bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C093: Unlocking the potential of Metformin: Revealing its impact on colorectal cancer cells at a molecular level
Authors: Hijazi Jamila , Khoueiry Pierre , Eid Assaad , Darwiche Nadine , Nemer Georges
Published: December 2023

Metformin is a drug commonly used to treat type-2 diabetes, but recent studies suggest that it may also have anti-cancer effects by influencing cell cycle arrest and apoptosis. While previous studies have focused on metformin's effect on mTor, the downstream genetic pathways underlying its anti-proliferation mechanism remain unclear. Identifying these pathways may help predict patient response and allow for tailored treatment plans.   This study aims to investigate the early genetic pathways involved in colon cancer using an in-vitro cell model and assess the impact of metformin on cell cycle and cancer proliferation in colon cancer cells, taking into account the p53/p21 status. Four different metformin concentrations were used on the HCT116 colon cancer cell line and its genetic modified forms. To determine cell viability and to measure cell cycle and apoptosis, MTT assay and flow cytometer were used. RNA-seq was performed on HCT116 after 24 hours of metformin treatment and  pathway analysis was conducted using the Pathway Studio software.   Results showed a significant decline in cell viability in response to metformin treatment, with an increase in the apoptosis phase. Transcriptomic analysis revealed that over 3,000 genes were significantly down-regulated, while 1,200 genes were up-regulated. Metformin promotes cell death and fragmentation at the SubG0 level, particularly in the case of p21 null, but p53 likely plays a primary role in driving apoptosis in colorectal cancer cells.   In conclusion, metformin has potential in inhibiting proliferation and inducing apoptosis in colorectal cancer cells, affecting molecular pathways involved in the disease. However, further investigation through next-generation sequencing and molecular targeting is necessary to fully understand the disease at different levels.

Citation Format: Jamila Hijazi, Pierre Khoueiry, Assaad Eid, Nadine Darwiche, Georges Nemer. Unlocking the potential of Metformin: Revealing its impact on colorectal cancer cells at a molecular level [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C093.
Abstract C098: Targeting high-expression LGR5 by an R-spondin-based peptibody-drug conjugate is efficacious against neuroblastoma
Authors: Toh Yukimatsu
Published: December 2023

Neuroblastoma (NB) is a pediatric tumor that predominantly affects infants and young children, with high-risk (HR) disease being diagnosed in approximately 50% of patients at 18 months or older. LGR4-6 are membrane receptors that bind RSPO ligands, activating Wnt signaling. LGR5, specifically expressed in adult stem cells, is highly upregulated in gastrointestinal (GI) cancers. In NB, high LGR5 expression is associated with aggressive disease and poor outcomes. Knockdown of LGR5 reduces cell growth in LGR5-high NB cell lines. The R-spondin-LGR5 axis has emerged as a potential therapeutic target due to its involvement in stem cell proliferation and self-renewal, as well as its overexpression in certain cancers, including neuroblastoma. RSPO-based peptibody drug conjugate (PDC) is a promising approach to target LGR4/5 for HR-NB therapy. PDCs are designed to selectively deliver the potent Pyrrolobenzodiazepine (PBD) dimer SG3199 to LGR5 high-expressing neuroblastoma cells using a peptibody that mimics the R-spondin binding activity of LGR5 ligands. Our preclinical study showed the efficacy of DAR2 R-spondin-based PDCs, generated through microbial transglutaminase-mediated site-specific conjugation, inducing cell death both in vitro and in vivo. Furthermore, these PDCs demonstrate reduced tumor growth and improved survival in xenograft animal models of neuroblastoma derived from the SK-N-AS cell lines. Our findings suggest that targeting LGR5 with RSPO2-based PDCs may offer a promising potential for treating neuroblastoma.

Citation Format: Yukimatsu Toh. Targeting high-expression LGR5 by an R-spondin-based peptibody-drug conjugate is efficacious against neuroblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C098.
Abstract C134: The MDM2 degrader KTX-049 is highly potent in TP53 wild-type (p53 WT) Merkel cell carcinoma (MCC)
Authors: Ananthapadmanabhan Varsha , Chutake Yogesh , Filiatrault Jessica , Schalm Stefanie , McDonald Alice , DeCaprio James A
Published: December 2023

Background and aims: MCC is a highly aggressive neuroendocrine carcinoma of the skin with a high fatality rate. Clonal integration of Merkel cell polyomavirus (MCPyV) occurs in about 80% of all MCCs. These virus positive MCC (MCCP) tumors have a low tumor mutational burden and usually express wild type (WT) p53 (TP53). In contrast, virus negative MCC (MCCN) tumors present a predominantly UV mutational signature, a high mutational burden and often have alterations in p53. MCCP tumors express MCyV small T antigen (ST) and a truncated form of large T antigen (LT). The MCyV ST in MCCP tumors, recruits MYCL and EP400 to form the SLaP complex that specifically trans-activates several genes. A direct target of the SLaP complex is MDM2, an E3 ubiquitin ligase of p53 that inhibits p53-mediated tumor suppression. The use of MDM2 inhibitors can stabilize p53 in p53 WT tumors. However, currently, no MDM2 inhibitors are approved for treatment of MCC. Furthermore, MDM2 degraders have not been studied in the context of MCC. Here, we aim to analyze the efficacy of KTX-049, a potent MDM2 degrader, in MCC and compare its efficacy to the previously reported and highly potent MDM2 inhibitor, DS-3032.

Experimental procedures: Established MCCP cell lines with functional p53, non-functional p53 and two p53 WT MCCP patient derived cell lines (PDCLs) were treated with KTX-049 or DS-3032 and the effect on cell viability was analyzed using a luminescence-based assay. Apoptosis induction was studied using the caspase 3-7 Glo assay. The p53 response in MCC cells post KTX-049 or DS-3032 treatment was assessed by western blot (WB) analysis of p53 and its downstream effectors.

Results:  KTX-049 and DS-3032 reduced cell viability of p53 WT MCCP cell lines but not cell lines with non-functional p53. Notably, all sensitive cell lines had ≥100-fold lower absolute IC50 values for KTX-049 as compared to DS-3032. Additionally, KTX-049 effectively reduced cell viability of the sensitive cell lines even after brief exposures.  KTX-049 also triggered a rapid and sustained p53 response and apoptosis induction in p53 WT MCC cells.

Conclusions: KTX-049 is a promising MDM2 degrader effective against p53 WT MCC cell lines. These results provide evidence for in vivo exploration of KTX-049 in models of MCC.

Citation Format: Varsha Ananthapadmanabhan, Yogesh Chutake, Jessica Filiatrault, Stefanie Schalm, Alice McDonald, James A DeCaprio. The MDM2 degrader KTX-049 is highly potent in TP53 wild-type (p53 WT) Merkel cell carcinoma (MCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C134.
Abstract C159: ALK signaling primes the DNA damage response allowing exploitation of ATR inhibition in ALK-driven Neuroblastoma
Authors: Borenäs Marcus , Umapathy Ganesh , Lind Dan E. , Lai Wei-Yun , Guan Jikui , Johansson Joel , Jennische Eva , Schmidt Alexander , Gabre Jonatan , Bemark Mats , Hall Michael N. , Eynden Jimmy Van den , Hallberg Bengt , Palmer Ruth H.
Published: December 2023

High-risk neuroblastoma currently presents significant clinical challenges. Oncogenes such as MYCN and ALK, which are often involved in high-risk neuroblastoma, result in increased replication stress in cancer cells, offering therapeutically exploitable options. We previously identified an ATR/ALK inhibitor combination as an effective therapeutic approach in two independent genetically modified mouse neuroblastoma models. Here we show that ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. Remarkably, the importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to ALKi/ATRi combination treatment that resulted in robust and sustained responses. Here, we describe the mechanism underlying the remarkable tumor response to combined ATR/ALK inhibition. Our results identify a unique ability of ATR inhibition to trigger tumor regression in neuroblastoma and underscore the importance of further exploring combined ALK/ATR inhibition in neuroblastoma, particularly in high-risk patient groups with oncogene-induced replication stress.

Citation Format: Marcus Borenäs, Ganesh Umapathy, Dan E. Lind, Wei-Yun Lai, Jikui Guan, Joel Johansson, Eva Jennische, Alexander Schmidt, Jonatan Gabre, Mats Bemark, Michael N. Hall, Jimmy Van den Eynden, Bengt Hallberg, Ruth H. Palmer. ALK signaling primes the DNA damage response allowing exploitation of ATR inhibition in ALK-driven Neuroblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C159.
Abstract IA001: Patient-derived tumor organoids to probe the cancer immune interface
Authors: Dijkstra Krijn K
Published: December 2023

The development of rational (combination) immunotherapies is limited by an incomplete understanding of what determines a tumor’s sensitivity to immune attack. Despite great heterogeneity in resistance mechanisms between patients, functional model systems to study cancer/immune cell interactions at the level of individual patients have been lacking. Here we highlight the potential of organoid/immune cell co-cultures as individualized models of anti-tumor immunity.  First, we established a co-culture platform of autologous tumor organoids and peripheral blood lymphocytes from patients with mismatch-repair deficient colorectal cancer (dMMR-CRC) and non-small-cell lung cancer (NSCLC). This allows enriching tumor-reactive T cells from peripheral blood of individual patients, and creating personalized test systems to evaluate their capacity to kill matched tumor organoids. Second, subclonal immune escape is a major barrier to achieving complete responses to cancer immunotherapies. While most tumours consist of multiple genetically distinct clones, directly investigating the potential for immune escape at the clonal level has been impossible so far, due to challenges in isolating and propagating individual tumour subclones from human cancers for functional studies. By leveraging the multi-region TRACERx study, we established multi-region organoid libraries of >20 parallel sublines from patients with NSCLC. Co-cultures of each subline with autologous tumour infiltrating lymphocytes (TIL) reveal substantial heterogeneity in the capacity of individual clonal sublines to elicit a T-cell response. We show that subclonal immune escape can be mediated by antigen-dependent and -independent mechanisms. These results show (i) that tumour evolution can give rise to distinct cancer clones with intrinsic differences in immune evasion capacity and (ii) provide an approach to prospectively identify and isolate immune evading subclones from cancer patients. Third, analysis of a clinical cohort of patients treated with anti-PD1 therapy revealed that gamma delta T cells are critical mediators of the response in dMMR-CRC patients with genetic inactivation of beta-2-microglobulin (B2M). Co-cultures of organoids and gamma delta T cells provide direct evidence that loss of B2M increases reactivity of patient-derived gamma delta T cells towards tumor organoids. This highlights the need for functional models that move beyond conventional T cells. Future developments are directed towards establishment of complex co-culture systems to study how communication between organoids and immune cells is mediated by cell surface factors and secreted molecules, and how cellular crosstalk is altered in cancer.

Citation Format: Krijn K Dijkstra. Patient-derived tumor organoids to probe the cancer immune interface [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA001.
Abstract IA008: Mechanisms and consequences of pancreatic cancer stromal evolution
Authors: Sherman Mara
Published: December 2023

The mechanisms underlying evolution of tumor-associated stroma remain poorly understood.  In solid tumors featuring a prominent stromal reaction, an improved understanding of the functions and origins of abundant stromal cell types may facilitate the development of new and effective therapies.  Pancreatic ductal adenocarcinoma (PDAC) is the quintessence of a fibro-inflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type which drives the stromal reaction in PDAC, and recent reports suggest that stromal CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types which support and others which suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. We have developed a novel mouse model to track PSC differentiation and function during pancreatic tumor progression in vivo. This model revealed that PSC-derived CAFs in fact give rise to a numerically minor but functionally significant subset of PDAC CAFs, and may represent a viable therapeutic target. We adapted our mouse model to enable targeted ablation of PSCs and derivative CAFs within their host tissue for the first time. Functional studies in this model reveal non-redundant functions for PSC-derived CAFs in shaping the PDAC microenvironment, and highlight the significance of mesenchymal lineage heterogeneity for pancreatic tumorigenesis. Further, we find that tumor genotype with respect to p53 status dictates stromal evolutionary routes with respect to cell of origin, a finding that may extend to additional cancer cell-intrinsic genomic alterations. Together, these findings shed light on mechanisms that shape the tumor microenvironment during pancreatic cancer progression, and may hold relevance in additional solid tumor types.

Citation Format: Mara Sherman. Mechanisms and consequences of pancreatic cancer stromal evolution [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA008.
Abstract LB_B06: Single cell transcriptomics guided identification of antigen combinations for the design of logic-gated CAR therapies
Authors: Madan Sanna , Chang Tiangen , Wang Binbin , Schäffer Alejandro A. , Ruppin Eytan
Published: December 2023

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant efficacy in treating hematological cancers but faces challenges in treating solid tumors due to antigen heterogeneity and off-tumor, on-target expression in normal tissues. To combat these challenges, we developed a novel genetic algorithm approach to analyze patient tumor single-cell transcriptomics data. This algorithm identifies combinations of cell surface antigens specific to cancer cells by incorporating "AND," "OR," and "NOT" logic. Our method is generalizable to combinations of any size and demonstrates rapid convergence across different parameter choices. When applied to breast cancer datasets, our algorithm identified optimal combinations of triplet antigens that outperformed clinically tested single target antigens in discriminating tumor cells from non-tumor cells across patient samples. In sum, our approach may guide the design of logic-gated CAR therapies aimed at multiple target antigens, thereby increasing the safety and selectivity of these therapies.

Citation Format: Sanna Madan, Tiangen Chang, Binbin Wang, Alejandro A. Schäffer, Eytan Ruppin. Single cell transcriptomics guided identification of antigen combinations for the design of logic-gated CAR therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B06.
Abstract LB_B09: Loss of folate enzyme ALDH1L1 promotes cancer cell proliferation and xenograft tumor growth
Authors: Fogle Halle M , You Mikyoung , Sharma Jaspreet , McCormac Jonathan , Krupenko Natalia I , Krupenko Sergey A
Published: December 2023

Background: ALDH1L1 (aldehyde dehydrogenase 1 family member L1, or cytosolic 10-formyltetrahydrofolate dehydrogenase), an enzyme in folate metabolism, is abundantly expressed in several tissues. This enzyme converts 10-formyltetrahydrofolate to tetrahydrofolate (THF) and CO2 while reducing NADP+ to NADPH. ALDH1L1 is ubiquitously downregulated human cancers through DNA promoter methylation, while one cancer cell line, RT4 (derived from papillary bladder cancer), maintains high expression of ALDH1L1. Aims: We tested the hypothesis that loss of ALDH1L1 expression could provide a proliferative and survival advantage for cancer cells and tumor growth.

Methods: The ALDH1L1 gene in RT4 cells was knocked down using the shRNA technique. Proliferation was evaluated using MTT assays and xCELLigence real-time cellular analysis (RTCA). Cell migration was assessed by wound healing assays. NADP+/NADPH levels and reduced folate pools were measured by ELISA and the ternary complex assays, respectively. RT4 tumors were generated in nude mice from RT4 lines by subcutaneous injections into both flanks of athymic nude mice. Tumor growth was monitored every week for 12-weeks, after which the tumors were harvested. ALDH1L1 levels in tumors were measured by Western Blot assays, while tumor proliferation was assessed by the Ki-67/H&E staining of the tumor tissue sections.

Results: We found that doubling time did not differ between the wild-type (RT4) and shControl (shC) cell lines. Doubling time for the sh506 and sh572 clones was shorter than the controls by 68% and 79%, respectively. Proliferation and migration were significantly increased in sh506 and sh572 cells compared to the control lines. NADP+/NADPH levels were significantly increased for only the sh572 clone. Interestingly, tumor volume and weight were increased in both sh506 and sh572 derived tumors compared to shC tumors. The sh506 and sh572 tumors also showed a slightly increased Ki-67 proliferation index. The ALDH1L1 protein expression was completely lost in sh572 tumors but only partially decreased in sh506 tumors.

Conclusions: Our study indicates that RT4 clones lacking ALDH1L1 have increased cell proliferation and tumor growth compared to wild-type RT4 cells, supporting the role of ALDH1L1 as a metabolic regulator of proliferation.

Citation Format: Halle M Fogle, Mikyoung You, Jaspreet Sharma, Jonathan McCormac, Natalia I Krupenko, Sergey A Krupenko. Loss of folate enzyme ALDH1L1 promotes cancer cell proliferation and xenograft tumor growth [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B09.
Abstract LB_C15: PI3Kδ/γ inhibitor as a novel immune-regulatory radiosensitizer
Authors: Yoon Yi Na , Kim Jae-Sung
Published: December 2023

Radiotherapy is known to augment anti-tumor immunity, yet its concurrent induction of immunosuppressive responses presents a significant obstacle to efficacious treatment. This study showed that a new PI3Kδ/γ inhibitor along with irradiation promotes systemic anti-tumor immunity and abscopal response by reducing activity of immune suppressive cells. The combination systemically decreased proliferation of regulatory T cells (Tregs) and enhanced the number of tumor specific CD8a+ T cells in tumor microenvironment, thereby leading to tumor regression. Interestingly, this effect lasts for 14 days after radiation and even causes distant tumors to regress, known as the abscopal effect. Moreover, molecular analysis shows that the combination treatment creates immune-stimulatory tumor microenvironment in tumors, suggesting that the combined therapy converts immune cold tumor into hot. These findings highlight the promise of using PI3Kδ/γ inhibitors to enhance anti-tumor immunity in solid tumors treated with radiotherapy, providing the evidence for the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.

Citation Format: Yi Na Yoon, Jae-Sung Kim. PI3Kδ/γ inhibitor as a novel immune-regulatory radiosensitizer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C15.
Abstract LB_C17: Spatial tumor immune microenvironment analysis of KRAS-mutated Non-Small Cell Lung Cancer and immunotherapy outcome
Authors: Zhao Dan , Li Haiqing , Mambetsariev Isa , Mirzapoiazova Tamara , Chen Chen , Fricke Jeremy , Wheeler Deric , Arvanitis Leonidas , Pillai Raju , Afkhami Michelle , Chen Bihong T. , Sattler Martin , Erhunmwunsee Loretta , Massarelli Erminia , Kulkarni Prakash , Amini Arya , Armstrong Brian , Salgi Ravi
Published: December 2023

Targeting KRAS in lung cancer is promising and the immune modulatory effects of KRAS inhibition is interesting. Understanding the local tumor immune architectures are important to overcome the treatment resistance of immunotherapy and targeted therapy. We conducted spatial immune tumor microenvironment (iTME) profiling using FFPE samples of 25 KRAS mutated non-small cell lung cancer patients treated with immune checkpoint inhibitors (ICIs), which included 12 responders and 13 non-responders. We used an eleven-markers panel (CD3, CD4, CD8, Foxp3, CD68, Arginase-1, CD33, HLA-DR, Pan-Keratin (PanCK), PD-1 and PD-L1). We studied the tumor and immune cell compositions and spatial features at single cell level with cellular neighborhood and fractal analysis. We found spatial features and the different subgroups of CD68 positive cells and Foxp3+ cells associated with responses and resistance to ICIs. We found that CD68+ cells, CD33+ cells and Foxp3+ cells are associated with resistance to ICIs of KRAS mutated lung cancer. Interestingly, we found that cells had non-nuclear expression of Foxp3 were associated with ICIs resistance. We identified a population of CD68 weakly positive cells in the tumor tissues were associated with responses to ICIs. We identified two different groups of non-responders: one with high diversity of cells and one with low diversity, while all the responders had high diversity. We identified nine cellular neighborhoods (C0-C8) with C0 in majority of non-responders, which was enriched with PanCK+, CD33+, and Foxp3+ T regulartory cells. Conversely, most responders were enriched with C3 and C6-C7, which contained CD8+ T cells and CD68 weakly positive cells. Our study had revealed the spatial immune features of KRAS mutated lung cancer and their association with immunotherapy outcome which could be helpful for KRAS targeting and immunotherapy.

Citation Format: Dan Zhao, Haiqing Li, Isa Mambetsariev, Tamara Mirzapoiazova, Chen Chen, Jeremy Fricke, Deric Wheeler, Leonidas Arvanitis, Raju Pillai, Michelle Afkhami, Bihong T. Chen, Martin Sattler, Loretta Erhunmwunsee, Erminia Massarelli, Prakash Kulkarni, Arya Amini, Brian Armstrong, Ravi Salgi. Spatial tumor immune microenvironment analysis of KRAS-mutated Non-Small Cell Lung Cancer and immunotherapy outcome [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C17.
Abstract PR017: Discovery and clinical evaluation of a potent and selective A2A/2B dual receptor antagonist
Authors: DeMong Duane , Ranganath Sheila , Cumming Jared , Larsen Matthew , Zhang Yonglian , Plummer Christopher , Ali Amjad , Palmieri Anthony , Barry Evan , Daublain Pierre , Gupta Pranav , Chatterjee Manash , Giranda Vincent , Presland Jeremy , Schneider Sebastian , Ciaccio Paul , Tatosian Daniel , Sather Aaron , Turnbull Ben , Silverman Steven , Chobanian Harry , Krishnamurthy Harini , Wnek Richard , Afshar Roshi , Crowley Stephen , Miller Alita , Ayers Mark , Whitehead Alan , Hinton Marlene , Chiang Derek , Orr Robert , Chrencik Jill
Published: December 2023

Elevated adenosine levels present in the tumor microenvironment (TME) produce a net immunosuppressive effect through inhibition of T cell function by two mechanisms of action: Direct T cell effects via A2A receptor agonism and indirect T cell effects via agonism of A2A and A2B receptors on myeloid cells. Our team sought to identify a small molecule dual antagonist of the A2A and A2B receptors with the ability to decrease the immunosuppressive effects of adenosine in the TME and restore anti-tumor immune response. Drawing on our prior experience in the design of A2A receptor antagonists for the potential treatment of Parkinson’s disease, we developed a molecule with sub-nanomolar and single-digit nanomolar affinities for the A2A and A2B receptors respectively and greater than 100-fold selectivity over the related A1 and A3 receptors. A single dose assessment of this molecule in human subjects demonstrated the ability to achieve >99% target engagement (TE) at the A2A receptor and >90% TE at the A2B receptor at trough concentration. This presentation will, for the first time, describe the discovery and early clinical evaluation of this molecule, including disclosure of the structure, human pharmacokinetics, safety, and tolerability.

Citation Format: Duane DeMong, Sheila Ranganath, Jared Cumming, Matthew Larsen, Yonglian Zhang, Christopher Plummer, Amjad Ali, Anthony Palmieri, Evan Barry, Pierre Daublain, Pranav Gupta, Manash Chatterjee, Vincent Giranda, Jeremy Presland, Sebastian Schneider, Paul Ciaccio, Daniel Tatosian, Aaron Sather, Ben Turnbull, Steven Silverman, Harry Chobanian, Harini Krishnamurthy, Richard Wnek, Roshi Afshar, Stephen Crowley, Alita Miller, Mark Ayers, Alan Whitehead, Marlene Hinton, Derek Chiang, Robert Orr, Jill Chrencik. Discovery and clinical evaluation of a potent and selective A2A/2B dual receptor antagonist [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR017.
Abstract A012: Perceptions about the need for colorectal cancer screening among male refugees in Salt Lake City
Authors: Onigbogi Olanrewaju , Kah Kebba
Published: December 2023

Background: Colorectal Cancer (CRC) disproportionately affects Blacks in the United States (US) with an incidence rate >20% compared with Whites. In addition, Blacks are diagnosed at an earlier age and with more advanced disease. The population of migrants from Africa and the Middle East increased about four-fold over the past three decades. Therefore, increasing the uptake of CRC screening in this population may be critical in reducing the disparities in cancer-related morbidity and mortality in the US in the future. This study was therefore designed to elicit the perceptions of immigrants about the need for CRC screening. Methods: Twenty-three willing participants who identified as refugees from Africa or the Middle East who arrived within the past 2 years were recruited into three Focus Group Discussion (FGD) sessions in Salt Lake City. The discussions were audio-taped, transcribed and coded using the Dedoose software. Inter-observer variability was 74%. Results: Nineteen respondents (82%) reported awareness of the existence of CRC screening possibilities. Ten (43%) indicated that they will be willing to do the test if readily offered. Five major themes were identified: (1) Mistrust- Distrust of the system due to unfulfilled promises as refugees (2) Fear- fear of cancer based on past experiences (3) Fatalism-the belief that screening cannot lead to cure of cancer and (4) Doubts- doubts about whether Western culture can truly manage cancer. Conclusion: Perceptions about the need for CRC screening are accompanied by myths based on past experiences. There is also a need to explore targeted CRC prevention education with culture or religion specific inputs to improve CRC screening uptake among this population.

Citation Format: Olanrewaju Onigbogi, Kebba Kah. Perceptions about the need for colorectal cancer screening among male refugees in Salt Lake City [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A012.
Abstract A013: Advancing colorectal cancer outreach & screening strategies: Tailoring approaches for two-spirit and urban Native LGBTQIA2S+ populations
Authors: Abrams Corinne E.
Published: December 2023

Background: The focus of this one-year collaborative initiative between the Center for Indigenous Cancer Research at Roswell Park and Northwestern University’s Institute of Sexual and Gender Minority Health and Wellbeing is to refine and customize an existing colorectal cancer (CRC) screening program to suit the unique needs of Two-Spirit and Native American LGBTQ+ urban populations. This undertaking, grounded in exploratory and explanatory qualitative methodologies, is not intended to test a predefined hypothesis, but rather aims to learn, understand, and adapt based on community input and participation. Methods: The project's methodology incorporates two main objectives: (Objective 1) Conducting virtual roundtables with representatives from the Two-Spirit and Native LGBTQ+ community in NYC, with the goal of understanding indigenous perspectives on CRC outreach and screening, and to garner insights on how to tailor these interventions for Native sexual and gender minority populations in urban settings; (Objective 2) Applying qualitative data gleaned from Objective 1 to modify NCI-endorsed materials, with the aim of more effectively conveying outreach and screening information to Two-Spirit and Native LGBTQ+ urban communities. Results: The initiative has engaged a Two-Spirit artist and educator to assist in the organization and co-facilitation of six virtual roundtable conversations, involving a total of 14 participants. Each 90-minute dialogue aimed to solicit input on current education materials, as well as suggestions for their adaptation. A team of five Northwestern University medical students collaborated on the project, contributing to the analysis of the collected qualitative data. Next Steps: Findings from this initiative will offer crucial insights into how the visuals, messaging, and information contained in the S2S colorectal cancer education materials can be revised to better engage Two-Spirit and Native LGBTQ+ individuals. By the project's conclusion, partners will possess clear, community-informed directives on how to adapt CRC outreach and screening resources, paving the way for future testing and implementation.

Citation Format: Corinne E. Abrams. Advancing colorectal cancer outreach & screening strategies: Tailoring approaches for two-spirit and urban Native LGBTQIA2S+ populations [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A013.
Abstract A027: Creating partnerships to deliver community-based interventions for cancer prevention in a historically African American community
Authors: Rechis Ruth , Gardiner Haley , Oestman Katy , Nutt Stephanie , Walsh Michael T.
Published: December 2023

Be Well Communities™ is MD Anderson’s signature place-based approach for cancer prevention and control, working with communities to promote wellness and address modifiable risk factors for cancer. In this project, the planning phase of the Be Well Communities’ model was implemented in Acres Homes, a neighborhood in northwest Houston with more than 57,000 residents. While the changing demographics show increasing numbers of residents of Hispanic descent (43% of the population), Acres Homes still experiences effects of a legacy of Blacks experiencing poverty; more than half of the population of Acres Homes resides in census tracts that are considered areas of persistent poverty. Further, it is a medically underserved area with relatively high rates of unhealthy behaviors, as compared to Healthy People 2030 goals. To work toward addressing the disparities in health outcomes experienced by community residents, a community advisory group (Steering Committee) including residents, non-profit organizations, health care partners, city and county agencies, plus other stakeholders, was convened and aligned through a structured process to develop shared goals, foster multisector collaboration (as measured by a stakeholder survey administered twice), and enhance community capacity to improve health outcomes through development of a Community Action Plan. Clear, achievable goals were developed, multisector collaboration was enhanced, and more than 400 hours of capacity building support led to a Community Action Plan focused on healthy eating and active living, including 15 evidence-based interventions led by 18 organizations. The majority (93%) of the Steering Committee reports that this plan reflects community priorities and will reach the residents most in need. In the first 2 years of implementation nearly 40% of the residents of the community have been reached by programs including more than 5,000 residents participating in physical activity opportunities, classes and over 1000 individuals receiving outreach from a Community Health Worker within the safety-net hospital system to receive access to healthy food access and nutrition education programming. By listening and developing trust, the Be Well Communities team successfully worked with Acres Homes residents and organizations to enhance community capacity to address health inequities in one of Houston’s most historic communities. 

Citation Format: Ruth Rechis, Haley Gardiner, Katy Oestman, Stephanie Nutt, Michael T. Walsh Jr.. Creating partnerships to deliver community-based interventions for cancer prevention in a historically African American community [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A027.
Abstract A047: Increasing cancer-related community-engagement strategies among Historically Black Colleges and Universities and Minority Serving Institutions
Authors: Jeremiah Rohan D. , Murray Marcus , Standifer Maisha , Kendall LeChaun , Wright Carrie , Savonen Candace , Leeks Jeff
Published: December 2023

Addressing cultural beliefs and barriers is imperative to successfully designing and implementing behavior change interventions to increase cancer screening and treatment among underserved communities. Community-based participatory research (CBPR) fosters proven strategies that reduce barriers to cancer screening in several diverse population groups. Citizen scientists are laypersons who do not have formal science training but receive training to engage in research efforts responsive to community needs. Project Brotherhood, a community-based health organization on Chicago’s southside, has developed a community engagement model known as the Murray Model. It specifically engages black men in improving their health status. One aspect is engaging black men as citizen scientists to address cancer disparities within their communities. Evidence shows that citizen scientists were better equipped to understand lung cancer risks and increased their advocacy for better health within their communities. In partnership with Project Brotherhood and the University of Illinois Cancer Center, the National Cancer Institute, Informatics Technology for Cancer Research (ITCR) Training Network (ITN) Program is scaling up the citizen scientist Train-the-Trainer program at historically black colleges and universities and minority-serving universities. The Train-the-Trainer ITCR citizen scientist program is partnering with the Morehouse School of Medicine to increase its community and academic capacities in the Atlanta metro area to address cancer disparities.

Citation Format: Rohan D. Jeremiah, Marcus Murray, Maisha Standifer, LeChaun Kendall, Carrie Wright, Candace Savonen, Jeff Leeks. Increasing cancer-related community-engagement strategies among Historically Black Colleges and Universities and Minority Serving Institutions [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A047.
Abstract A070: The influence of cultural factors on health-seeking behaviors regarding prostate cancer among African immigrant men in the United States
Authors: Kaninjing Ernest , Ogunsanya Motolani , Van Voorhis Kaitlin , Asiedu Gladys , Kokayi Assata , Brennan Rae Walker , Young Mary Ellen , Odedina Folake
Published: December 2023

Background: The increasing number of African immigrants in the United States has contributed to the diversity of the country's Black population. However, there is limited research on the impact of immigration, particularly regarding chronic diseases like cancer, within the sub-Saharan African immigrant (SSAI) community. To address this gap, this study aimed to explore cultural factors among SSAIs to better understand the drivers of health disparities in prostate cancer outcomes. Methods: A qualitative approach using grounded theory was employed for this study. Participants were purposefully recruited to reflect the cultural diversity among SSAIs. Recruitment occurred at health fairs, community events and by snowball approach.  In-depth interviews were conducted with 16 participants, including prostate cancer survivors. Nine participants have lived in the US for at least 10 years. The average age of participants was 51 years. Country of birth for study participants include, Nigeria, Ghana, Cameroon, Kenya, and Ethiopia. Interviews were transcribed, verified, and de-identified then imported into NVivo 12 software. Four research team members, three of them African immigrants, performed open and axial coding, with consensus on the emerging findings. Results: This study identified several key cultural factors influencing SSAI men’s health behaviors. These factors include the perception of cancer in their country of birth, the low priority given to preventative care in their country of origin, and reluctance to embrace a Westernized diet, the perception of cancer in their country of origin as a death sentence, viewing cancer as a spiritual/religious attack, and associating cancer with affluence. In addition, these cultural factors made participants hesitant to discuss cancer, relying on religion for healing instead of medical care, and seeking healthcare only for cure. Conclusion: This study illuminates key cultural factors among SSAI men that influence their health-seeking behaviors. These findings highlight the need for culturally tailored behavioral interventions to address these factors and improve health outcomes within this understudied population.

Citation Format: Ernest Kaninjing, Motolani Ogunsanya, Kaitlin Van Voorhis, Gladys Asiedu, Assata Kokayi, Rae Walker Brennan, Mary Ellen Young, Folake Odedina. The influence of cultural factors on health-seeking behaviors regarding prostate cancer among African immigrant men in the United States [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A070.
Abstract A118: Prevalence and risk factors of breast cancer diagnoses among Native Hawaiian & Pacific Islander women
Authors: McNally Sarah A. , Salas-Escabillas Daniel J. , Sowizral Nicholas A. , Panapasa Sela V.
Published: December 2023

Purpose: Breast cancer is the most common type of cancer for women nationally with evidence indicating clear racial and ethnic disparities in risk and occurrence. Yet our understanding of the distinct, population-level impacts among Native Hawaiian and Pacific Islander (NHPI) women is limited. NHPIs show elevated levels of multiple comorbidities and emerging evidence from local community studies suggests NHPIs suffer disproportionately from higher incidence, advanced stage of diagnoses, and lower survivability rates from breast cancer. The purpose of this study was to investigate the prevalence, sociodemographic characteristics, and risk factors associated with NHPI women diagnosed with breast cancer. Methods/Data: We utilized the 2014 Native Hawaiian and Pacific Islander National Health Interview Survey (NHPI NHIS), a nationally representative survey conducted by the CDC-NCHS to collect high-quality data on health conditions, health risk behaviors, and healthcare utilization among NHPI populations.  Among 2,588 participants, 4% reported having ever been diagnosed with cancer, and among those breast cancer was the most common. Descriptive and regression analysis of socio-demographic characteristics, risk behaviors, and comorbidities to evaluate disparities in the incidence of breast cancer among NHPI women compared to other racial or ethnic populations. Findings/Conclusion: Population-based estimates of breast cancer prevalence among a diverse NHPI population show breast cancer inequities persist. Ongoing research is needed to better understand the underlying conditions and risks, prevention, and treatment of breast cancer in the population.

Citation Format: Sarah A. McNally, Daniel J. Salas-Escabillas, Nicholas A. Sowizral, Sela V. Panapasa. Prevalence and risk factors of breast cancer diagnoses among Native Hawaiian & Pacific Islander women [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A118.
Abstract B016: Associations between geographic residence, social support and resilience among Kentucky cancer survivors
Authors: Nguyen Hoa , Abraham Stephie , Baumgartner Kathy , Baumgartner Richard , Boone Stephanie
Published: December 2023

Background:  Rural and Appalachian cancer survivors have higher rates of invasive stage of disease, increased challenges in accessing health care services, and report poorer health outcomes and greater psychological distress compared to urban cancer survivors. Factors such as resilience-the ability of patients to bounce back after the trauma of a diagnosis- may be an important predictor of well-being, overall cancer experience, and treatment outcomes. In this exploratory study we assess whether residing in urban or rural geographic areas at diagnosis predicts level of self-perceived resilience and correlate relationships with mental and emotional health and social support. Methods: LADDER ‘Life After Diagnosis and Descriptors of Experience and Responses’ (LADDER) Study is an online pilot survey to evaluate experiences of Kentucky adult cancer survivors within the first year of diagnosis. Self-perceived resilience was measured by the 10-item Connor-Davidson Resilience Scale; higher scores indicate better resilience (range 0-40). Multivariable logistic regression was used to estimate Odds Ratios (OR) and 95% Confidence Intervals (CI) for likelihood of low resilience, dichotomized at median score. Spearman Rank Correlation Coefficients (ρ) measured the strength and direction of associations between continuous measures of anxiety, depression, social support, and resilience. Results: Among 46 participants, most were female aged 65 and older, living in non-Appalachian KY with 33% reporting a history of breast cancer. Rural cancer survivors scored 4 points lower in resilience on average than urban cancer survivors. In multivariable models, compared to urban KY survivors, rural KY survivors had a 2-fold higher likelihood of self-perceived low resilience (OR=2.70:95% 0.58-12.5)).  Adjusting for age, sex, Appalachian region, and employment partially attenuated the difference in resilience scores; however, estimates were not significant (OR=2.20: 95% 0.24-20.7). Social support, anxiety, and depression were moderately correlated with resilience among both urban (ρ= 0.36 to 0.64) and rural cancer survivors (ρ range: 0.21 to 0.54) Conclusion: The first year after a cancer diagnosis marks the transition into survivorship with major emotional adjustments. Additional recruitment of survivors will allow examination of diverse experiences post-diagnosis which may lead to interventions to improve quality of life in cancer survivors.

Citation Format: Hoa Nguyen, Stephie Abraham, Kathy Baumgartner, Richard Baumgartner, Stephanie Boone. Associations between geographic residence, social support and resilience among Kentucky cancer survivors [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B016.