tbuckley/cabot-search huggingface dataset:
Abstract 997: Bringing the first prehabilitation program to American Indian cancer patients
Authors: Jennifer Erdrich, Adriena Hernandez, Jennifer W. Bea, Cynthia A. Thomson
Journal: Cancer Research (2024)

Abstract Purpose. American Indian/Alaska Native (AI/AN) people have the worst cancer survival rates of any US racial group, are underrepresented in clinical trials and research, and have never been recruited for participation in any published prehabilitation (prehab) intervention conducted prior to cancer surgery. Description of Procedure. We are collaborating with tribal partners to design the first prehab translational clinical trial for AI patients diagnosed with obesity-related cancer, to be implemented prior to surgical resection of the tumor. Program components have been developed with community input through semi-structured interviews and guidance from the sponsoring tribal health facility, the San Carlos Apache Healthcare Corporation. Patients preparing for cancer surgery will engage in a 3-week multimodal intervention that entails home-based exercise, supervised fitness sessions, promotion of anti-inflammatory foods, and health education materials adapted for and by community members. Serum and tissue biomarkers, as well as lifestyle behavioral measures, will be compared pre and post intervention to assess responsiveness. In respect of tribal sovereignty, the experimental procedure includes protocol refinement and approval by the tribal health facility’s IRB and tribal council. Summary of Data. Our qualitative data reveal AI cancer survivors from the partnering tribal community have high interest in prehab and attest they would have participated if offered (100%). Their consensus feedback fashioned the specifics of the prehab translational clinical trial: 30 minutes daily walking, 60 minutes supervised resistance training twice weekly, 2 ounces walnut consumption daily, nutrition counseling, transportation assistance, and education/encouragement from staff and peers. Biospecimen sampling can be a sensitive topic for AI audiences, which we addressed early and found 75% of the interviewed survivors agreed to biospecimen collection without stipulation; this increased to 100% support once the rationale for biospecimens was explained. Conclusions: Published prehab studies in other populations administered for 3-5 weeks between diagnosis and surgery have shown improvements in functional capacity, attenuation of surgery-induced losses, alterations of inflammatory biomarkers, and patient safety. Our community-informed prehab translational clinical trial for AI patients is the first of its kind, and anticipated to demonstrate feasibility, patient acceptability, behavioral changes in lifestyle, and the potential to modulate inflammatory biomarkers. Citation Format: Jennifer Erdrich, Adriena Hernandez, Jennifer W. Bea, Cynthia A. Thomson. Bringing the first prehabilitation program to American Indian 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 997.
Abstract 1330: Universal and potent chimeric antigen receptor-natural killer (upCAR-NK) cells for B-cell malignancy treatment
Authors: Daekee Kwon, Bo Kyung Moon, Mijung Han, Tae-Wook Lee, Ji-Han Lee, Kyung-Sun Kang
Journal: Cancer Research (2024)

Abstract Patient-specific CAR-T cells treatment is an innovative new drug that has shown excellent therapeutic effects against B cell blood cancer. However, side effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome and ultra-high treatment costs must be overcome, and off-the-shelf CAR-NK cells can be a good alternative. The purpose of this study was to combine cellular reprogramming, gene editing, and differentiation technologies to produce full-off-the-shelf NK cells derived from iPSCs and verify their efficacy and safety. To this end, somatic cell-derived iPSCs were produced, seven genes were edited using CRISPR/Cas9 technology (5 kinds of knockout and 2 kinds of overexpression), and differentiated into NK cells. upCAR (universal and potent chimeric antigen receptor)-iPSCs with seven genes edited showed bialleic INDEL in the coding sequence of five genes and no off-target effect. In addition, normal transcriptome and genetic stability were maintained. High-efficiency differentiated upCAR-NK cells showed a very high differentiation yield, in vitro proliferation, and freezing/thawing were possible. In addition, upCAR-NK cells secrete interferon-γ when they meet cancer cells, showing cytotoxic effects in vitro and in vivo. upCAR-NK cells themselves showed no obvious toxicity in vivo. In conclusion, this study developed upCAR-iPSCs and upCAR-NK cells platform technologies that are less likely to have side effects and can be economically developed for B cell blood cancer than CAR-T. In the future, this technology can be useful in developing full-off-the-shelf CAR-NK cells anti-cancer immune cell therapy with low side effects, high efficacy, and low price. Citation Format: Daekee Kwon, Bo Kyung Moon, Mijung Han, Tae-Wook Lee, Ji-Han Lee, Kyung-Sun Kang. Universal and potent chimeric antigen receptor-natural killer (upCAR-NK) cells for B-cell malignancy treatment [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 1330.
Abstract 5115: Designing targeted approaches for recurrent medulloblastoma
Authors: Jezabel Rodriguez Blanco
Journal: Cancer Research (2024)

Abstract Designing targeted therapies for recurrent medulloblastomaPediatric brain tumors are the leading cause of cancer-related death in children, with medulloblastoma (MB) being the most common type. Despite significant progress in the field, approximately 30% of children with MB will relapse. Recurrent MB is commonly metastatic and virtually none of these patients will live beyond the one-year hallmark. These sobering statistics highlight the significant unmet need for effective therapies for recurrent MB. The likely underlying cause of the constant failure of our current clinical approaches, which are based on data obtained from disease models recapitulating primary tumors, is the disparity in genomic and transcriptomic data between primary and relapsed disease. Because of these disparities, we hypothesize that by conducting mechanistic studies and drug screens in relapse disease models, we can improve the outcomes for children with recurrent MB. Our data, obtained through a bioinformatics mining approach to predict tumor response, enabled us to identify a clinically relevant candidate drug for the treatment of recurrent MB: Minnelide. This compound acted on MYC to reduce tumor growth and the metastatic dissemination of tumors with the genetic background often found in relapsed MB patients. Additionally, to further support the translational relevance of our data, Minnelide increased the efficacy of adjuvant therapeutics used in the clinical management of MB. Our findings not only highlight the potential for repurposing Minnelide to treat children with recurrent MB, but also the potential of our research approaches aimed at identifying novel therapeutics for relapsed cancers. Citation Format: Jezabel Rodriguez Blanco. Designing targeted approaches for recurrent medulloblastoma [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 5115.
Abstract 7297: Inhibition of lung tumorigenesis and potentiation of cancer preventive vaccines by a small molecule CA170 targeting the immune checkpoint protein VISTA
Authors: Qi Zhang, Jing Pan, Donghai Xiong, Yian Wang, Mark S. Miller, Ming You
Journal: Cancer Research (2024)

Abstract The V-domain Ig Suppressor of T cell Activation (VISTA) is expressed on cells of the myeloid and lymphoid lineages and is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Furthermore, a tripeptide small molecule antagonist of VISTA, CA170, exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. We have previously demonstrated that KRAS or EGFR vaccines are effective in preventing lung tumorigenesis driven by either KRAS or EGFR in a pure prevention setting but are less effective in mice carrying existing lesions. Here, we determined if combining an MHC class II-restricted multi-antigen vaccine targeting KRAS or EGFR with CA170 will provide enhanced efficacy in preventing lung cancer progression. Using tetracycline-inducible KRAS and EGFR transgenic mice, we found that lung tumor development was significantly suppressed when CA170, delivered by aerosol inhalation to minimize systemic toxicity, was combined with either KRAS or EGFR MHCII-directed peptide vaccines using a post-initiation model. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 significantly increases tumor infiltrating CD8+ T cells and enhances effector-memory T cell frequencies and functions of both CD4+ and CD8+ T cells. These changes coincide with significant reductions in G-MDSCs (granulocytic myeloid-derived suppressor cells) and Foxp3+ Treg populations within lung tumors from mice treated with CA170. We found that the KRAS and EGFR preventive vaccines primarily induced the expansion of CD4+ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory, and regulatory T cells, and drive an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS and EGFR preventive vaccines in transgenic mouse models of lung cancer. Citation Format: Qi Zhang, Jing Pan, Donghai Xiong, Yian Wang, Mark S. Miller, Ming You. Inhibition of lung tumorigenesis and potentiation of cancer preventive vaccines by a small molecule CA170 targeting the immune checkpoint protein VISTA [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 7297.
Abstract 7228: In-vitro efficacy of Dordaviprone/GSK126 combination therapy on castration resistant and neuroendocrine prostate cancer
Authors: Connor Purcell, Praveen Srinivasan, Maximilian Pinho-Schwermann, William MacDonald, Elizabeth C. Ding, Vida Tajiknia, Wafik El-Deiry
Journal: Cancer Research (2024)

Abstract Neuroendocrine prostate cancer (NEPC) is an aggressive histologic subtype associated with poor prognosis that commonly arises in later stages as a mechanism of treatment resistance. Activation of oncogenic drivers, in combination with epigenetic changes (such as EZH2 overexpression and DNA methylation) further promotes tumor proliferation and expression of downstream neuroendocrine lineage pathways (in part controlled by transcription factors, including SOX2, ASCL1, and BRN2). Importantly, EZH2 inhibitors (EZH2i) can restore AR expression in CRPC (Ku et al., 2017). Imipridones, including Dordaviprone (ONC201), show promise in treating neuroendocrine tumors by interacting with DRD2 and CLpP (Anderson et al., 2022). These results warrant investigation into the potential for synergism in imipridone/EZH2i combination therapies. In the PCa cell lines LNCap, PC3, 22Rv1, and DU145 the combination of ONC201 and EZH2i GSK126 was assessed. Cell viability data after treatment with ONC201 and GSK126 reveals several dose ranges with potential synergistic activity after 72h. Preliminary western blots after 72 hours of GSK126 treatment indicate modulation of proteins relevant to the mechanism of action of imipridones, specifically DR5 and CLpP, in LNCap, PC3, and 22Rv1. Notably, the decrease in DR5 expression warrants investigation into the effects of EZH2i on TRAIL sensitivity and whether imipridones may rescue DR5 expression to maintain TRAIL sensitivity. Subsequent experiments will investigate dosing and time point-based effects on viability and protein expression, in addition to assessing the synergy of other imipridones and EZH2i’s. Further, while the cell lines PC3, 22Rv1, and DU145 are castration-resistant, the neuroendocrine prostate cell line NCI-H660 will be used as a positive control as it expresses higher neuroendocrine features, including DRD2. Additionally, the modulation in DR5 expression warrants inquiry into the effects of combination therapy on tumor-immune cell interactions. Further, we will manipulate the expression of neuroendocrine transcription factors to assess changes in therapy sensitivity. Citation Format: Connor Purcell, Praveen Srinivasan, Maximilian Pinho-Schwermann, William MacDonald, Elizabeth C. Ding, Vida Tajiknia, Wafik El-Deiry. In-vitro efficacy of Dordaviprone/GSK126 combination therapy on castration resistant and neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7228.
Abstract 4896: A high throughput method of identifying cells with increased genomic content across diverse cancer tissues
Authors: Shilpa Priyadarsini Nair, Kenneth J. Pienta, Sarah R. Amend
Journal: Cancer Research (2024)

Abstract Cancer cells with increased genomic content have been associated with recurrence and poor patient outcomes. The current manual identification of these rare cells by pathologists is time-consuming and labor intensive, given their scarcity within tissue samples. This study introduces a robust methodology for the automated identification of cancer cells with increased genomic content within prostate cancer tissues. Leveraging Qupath software integrated with the Stardist extension, our approach combines precise nuclear segmentation with threshold setting using a Python script. This methodology enables the specific identification of noncancerous small cells, cancerous cells, and those exhibiting genomic content significantly surpassing the average cancer cell (3x to 5x), complemented by thresholds based on hematoxylin intensity for enhanced result accuracy. Thus, our methodology offers an efficient solution to streamline the identification processes for these challenging cells. We have extensively validated our method across diverse models, including animal and human models, transgenic and subcutaneous models, and Human Tissue Microarrays (TMAs), to identify cancer cells with increased genomic content. The rarity of these cells within tissue samples underscores the practical significance of our research, providing a solution to the current difficulties faced by researchers and clinicians in their identification. The integration of this methodology aims to improve efficiency in cancer tissue analysis. Ongoing efforts are directed towards the evaluation of this high-throughput methodology using animal models and TMAs with known outcomes, further substantiating its applicability and potential clinical relevance. Citation Format: Shilpa Priyadarsini Nair, Kenneth J. Pienta, Sarah R. Amend. A high throughput method of identifying cells with increased genomic content across diverse cancer tissues [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 4896.
Abstract 5624: Dec2, a circadian rhythm gene facilitates pancreatic cancer dormancy through evasion of antitumor immunity
Authors: Lan Wang, Chris Harris, Orjola Prela, Wade C. Narrow, Darren R. Carpizo
Journal: Cancer Research (2024)

Abstract Metastatic recurrence following curative intent oncologic surgery is a major clinical problem in patients with pancreatic ductal adenocarcinoma (PDAC). These recurrences are from disseminated tumor cells (DTCs) and can sometimes occur years after surgery indicating that DTCs undergo a period of dormancy. The mechanisms that drive cancer dormancy and its awakening are poorly understood in part due to a lack of animal models that recapitulate dormant tumor cell biology. We created a novel model of PDAC dormancy where mice undergo surgery to remove the primary tumor and are followed for evidence of metastatic recurrence. Dormant DTCs can be isolated from mice without clinical evidence of recurrence for molecular studies. Single cell RNAseq of dormant DTCs detected that the circadian rhythm gene, Dec2 is upregulated. We knocked out (KO) Dec2 from murine pancreatic cancer cells and when implanted into the model we found almost no mice developed metastatic recurrence. When immunodeficient or immunocompetent mice depleted of CD4 and CD8 T cells were used as hosts, we observed no difference in survival in mice engrafted with Dec WT vs. KO cells indicating the survival benefit in the Dec KO group was due to an immune mediated mechanism. We performed a differential expression analysis on bulk RNAseq data comparing the Dec2 WT vs. KO cells and found antigen presentation a top upregulated pathway. We then observed that surface MHC-I was significantly upregulated in Dec2 KO cells as compared to wild type cells. Further mechanistic studies revealed that proteosome activity was significantly higher in Dec2 KO cells and treatment with proteosome inhibitors decreased surface MHCI levels in Dec2 KO cells. Cut and tag experiments revealed that Dec2 binds the promoter of a number of genes that regulate the proteosome. In conclusion, Dec2 promotes cancer dormancy by down regulating cell surface MHCI which facilitates immune evasion. Citation Format: Lan Wang, Chris Harris, Orjola Prela, Wade C. Narrow, Darren R. Carpizo. Dec2, a circadian rhythm gene facilitates pancreatic cancer dormancy through evasion of antitumor immunity [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 5624.
Abstract 1345: NAV-201, an orally bioavailable small molecule NK cell activator enhancing antibody-mediated cancer therapies
Authors: Nicholas C. Nicolaides, Luigi Grasso, J. Brad Kline
Journal: Cancer Research (2024)

Abstract Tumors employ a number of mechanisms to suppress a patient’s immune anti-tumor responses. Recently, we uncovered an immunosuppression mechanism that tumors employ to avoid humoral immune responses that involves tumor-produced proteins, called Humoral Immuno-Oncology (HIO) factors. These HIO factors are able to suppress antibody-mediated tumor cell killing via direct binding to antibodies that alter their Fc domain interactions with the C1q protein to suppress complement dependent cytotoxicity (CDC) and reduce antibody engagement with CD16a Fc receptors on immune-effector cells, including NK cells, to suppress antibody dependent cellular cytotoxicity (ADCC). HIO factor immunosuppression of ADCC appears to involve the reduced binding affinity of antibody to CD16a Fc receptors. In an attempt to identify agents that may enhance antibody-CD16a binding affinity to overcome HIO factor immunosuppression, we sought to identify agents that can restore this interaction by screening natural small compound libraries via an IgG1-CD16a based ELISA assay. One lead compound was identified that was subsequently optimized by structural activity relationship analysis. This compound, named NAV-201, specifically binds CD16a and enhances the affinity of antibody binding to both the low affinity CD16a-158F and high affinity CD16a-158V allotypes. Moreover, we found that NAV-201 can also bind to the mouse CD16a ortholog and enhance its antibody binding affinity, making NAV-201 suitable for efficacy testing in mouse models. In vivo, NAV-201 was found to be well tolerated up to at least 120 mg/kg when administered orally and daily to mice, have a serum half-life of 18 hours, enhance systemic levels of the NK cell produced INF-γ and TNF-α cytokines, and enhance the therapeutic efficacy of antibodies in mouse xenografts. Together, these data support the further development of NAV-201 for human testing to improve and/or enhance the efficacy of antibody-based therapies in HIO factor positive cancers. Citation Format: Nicholas C. Nicolaides, Luigi Grasso, J. Brad Kline. NAV-201, an orally bioavailable small molecule NK cell activator enhancing antibody-mediated cancer therapies [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 1345.
Abstract 2908: EDB+FN is an attractive therapeutic target in oncology: Insights from protein expression analysis of solid tumors
Authors: Sara Lewandowski, Liyang Diao, Alyssa Quigley, Marsha Crochiere, Jan Pinkas
Journal: Cancer Research (2024)

Abstract Stroma plays a major role in the initiation, growth, survival, and drug-resistance of solid tumors, yet few therapeutics specifically target tumor-associated stroma. Extra-domain-B fibronectin (EDB+FN) is an oncofetal splice variant of fibronectin upregulated in solid tumor stroma, which is associated with tumor growth, angiogenesis, and metastases. Here we developed an immunohistochemistry (IHC) assay to assess EDB+FN protein expression in the stroma of tumor and normal tissues to characterize the potential of EDB+FN as a therapeutic target for solid tumors with high unmet need. We validated a primary detection antibody and titrated assay conditions to achieve specificity and a broad dynamic range of EDB+FN expression levels across indications, including thyroid cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, soft tissue sarcoma, pancreatic cancer, non-small cell lung cancer, ovarian cancer, and renal cancer. Considering the stroma-specific expression pattern of EDB+FN, we developed a scoring algorithm weighting both the intensity and distribution of EDB+FN expression specifically in the stroma compartment and separately in tumor cells. Using this assay and scoring approach, we screened more than 200 tumor samples from 10 solid tumor indications and found EDB+FN to be highly differentially expressed in tumor-associated stroma with little to no expression on tumor cells and trace to undetectable levels in healthy tissue. EDB+FN was expressed across the indications evaluated with a wide range of expression both within and between indications. Stromal EDB+FN expression was not correlated with stromal density, which also varied widely within and across indications. In parallel, we developed an algorithm using digital pathology to approximate pathologist scoring of stromal density and EDB+FN expression, allowing streamlined screening of preclinical samples for in vivo studies and indication selection. The disease-specific expression pattern of EDB+FN and high incidence of expression across indications make EDB+FN an ideal target for high-unmet-need solid tumors. The specificity and dynamic range of our IHC assay for detection of EDB+FN protein expression position it as a robust potential biomarker assay for EDB+FN-targeting therapeutics. Citation Format: Sara Lewandowski, Liyang Diao, Alyssa Quigley, Marsha Crochiere, Jan Pinkas. EDB+FN is an attractive therapeutic target in oncology: Insights from protein expression analysis of solid tumors [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 2908.