tbuckley/cabot-search huggingface dataset:
Abstract 946: Landscape of HRD aberration in EGFR mutated lung cancer and the role of PARP-inhibitor in EGFR mutated lung cancer with HRD aberration
Authors: Jinah Kim, Horyun Choi, Liam Il-Young Chung, Young Kwang Chae
Journal: Cancer Research (2024)

Abstract Introduction: Olaparib, an oral poly polymerase (PARP) inhibitor has received approval for treating malignancies displaying homologous recombination deficiency (HRD). Current data is insufficient in establishing the role of PARP inhibitors in non-small cell lung cancer (NSCLC) in the setting of third generation EGFR tyrosine kinase inhibitor (TKI) use. Preclinical investigation suggests heightened PARP inhibitor sensitivity of TKI-resistant EGFR mutant NSCLC cells compared to TKI-sensitive cells. Methods: We utilized The Cancer Genome Atlas (TCGA) to investigate the prevalence of HRD gene mutations in patients with NSCLC harboring EGFR mutations. We also present a case demonstrating a favorable response to the dual therapy of olaparib and osimertinib in NSCLC harboring EGFR, RAD50, and ARID1A mutations that progressed on osimertinib. Results: There were 2298 patients in the NSCLC cohort (MSKCC database). Among 687 patients with EGFR mutations, 24 patients (3.5%) exhibited ARID1A mutations, 8 patients (1.2%) had BRCA1 mutations, 11 patients (1.6%) had BRCA2 mutations, and 5 (0.7%) had RAD50 mutations. A 71-year-old female presented with stage IV adenocarcinoma of the lung. She had recurrent malignant pericardial effusion requiring pericardiocentesis for previous cardiac tamponade. Computed tomography (CT) of the chest revealed a 3cm irregular left hilar mass with bilateral mediastinal and hilar lymph nodes. Tissue next generation sequencing (NGS) at baseline identified EGFR exon19 deletion along with RAD50 R726H which is a HRD pathway gene. Circulating tumor DNA (ct-DNA) NGS (Guardant360) showed EGFR E746_A750del 4.8%. The patient achieved partial response to osimertinib for 28 months. Follow-up CT showed disease progression. Olaparib 200mg twice daily was added to osimertinib based on repeat ct-DNA NGS indicating a new ARID1A alteration (splice site SNV) along with the known BRCA1 mutation. Follow up scans currently have consistently demonstrated ongoing partial response for 19 months. Combining olaparib with osimertinib can be effective in an osimertinib-resistant NSCLC patient with EGFR mutation and HRD aberration. The favorable response could be attributed not only to pre-existing RAD50 mutation but also to acquired mutations in ARID1A HRD genes. Conclusion: HRD aberrations are uncommon in EGFR mutated lung cancer patients. Further investigation on the role of PARP inhibitor in EGFR mutated lung cancer is warranted. Citation Format: Jinah Kim, Horyun Choi, Liam Il-Young Chung, Young Kwang Chae. Landscape of HRD aberration in EGFR mutated lung cancer and the role of PARP-inhibitor in EGFR mutated lung cancer with HRD aberration [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 946.
Abstract 7069: NEK2 is frequently upregulated in esophageal adenocarcinoma associating with poor prognosis
Authors: Lei Chen, Heng Lu, Farah Ballout, Tianling Hu, Zheng Chen, Dunfa Peng
Journal: Cancer Research (2024)

Abstract Esophageal adenocarcinoma (EAC) has become a significant clinical challenge due to rapid increase in the incidence during the past four decades in the USA and Western countries. However, the prognosis of EAC patients is still poor with 5-year overall survival rate about 20%. There is an urgent need to identify novel therapeutic targets associated with EAC biology. NEK2 is the first identified human NEK (Never in mitosis A (NIMA) related kinase) gene among the 11 serine/threonine kinases family. Aberrant NEK2 expression is reported in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEK2 in EAC and its precancerous condition (Barrett’s esophagus, BE) has not been investigated. Using bioinformatic approaches, we first analyzed the TCGA and 9 GEO databases (a total of 10 databases in which eight contain EAC and 6 contain BE) and found that NEK2 was significantly upregulated in EAC as compared to normal esophagus in 7 of the 8 databases. Meanwhile, genomic alterations of NEK2 are only found in 1.2% of EAC. We validated the overexpression of NEK2 using qRT-PCR, western blotting, immunohistochemistry in EAC cell lines and in primary EAC tissues. Functionally, we demonstrated that overexpression of NEK2 in EAC cells promoted tumor cell growth. Targeting NEK2 in EAC cells significantly inhibited EAC tumor growth. Our data suggests that frequent overexpression of NEK2 plays an important role in EAC. Citation Format: Lei Chen, Heng Lu, Farah Ballout, Tianling Hu, Zheng Chen, Dunfa Peng. NEK2 is frequently upregulated in esophageal adenocarcinoma associating with poor prognosis [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 7069.
Abstract 5316: SM2256: A bispecific conditional CD40 and 4-1BB dual agonist for enhanced solid tumor immune response
Authors: Wenjing Song, Simin Yang, Yi Wei, Shihao Lu, Huiqin Geng, Xiaodan Liu, Hong Zhou, Siyao Xie, Xing Zhang, Sheila Zhou, Yanbin Liang
Journal: Cancer Research (2024)

Abstract Background: Monoclonal antibodies targeting the co-stimulatory receptors CD137 (4-1BB) and CD40 have displayed encouraging activity against a wide range of solid tumors in preclinical animal models. However, their clinical development as monotherapy has been hindered by dose-related liver toxicity, leading to limited efficacy at safe doses. To address this challenge and bolster tumor-specific immunity by orchestrating the interaction between dendritic cells (DCs) and cytotoxic T cells, we introduce SM2256 - a bispecific conditional CD40 and 4-1BB dual agonist. SM2256 physically bridges DCs and T cells, enhancing T cell priming and reactivation. In preclinical animal studies, SM2256 exhibited both excellent tolerability and potent anti-tumor activity. Methods: SM2256 was engineered by fusing high-affinity, non-ligand-blocking VHH domains targeting 4-1BB and CD40 to a silenced IgG1 Fc backbone. This fusion resulted in a tetravalent bispecific antibody capable of conditionally activating CD40 and 4-1BB upon mutual receptor binding. We assessed the binding specificity and affinity of SM2256 to human CD40 and 4-1BB using ELISA and flow cytometry. The target-dependent activation of CD40 and 4-1BB was confirmed via reporter assays and co-culture systems using primary DCs and T cells. In vivo safety and anti-tumor efficacy were evaluated in a syngeneic transplantation model using the MC38 cancer cell line in B-h41BB/B-hCD40 double humanized mice. Results: SM2256 exhibited sub-nanomolar binding affinity to recombinant human and cynomolgus monkey CD40 and 4-1BB, activating 4-1BB-NFκB-luc and CD40-NFκB-luc reporter cell lines at picomolar concentrations in a strictly target-dependent manner. Furthermore, SM2256 physically facilitated the interaction between DCs and T cells, leading to increased expression of DC co-stimulatory ligands and elevated secretion of cytokines by T cells in mixed lymphocyte cultures. In a syngeneic tumor transplantation model, SM2256 significantly restrained the growth of MC38 tumors in B-h41BB/B-hCD40 double humanized mice. Conclusions: SM2256 is a novel conditional CD40 and 4-1BB dual agonist that demonstrates promising preclinical efficacy against solid tumors while boasting an improved safety profile when compared to existing monoclonal antibodies. Citation Format: Wenjing Song, Simin Yang, Yi Wei, Shihao Lu, Huiqin Geng, Xiaodan Liu, Hong Zhou, Siyao Xie, Xing Zhang, Sheila Zhou, Yanbin Liang. SM2256: A bispecific conditional CD40 and 4-1BB dual agonist for enhanced solid tumor immune response [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 5316.
Abstract 7063: Monitoring metabolic plasticity in the tumor microenvironment <i>in vivo</i> by mitophagy generated extracellular vesicles
Authors: Purva V. Gade, Marissa Howard, Angela Rojas, Layla Hasanzadah, Lance Liotta, Fatah Kashanchi
Journal: Cancer Research (2024)

Abstract Tumor metabolic reprogramming is a hallmark of cancer progression, survival, and therapeutic resistance. A targetable class of cancer metabolic adaptation exploits mitophagy known to be linked to the cancer phenotype. Mitophagy selectively eliminates dysfunctional mitochondria by targeting them, via autophagosome shuttling, to the lysosome for degradation. Cancer cell mitophagy is triggered by elevated oxidative stress and mitochondrial DNA damage caused by hypoxia, radiotherapy, and immunotherapy. A high mitophagy demand can overwhelm the lysosome capacity resulting in the accumulation of damaged mitochondria and can suppress biogenesis of healthy mitochondria. We hypothesize that the newly discovered secretory mitophagy mechanism exports damaged mitochondrial fission-released segments to reduce the overload pressure on the lysosomal system, and thereby sustains cancer cell survival in the face of therapeutic mitochondrial stress. We have discovered a form of secretory mitophagy occurring in vivo in a growing solid tumor. Our molecular analysis of the full repertoire of extracellular vesicles, EVs, shed into the resident tumor interstitial fluid, IF, in vivo yielded a rich set of information about the functional state of mitochondria within the tumor cells, and the host cells. A set of proteins required for sequential steps of fission-induced mitophagy preferentially populated the CD81 positive IF EVs, including PINK1, DRP1 and FIS1. The export of cellular mitochondria proteins to CD81 positive EVs was confirmed by density gradient isolation from the bulk EV isolate followed by anti-CD81 immunoprecipitation, Mito Tracker export into CD81 positive EVs, ultrastructural characterization and Exoview analyzer. Further, we stimulated mitochondrial oxidative stress and blocked the fusion of the mitophagosome with the lysosome, which markedly stimulated the export of the secretory mitophagy unit. The outcome is new understanding of the importance of secretory mitophagy that can constitute a therapeutic target, and a new clinically relevant means of monitoring the in vivo state of mitophagic flux within the tumor microenvironment by means of mitophagy derived EVs. Citation Format: Purva V. Gade, Marissa Howard, Angela Rojas, Layla Hasanzadah, Lance Liotta, Fatah Kashanchi. Monitoring metabolic plasticity in the tumor microenvironment in vivo by mitophagy generated extracellular vesicles [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 7063.
Abstract 999: Clinical trial matchmaking: Connecting sites to sponsors
Authors: Lyndsey Griffin, Latha Shivakumar, Leigh Boehmer, Savannah Dodson, Elana Plotkin, Sumanta Pal, Al B. Benson
Journal: Cancer Research (2024)

Abstract Background: Oncology programs may encounter many challenges engaging in clinical trials. The Association of Community Cancer Center’s (ACCC) Community Oncology Research Institute (ACORI) conducted a survey to gather insights on barriers to clinical trial provision and implementation, patient recruitment, and identifying resources to support cancer programs. Methods: A survey of 29 questions was administered via Qualtrics. The survey focused on research-naïve sites (i.e., sites with little to no clinical research experience). Survey recipients were identified from ACCC’s membership database, and the survey was open from May 5 to October 10, 2023. One survey response was captured per program. Results: Of the 350 respondents, most were physicians, investigators, or oncology fellows (20%), directors/administrators (16%), patient navigators (12%), and APPs (12%). Responding programs were categorized as a comprehensive community cancer program (28%), community practice (26%), or academic medical center (21%). Eighty percent of respondents indicated their program currently conducts clinical research. The most common challenges included: patient recruitment (40%), limited staffing (36%), limited clinician time (32%), and lack of training in research administration and conduct (25%). The top 3 resources desired were communication about clinical research opportunities (65%), connections to clinical trial sponsors (49%), and clinical research coordinator training (41%). Conclusions: Survey results showed a clear need for improved communication regarding clinical research opportunities, connections to clinical trial sponsors, and education around clinical trial implementation. Data from this survey will be used to match sites with trial sponsors, especially sites that serve patients with cancer from under resourced geographic, socioeconomic, racial, and ethnic groups. Future efforts will seek to engage clinical trial sponsors in improving trial engagement and feasibility, workforce support, training, and clinical mentorship. Citation Format: Lyndsey Griffin, Latha Shivakumar, Leigh Boehmer, Savannah Dodson, Elana Plotkin, Sumanta Pal, Al B. Benson. Clinical trial matchmaking: Connecting sites to sponsors [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 999.
Abstract 994: Single analyte profiling of the mutational, immune and microbiome landscape in african american colon cancer patients
Authors: Carino Gurjao, Edmond Chan, Michael J. Lee, Sho Hangai, Raul Rabadan, Tal Korem, Hanina Hibshoosh, Benjamin Izar
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) disproportionately affects African American (AA) patients who experience a higher incidence and mortality than any other demographic groups in the United States. Yet molecular profiling in this population is scarce. Here, we performed whole-exome sequencing (WES) of 342 immediately snap-frozen tissues comprising AA CRC and matched, distant normal colon and identified distinct genomic drivers, DNA signatures, and, surprisingly, mosaic pathogenic mutations that are not present in the patient-matched CRC. We inferred T cell infiltration and tissue-resident microbiome (TR-M) directly from WES, enabling integrative analyses. Compared to normal colon, T cell infiltration is strongly decreased in tumours with microsatellite stability (MSS), while microsatellite unstable (MSI) and Polymerase Epsilon (POLE) mutant tumours had similar levels, suggesting immune evasion in MSS rather than increased T cell infiltration in MSI/POLE-mutants. Analyses of matched normal and tumour tissues revealed the evolving TR-M at unprecedented granularity and identified distinct niches of interactions with genomic and tumour-microenvironmental features. Together, this study represents the largest comprehensive genomic analysis of CRC in AA and provides a framework for performing a multi-layered analysis from a single analyte, thus, affording a cost-effective approach to expedite medical discoveries in underrepresented ancestries. Citation Format: Carino Gurjao, Edmond Chan, Michael J. Lee, Sho Hangai, Raul Rabadan, Tal Korem, Hanina Hibshoosh, Benjamin Izar. Single analyte profiling of the mutational, immune and microbiome landscape in african american colon cancer patients [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 994.
Abstract 5430: Discovery of CYP26A1 as a link between WNT and retinoic acid signaling pathways that modulates retinoid-induced differentiation of <i>APC</i>-mutant colorectal cancer cells
Authors: Caroline O. Facey, Victoria O. Hunsu, Chi Zhang, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2024)

Abstract APC mutation is the main driver mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. We hypothesize that a functional link exists between WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induced wt-APC expression in APC-mutant CRC cells and assessed the ability of all-trans-retinoic acid (ATRA) to induce differentiation. Notably, ATRA substantially increased expression of the WNT-target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, RA and WNT pathways crosstalk to modulate CYP26A1 metabolism of retinoids and retinoid agents. We found that inducing wt-APC augments ATRA-induced cell differentiation by: i) decreasing cell proliferation; ii) suppressing ALDH1A1 expression; iii) decreasing ALDH+ SCs; and iv) increasing neuroendocrine cell differentiation. NanoString profiling and bioinformatics also identified a novel CYP26A1-based network that links WNT and RA signaling. Moreover, in an effort to translate manipulation of the WNT/RA imbalance as a therapeutic approach in vitro, we treated HT29, SW480, and HCT116 CRC cells with inhibitors against CYP26A1 enzyme activity and WNT signaling. We found that CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Furthermore, decreased CYP26A1 expression in tumor vs normal tissue was determined to be a predictor of patient survival in patients who have wt-APC. Thus, by inducing wt-APC expression and exogenously activating RA signaling, we found a way to increase differentiation of SCs along the NEC (and other) lineage(s). Translating this strategy in vivo might lead to new, more effective treatments involving retinoids for CRC patients. Citation Format: Caroline O. Facey, Victoria O. Hunsu, Chi Zhang, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman. Discovery of CYP26A1 as a link between WNT and retinoic acid signaling pathways that modulates retinoid-induced differentiation of APC-mutant colorectal cancer cells [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 5430.
Abstract 5432: The role of nuclear factorκB-inducing kinase in ovarian cancer stem cells, chemoresistance, and relapse
Authors: Cassidy C. Lucht, Mikella Robinson, Samuel F. Gilbert, Omar Lujano Olazaba, Carrie D. House
Journal: Cancer Research (2024)

Abstract Ovarian cancer is the most lethal gynecological cancer in the United States, largely due to its high relapse rates. Research suggests these high relapse rates are due to cancer stem-like cells (CSCs), a subpopulation of tumor cells that are resistant to chemotherapy and have enhanced tumor-initiation capacity. Post-treatment, CSCs self-renew to re-establish new tumors, leading to recurrent disease that is now resistant to chemotherapy. Given that over-expression of NF-κB has been linked to CSCs, cancer progression, and chemoresistance in various tumors, including ovarian, studies uncovering the mechanisms of this pathway are needed to develop novel therapeutics for ovarian cancer treatment. The upstream activator of the alternative NF-κB pathway, Nuclear Factor κB-inducing Kinase (NIK), could be an enticing target for eliminating CSCs, however its function in these cells is not established. In our current studies, we show that HGSOC cells grown as CSC-enriching 3D spheroids have increased NIK expression and activity relative to monolayer cultured cells. Moreover, cells expressing CSC markers (CD117+/CD133+), have increased NIK gene expression, further supporting an association between NIK and CSC maintenance. Upon treatment with chemotherapies carboplatin and paclitaxel, NIK gene expression increased in the surviving population, indicating a role in chemoresistance. Knockdown of NIK using siRNA led to changes in alternative NF-kB transcriptional activity and higher sensitivity to carboplatin and paclitaxel relative to vehicle controls. Current studies are evaluating the role of NIK in tumor-initiation capacity, asymmetric division, proliferation, and changes in expression of stemness genes. Lastly, an in vivo relapse model will test the feasibility of using a NIK inhibitor following chemotherapy to prevent relapse and prolong survival. Findings from this work will further define the role of NF-kB pathway components in facilitating CSCs survival and re-establishment of tumors and identify a new potential target for eliminating CSCs in ovarian cancer. Citation Format: Cassidy C. Lucht, Mikella Robinson, Samuel F. Gilbert, Omar Lujano Olazaba, Carrie D. House. The role of nuclear factorκB-inducing kinase in ovarian cancer stem cells, chemoresistance, and relapse [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 5432.