis inducer, erastin treatment leads to DDR2 upregulation and phosphorylation, independent of collagen I. Furthermore, DDR2 silencing not only prevent ferroptosis but also abolished the robust cell proliferation of murine recurrent tumor cells. Both the ferroptosis protection and reduction of active cell growth may be compatible with the compromised YAP/TAZ upon DDR2 inhibition. Collectively, these findings suggest the role of DDR2 in recurrent breast tumors to drive aggressive cell growth but at the same time reveals its weakness to YAP/TAZ-mediated ferroptosis, providing potential molecular mechanism to target recurrent breast cancers. Citation Format: Chao-Chieh Lin, Jen-Tsan Chi. The Hippo pathway on breast tumor recurrence &amp;lt;and&amp;gt; collateral vulnerability to ferroptosis [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 359.
Abstract 3975: A therapeutic screening platform for assessing antigen-specific T cell-mediated tumor killing <i>in vitro</i>
Authors: Elsenoor Klaver, Henry Leonard, Elizabeth Lieverse, Oliver Brand, Olivier Reelfs, Christopher Kirkham, Lauren Schewitz-Bowers, Louise Brackenbury
Journal: Cancer Research (2024)

Abstract Many cancers remain resistant to conventional therapies, consequently there has been an exponential rise in the number of therapeutics harnessing the power of the immune system in an oncology setting, with several remarkable examples of success. High frequencies of infiltrating tumor-specific T cells have been linked to improved patient outcomes, which highlights the importance of uncovering how therapeutics can enhance their function. To explore this functionality in a preclinical setting it is critical to have physiologically relevant models. Here, we demonstrate that common issues, such as low precursor frequencies and restricted HLA-types can be overcome via access to HLA-typed samples and use of expansion platforms which attain high numbers of antigen-specific T cells. Furthermore, we show how these systems enable vaccine immunogenicity screening and assessment of therapeutic efficacy. Healthy blood donations were screened for HLA type and antigen-specific T cells were expanded by either co-culture with peptide-pulsed dendritic cells or polyclonal stimulation following multimer enrichment and FACS sorting. Following expansion, the large number of antigen-specific T cells generated enabled the T cells to be assessed via phenotyping, cytokine secretion, or functional killing assays in a 2D or 3D tumor setting. Tumor targets with either 1) endogenous antigen expression, 2) antigen introduced via lentiviral overexpression or 3) peptide loading of MHC class I were utilized. Validated readouts for measuring antigen-specific killing included flow cytometry and time-lapse imaging (IncuCyte), alongside quantification of antigen-specific IFNɣ responses by ELISpot. These pre-clinical platforms represent a suite of physiologically relevant T cell assays which can be used to perform candidate selection in tumor associated antigen/neoantigen vaccine drug development programs, pharmacological inhibition of checkpoint pathways, or co-stimulatory agonist discovery. In combinatorial approaches with radio- or chemotherapy, the development of novel immunotherapies offers hope to many patients with treatment-resistant cancers. Citation Format: Elsenoor Klaver, Henry Leonard, Elizabeth Lieverse, Oliver Brand, Olivier Reelfs, Christopher Kirkham, Lauren Schewitz-Bowers, Louise Brackenbury. A therapeutic screening platform for assessing antigen-specific T cell-mediated tumor killing in vitro [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 3975.
Abstract 3591: Upregulation of CXCL8 is an early step in the oncogenic transition of human thyroid cells by <i>BRAFV600E</i>
Authors: Rhitajit Sarkar, Priyanka Bolel, Joanna Klubo-Gwiezdzinska, Marvin C. Gershengorn
Journal: Cancer Research (2024)

Abstract Introduction: BRAFV600E is one of the most common oncogenic mutations in human thyroid cancers, especially in papillary thyroid carcinoma (PTC). However, the early molecular changes caused by this mutation have not been studied previously in human thyrocytes in vitro. Methods: Primary cultures of cells derived from noncancerous thyroid tissue of patients (at least n=3) were infected with BRAFV600E adenovirus to mimic the mutated condition. Changes induced by the infection were measured at early times (&amp;lt;24h). Transcriptome analysis was performed on infected thyrocytes (n=6) to determine the highest differentially expressed genes between the control and infected groups, which were then verified at the gene and protein levels. RNAi downregulation experiments were performed to determine the cross-regulatory function of the genes. Results: The induction of BRAFV600E mutation, confirmed at the protein level, increased proliferation of the cells, and morphological changes were observed at approximately 24h post-infection. The decreased expression of thyroid-specific genes, viz. TSHR, TG, and TPO were observed after &amp;gt;72h post-introduction of BRAFV600E mutation. Transcriptome and protein expression analysis of BRAFV600E-positive thyrocytes showed the overexpression of chemokines CXCL8 and CXCL12, and upregulation of endothelial cell-specific molecule 1 (ESM1). These molecules are known to be associated with increased neoangiogenesis and proliferation. Functional studies showed that siRNA knockdown of CXCL8 decreased the expressions of CXCL12 and ESM1, whereas knockdown of either CXCL12 or ESM1 did not decrease the expression of CXCL8. Conclusion: Increased proliferation, de-differentiation, upregulation of chemokines, and endothelial-specific factor are effects associated with BRAFV600E-driven thyroid carcinogenesis. CXCL8 appears to play an important early regulatory role in this process. Citation Format: Rhitajit Sarkar, Priyanka Bolel, Joanna Klubo-Gwiezdzinska, Marvin C. Gershengorn. Upregulation of CXCL8 is an early step in the oncogenic transition of human thyroid cells by BRAFV600E [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 3591.
Abstract 2134: Disaggregating breast cancer mortality trends in Asian American women from 2005-2020
Authors: Mia Marcotte, Yashi Chauhan, Vedha Penmetcha, Caroline Thompson, Candice Thompson, Malathi Srinivasan, Gloria Kim, Xinran Qi, Robert Huang, Adrian Bacong
Journal: Cancer Research (2024)

Abstract Background: Breast cancer (BC) is the second leading cause of death among women and has disproportionately higher rates of mortality in certain racial groups, including Asian Americans (AA). While differences in BC mortality between AA and other racial groups have been identified, few studies have disaggregated nationwide AA mortality data. Methods: Using National Vital Statistics System mortality data, BC-related deaths were analyzed among AA groups (Asian Indian, Chinese, Filipina, Japanese, Korean, Vietnamese), Native Hawiian and Pacific Islanders (NHPIs), and non-Hispanic Whites (NHWs) from 2005-2020. We calculated cancer proportional mortality ratios (PMRs), age-adjusted mortality rates (AAMRs), standard mortality ratios, and used JoinPoint regression for average annual percentage change (AAPC). Results: Among 13677 AA, 522 NHPI, 501282 NHW descendants, 14.3% cancer deaths were due to BC. PMRs increased for all racial groups except Filipina. AAMRs significantly decreased in NHWs (AAPC -1.61; CI -1.70 to -1.48) while significantly increasing for aggregate AAs (AAPC 0.45; CI 0.08 to 0.94). Among AAs, Filipinas had the highest AAMR. AAMRs significantly increased for Asian Indians (AAPC 2.05; CI 1.20 to 3.46), Filipinas (AAPC 0.61; CI 0.15 to 1.46), Koreans (AAPC 2.72; CI 1.57 to 4.65) and Vietnamese women (AAPC 3.63; CI 2.26 to 6.20), but significantly decreased for Japanese (AAPC -1.41; CI -2.22 to -0.53). Conclusions: We observed heterogenous and converging BC mortality trends across AA groups. These trends elucidate which populations within the broader AA group have disproportionately higher death rates and therefore should be targeted for BC prevention protocols (e.g., Asian Indian and Filipina). Identifying such trends can also help elucidate disparities in cancer care and the overall social determinants that affect women with BC. Understanding disaggregated trends can inform more inclusive screening practices and culturally tailored interventions and treatments to reduce BC deaths in vulnerable populations. Citation Format: Mia Marcotte, Yashi Chauhan, Vedha Penmetcha, Caroline Thompson, Candice Thompson, Malathi Srinivasan, Gloria Kim, Xinran Qi, Robert Huang, Adrian Bacong. Disaggregating breast cancer mortality trends in Asian American women from 2005-2020 [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 2134.
Abstract 1850: From proteomic analysis to early investigations of combining inhibitors targeting PCNA and histone deacetylase
Authors: Caroline M. Li, Krystine Garcia-Mansfield, Robert G. Lingeman, Long Gu, Robert J. Hickey, Patrick Pirrotte, Linda H. Malkas
Journal: Cancer Research (2024)

Abstract Proteomic changes were investigated in a neuroblastoma cell line, SK-N-AS, treated with a small molecule inhibitor, AOH1996, designed to specifically bind proliferating cell nuclear antigen (PCNA) in cancer. PCNA is crucial to DNA replication, DNA repair, transcription, cell cycle control, and chromatin organization through interactions with different proteins. Pathway analysis of differential protein expressions between treated and untreated cells revealed less G2/M DNA damage checkpoint regulation and decreased assembly of RNA polymerase complex. Phosphoproteomic analysis by PTM Signature Enrichment Analysis (PTM-SEA) identified signatures of kinase activities, signaling pathways, and perturbations. Specifically, the histone deacetylase inhibitors belinostat and vorinostat were identified as enriched perturbation signatures. Both inhibitors were tested in combination with AOH1996 in SK-N-AS as well as cell lines derived from breast, lung, ovarian, and pancreatic cancer, revealing drug synergies at specific dose combinations. Western blot analysis showed that belinostat decreased protein expression of PCNA, suggestive of mechanistic synergies with AOH1996+belinostat combination therapies. Our proteomic analysis reveals a therapeutic potential of combining AOH1996 and histone deacetylase inhibitors for treating cancer with possibly lower drug dose and toxicities compared to single drug treatment. Citation Format: Caroline M. Li, Krystine Garcia-Mansfield, Robert G. Lingeman, Long Gu, Robert J. Hickey, Patrick Pirrotte, Linda H. Malkas. From proteomic analysis to early investigations of combining inhibitors targeting PCNA and histone deacetylase [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 1850.