tbuckley/cabot-search huggingface dataset:
Abstract 5395: The influence of hyperthermia on epigenetic signaling in dysbiotic tumor vasculature
Authors: Hailey Kristian, Samir Jenkins, Robert Griffin, Ruud Petrus Dings
Journal: Cancer Research (2024)

Abstract The overall use of antibiotics has increased significantly in recent years. Although they resolve infections, oral antibiotics (ABX) severely alter the gut microbiota, disrupting commensal bacteria crucial for maintenance of various homeostatic processes. ABX-induced microbial imbalance, or dysbiosis, has systemic and long-lasting deleterious effects on the host. For example, we and others have shown that distal, non-GI tract solid tumors show accelerated progression during dysbiosis due to vascular immune suppression. Localized hyperthermia has been increasingly recognized to elicit various cellular responses, yet the epigenetic effects of hyperthermia on the tumor vasculature during ABX-induced dysbiosis are unknown. The balance of histone acetylation and deacetylation plays a critical role in the regulation of gene expression and thereby cellular processes. Therefore, we assessed which histone deacetylases (HDACs) are expressed and their abundance in endothelial cells of various sources with or without dysbiotic stress and/or hyperthermia to understand the utility of thermal medicine to promote normal functioning of the vasculature in dysbiotic patients. We found that HDAC expression levels differed among endothelial origins and that hyperthermia (60 min of either 41.5 °C or 43 °C) influenced the HDAC levels differentially. Especially HDAC 2, 3 and 8 were inhibited by hyperthermia. Additionally, we found that the vasculature receptors for endogenous HDAC inhibitors, GPR41, GPR43, and GPR109a are less abundant intrinsically on dysbiotic than orthobiotic tumor endothelial cells and that hyperthermia increased this expression. Although further studies are warranted, these results demonstrate that hyperthermia exerts epigenetic effects and is capable of overcoming the dysbiosis-induced phenotype. Since anti-cancer treatment with HDAC inhibitors has shown promise in the clinic but is hindered by systemic toxicities, localized hyperthermia may become a viable alternative in the future. Citation Format: Hailey Kristian, Samir Jenkins, Robert Griffin, Ruud Petrus Dings. The influence of hyperthermia on epigenetic signaling in dysbiotic tumor vasculature [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 5395.
Abstract 7577: A new cancer therapy strategy: Synthetic lethality induced by inhibition of mTOR and cMYC and JNK activation
Authors: Hui Chen, Jason Rivera, Marc Paradise, Zihan Xu, Giuliana Mognol, Judith Varner
Journal: Cancer Research (2024)

Abstract Cancer cells are characterized by aberrant signal transduction and cell cycle control pathways that lead to unchecked cell proliferation. Uncontrolled cancer cell proliferation, as well as immune suppressive macrophage proliferation, contribute to tumor growth and spread. Effort to suppress tumor cell growth using Inhibitors of PI3K or MEK signaling pathways can initially inhibit tumor growth, but resistance develops due to upregulation of the alternative pathway. We identified a novel series of allosteric tyrosine kinase receptor inhibitors that induce synthetic lethality in AML, lung carcinoma, pancreatic carcinoma, and other tumor cells and in proliferating macrophages in vitro and in vivo by simultaneously inhibiting cMyc and Tor and activating the stress activated kinase JNK, leading to p53 mediated cell cycle arrest. Select kinase inhibitors with a unique positioning of a single side chain inhibited CDK8/19 and thereby Myc while stimulating phosphorylation and activation of JNK and p38. JNK activation promoted sustained ATF-2 and cJun-mediated p53 and Chk1/Chk2 activation, thereby promoting cell cycle arrest in G2/M and ultimately, apoptosis. These inhibitors potently suppressed tumor growth in vivo by halting both tumor cell and macrophage proliferation in G2/M. They synergized with anti-PD-1 and anti-CTLA-4 and led to tumor eradication and immunological memory formation. These studies identify novel allosteric inhibitors with potent synthetically lethal anti-tumor activity. Citation Format: Hui Chen, Jason Rivera, Marc Paradise, Zihan Xu, Giuliana Mognol, Judith Varner. A new cancer therapy strategy: Synthetic lethality induced by inhibition of mTOR and cMYC and JNK activation [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 7577.
Abstract 5724: Preclinical evaluation of a novel CHK1 inhibitor encapsulated within the liposome, SMP-3124, for the treatment of solid cancer
Authors: Yuka Kumagai, Ryosaku Inagaki, Kana Shimizu, Wataru Hirose, Naoaki Shimada, Kento Hayashi, Yoshiko Fukuoka, Makoto Matsuoka, Seiji Kamioka, Hitoshi Ban, Hiroki Umehara, Yusuke Sawayama
Journal: Cancer Research (2024)

Abstract Checkpoint kinase 1 (CHK1) is a serine/threonine kinase which plays a critical role for DNA damage responses (DDR) throughout the cell cycle in human cells. CHK1 is mainly activated by replication stress resulting in single-stranded DNA breaks induced by chemotherapeutic agents or mutations in DNA repair related genes. These kinds of stresses are reported to increase the dependency on DDR pathway molecule including CHK1. Therefore, targeting CHK1 is promising strategy for drug discovery. In fact, CHK1 inhibition induces S phase arrest and inhibits cell growth in wide range of cancer cell lines. Recently, a number of drugs in this pathway are tested in clinical trials. Although some of them showed obvious clinical responses in both monotherapy and combination therapy, their efficacies are limited because of their toxicities. To maximize the efficacy, we utilized CHK1 inhibitor with liposomal formulation which changes drug distribution to achieve longer drug retention in plasma and accumulation in tumor. Here, we generated SMP-3124, a novel and selective CHK1 inhibitor encapsulated within the liposome. SMP-3124 showed durable pharmacodynamic response due to the liposomal accumulation in the tumor in xenograft model. We confirmed potent anti-tumor activities of SMP-3124 in multiple subcutaneous xenografted models without severe side effects. In addition, SMP-3124 showed prolonged overall survival in both peritoneal dissemination and orthotopic model using human ovarian cancer cells. SMP-3124 synergistically inhibited tumor growth in combination with gemcitabine without additional hematological toxicities induced by gemcitabine. We are planning to an investigational new drug application in 2024. Citation Format: Yuka Kumagai, Ryosaku Inagaki, Kana Shimizu, Wataru Hirose, Naoaki Shimada, Kento Hayashi, Yoshiko Fukuoka, Makoto Matsuoka, Seiji Kamioka, Hitoshi Ban, Hiroki Umehara, Yusuke Sawayama. Preclinical evaluation of a novel CHK1 inhibitor encapsulated within the liposome, SMP-3124, for the treatment of solid 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 5724.
Abstract 2243: A multi-ethnic population-based pilot study of multiple myeloma disparities
Authors: Angelica M. Rolon, April P. Vang, J. Elizabeth Quino, Ana Estrada, Eric Stewart, Rosemary D. Cress, Luis Carvajal-Carmona, Alexa Morales Arana
Journal: Cancer Research (2024)

Abstract To understand multiple myeloma (MM) disparities we established the Precision MEDicine, EqUity and Disparities Research in MultipLe MyeLomA (MEDULLA) study, a population-based study in California. Our study contacted, via the Cancer Registry of Greater California (CRGC), 100 adult MM patients from four racial/ethnic groups: Non-Hispanic Black (NHB), Non-Hispanic White (NHW), Latinos, and Asians. Data collection included variables reported to the CRGC, a self-administered survey, and biospecimen saliva collection. The survey focused on demographics, risk factors, cancer treatment, family history, quality of life, and social determinants of health. Of the 400 MM patients, we had 95 patients who responded to the survey, giving a response rate of 24%. 44% of those who responded were NHW, 21% NHB, 19% Latinos, and 16% Asians. Those that provided a response tend to be living in a census tract location with lower proportions of poverty (p=0.0004), higher proportion of adults ages 25 years or over with a college degree (p=0.0011), higher median household income (p=0.0048), lower proportion of adults ages 25 years or over without a high school diploma (p&amp;lt;0.0001), and a lower proportion of individuals ages 16 or over who are unemployed (p&amp;lt;0.006). All respondents also have a lower comorbidity count and expressed being in good health. For minorities, we identified a trend where a higher response rate is seen if they live in an area where median household income is higher (p=0.0108). For every 1% increase in poverty rates, NHW living in such neighborhoods were 3% less likely to respond to the survey (p=0.04). For every 10% increase in the proportion of individuals having a college degree, response rate increased by 1.17 for minorities in that neighborhood (p=0.07). Minorities living in neighborhoods with high proportions of adults without a high school diploma and high unemployment rates are less likely to respond (p=0.02 and p=0.047, respectively). In conclusion, we found significantly lower participation rates among minority groups, with socio-economic factors affecting response rates. Our findings, therefore, suggest that future studies must develop improved community-focused and culturally tailored strategies to engage and meaningfully understand MM etiology and survivorship in such populations. Citation Format: Angelica M. Rolon, April P. Vang, J. Elizabeth Quino, Ana Estrada, Eric Stewart, Rosemary D. Cress, Luis Carvajal-Carmona, Alexa Morales Arana. A multi-ethnic population-based pilot study of multiple myeloma disparities [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 2243.
Abstract 890: Multimodal modeling of digitized histopathology slides improves risk stratification in hormone receptor-positive breast cancer patients
Authors: Kevin M. Boehm, Antonio Marra, Jorge S. Reis-Filho, Sarat Chandarlapaty, Fresia Pareja, Sohrab P. Shah
Journal: Cancer Research (2024)

Abstract In early-stage hormone receptor-positive breast cancer, genomic risk scores identify patients who stand to benefit from up-front chemotherapy but introduce financial and logistical hurdles to care. We assembled a cohort of 5,244 patients with 11,671 corresponding whole-side images of breast tumors stained with hematoxylin and eosin. We developed a multimodal machine learning model to infer risk of distal metastatic recurrence from routine clinical data. Specifically, the model interprets text from the pathologist’s report using a large language model and uses self-supervised vision transformers to interpret the corresponding whole-slide image. Tensor fusion joins the modalities to infer Genomic Health’s Oncotype DX recurrence score. Inferred recurrence score from the multimodal model correlated with measured score with a concordance correlation coefficient of 0.64 (95% C.I. 0.59 - 0.69) in the withheld test set, compared to 0.55 (95% C.I. 0.49 - 0.61) and 0.56 (95% C.I. 0.52 - 0.60) for the linguistic and visual unimodal models, respectively. The multimodal model attains an area under the precision-recall curve (AUPRC) of 0.69 (AUROC=0.88) for identifying high-risk disease in the full-information setting (when images and pathology reports with quantitative hormone receptor status and grade are available) in a withheld test set, compared to AUPRC of 0.61 and 0.66 for the linguistic and visual models, respectively. By comparison, in the same full-information setting, the clinical nomogram introduced by Orucevic et al. in 2019 achieves an AUPRC of 0.48. We suggest the operating point at which precision is 94.4% and recall is 33.3%. Digitized whole-slide images of routine breast biopsies and their associated synoptic pathology reports contain much of the information necessary to stratify patients by risk of distal metastatic recurrence, when modeled appropriately. Our model could enable hospitals to rapidly triage the need for genomic risk testing, possibly precluding one third of orders without loss of accuracy. This helps allocate scarce resources for genomic tests and valuable weeks prior to beginning therapy while maintaining the standard of precision oncology. Citation Format: Kevin M. Boehm, Antonio Marra, Jorge S. Reis-Filho, Sarat Chandarlapaty, Fresia Pareja, Sohrab P. Shah. Multimodal modeling of digitized histopathology slides improves risk stratification in hormone receptor-positive breast 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 890.
Abstract 1310: Social determinants of migrant health factors impacting prostate cancer care and survivorship among sub-Saharan African immigrant men diagnosed with prostate cancer
Authors: Ernest Kaninjing, Gladys Asiedu, Kaitlin Van Voorhis, Mary Ellen Young, Ebenezer Erefah, Emmanuel Agboola, Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Solomon Rotimi, Che Ngufor, Arnola Merriweather, John McCall, Anthony Hill
Journal: Cancer Research (2024)

Abstract Background: Sub-Saharan African Immigrants (SSAI) represent one of the fastest-growing segments of the immigrant population in the United States (US). Between 2010 and 2018, the SSAI population in the US increased by 53%, significantly outpacing the 12% growth rate for the overall foreign-born population in the US during that time frame. Despite these growing numbers, little is published about the extent to which SSAIs adapt to health behaviors more common in the US or remain immersed in the values, beliefs and practices reflective of their country of origin. Importantly, no study has comprehensively examined the Social Determinants of Health (SDOH) among this population relative to their migration experiences and their influence on health-seeking behaviors and decision-making regarding prostate cancer care and treatment options. Methods: This qualitative study employed grounded theory and the social determinants of migrant heath framework to better understand the needs of SSAI prostate cancer survivors in the United States and how to effectively support these survivors. In-depth interviews were conducted with 8 survivors who live in the states of Florida and Minnesota. Findings: Some participants reported limited access to care and financial challenges paying for drugs. In terms of coping with diagnosis and treatment, most of the participants relied on their faith, a positive outlook about survivorship and support of family members. Some participants relied on the coaching and support of a loved one who experienced prostate cancer in the past. Erectile dysfunction severely impacted the sexual life of most participants as they experienced difficulty getting an erection. Conclusion: Participants expressed the benefit of belonging to support groups with other survivors for social and emotional support. As the number of immigrants from sub-Saharan continue to rise, so too will the demand for culturally tailored care to address and reduce disparities in survivorship among this sub-population. Citation Format: Ernest Kaninjing, Gladys Asiedu, Kaitlin Van Voorhis, Mary Ellen Young, Ebenezer Erefah, Emmanuel Agboola, Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Solomon Rotimi, Che Ngufor, Arnola Merriweather, John McCall, Anthony Hill. Social determinants of migrant health factors impacting prostate cancer care and survivorship among sub-Saharan African immigrant men diagnosed with 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 1310.
Abstract 2588: Bioengineering of site-specific antibody labeling from basic research to spatial omics platforms
Authors: Kai Tao, Matthew J. Rames, MingChong Dai, Gulsu Sener, Samuel Olson, Srivathsan Ranganathan, Sila Ozdemir, Adam Oken, Michael Brasino, Randy Armstrong, Yu-Jui Chiu, Ece Eksi, Bruce Branchaud, Sadik Esener
Journal: Cancer Research (2024)

Abstract Over the last few years, spatial multi-omics platforms have emerged as a powerful tool for characterizing cancer biology in multiple dimensions. Notably, these systems typically rely on multiplex immunolabeling. Conventionally, multiplexing is accomplished through carefully selecting primary antibodies from different animal species, and in combination with their corresponding polyclonal secondary antibodies. However, given the practical complication related to the species availability of primary antibodies, the multiplexing labeling is still under constraint due to the necessity for matched secondary species labels and the availability. For decades, non-specific labeling of primary antibodies through amine- or thiol-reactive chemistries was widely performed. Evolving research and commercial products have sought to overcome this antibody-based multiplexing limitations by developing enzymatic reaction-directed chemical reaction or antibody targeting proteins that could contain affinity to the Fc or Fab regions of antibodies. However, these methods mentioned above have substantive limitations and side-effects on affinity, conjugation number, buffer incompatibilities, storage incompatibilities, insufficient conjugation, and uncontrolled stoichiometric labeling. Herein, we introduce an efficient, sustainable, reproducible site-specific antibody covalent labeling strategy through engineering anti-IgG secondary nanobodies. These infer the stability, high-affinity of species specific and easy-to-produce IgG binders with the permanence of controlled activation for proximity-driven intermolecular covalent conjugation, with a promise for efficient multiplexity. This labeling technology addresses antibody labeling challenges through currently available approaches, and would substantially enhance multiplexity in a wide variety of research and clinical settings. Citation Format: Kai Tao, Matthew J. Rames, MingChong Dai, Gulsu Sener, Samuel Olson, Srivathsan Ranganathan, Sila Ozdemir, Adam Oken, Michael Brasino, Randy Armstrong, Yu-Jui Chiu, Ece Eksi, Bruce Branchaud, Sadik Esener. Bioengineering of site-specific antibody labeling from basic research to spatial omics platforms [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 2588.
Abstract 2445: Peripheral blood immune phenotypes in pancreatic ductal adenocarcinoma
Authors: Kevin D. Pavelko, Jose C. Villasboas, William R. Taylor, Karen A. Doering, John B. Kisiel, Shounak Majumder
Journal: Cancer Research (2024)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a major cancer killer with a low 5-year survival rate of 12%. Diagnosing PDAC at an early stage is one of the strongest predictors of long-term survival. Therefore, novel methods for early detection of PDAC must be explored. In this pilot study we aimed to compare the peripheral blood immune cell phenotypes in PDAC cases and cancer-free controls. Method: CyTOF (cytometry by time-of-flight) was used to evaluate peripheral blood mononuclear cells (PBMC) from newly diagnosed treatment naïve patients with PDAC and sex and age matched cancer-free controls using a 29-marker immune phenotyping panel. Multiple analysis approaches including dimensionality reduction using tSNE and clustering using Phenograph were used to evaluate the results. Immune subsets having differential abundance differences were verified by manual gating. Results: Twenty patients were included in this pilot study (15 PDAC cases; 5 Cancer-free controls). Among the 15 PDAC cases, 5 were early stage (Stage 1-2). Thirty-two unique immune cell clusters were identified using the Phenograph algorithm: 10 unique clusters with properties consistent with monocytes/macrophages, 9 CD4 T cell clusters, 6 CD8 T cell clusters and 4 NK cells clusters. When comparing the case and control groups we noted lower percentages of CD8+CD27+ T-cells in cases. This was further verified by manual gating that confirmed the distribution of CD8+CD27+ T-cells relative to all T-cells were decreased in PDAC patients. In addition, a 57% increase in naïve CD4 T cells was found in case samples compared to controls. A principal component analysis of the clustering results identified two unique clusters of immune profiles that emerged providing a potential peripheral blood immune cell signature that could stratify and differentiate PDAC cases from controls. A CD14+CD16+CD4LoCD38+CD45RO+ population of monocytes was the primary cell population driving this difference. Conclusion: This study provides early evidence to indicate that a distinct PBMC immune phenotype may differentiate PDAC patients from control subjects. Further analysis in larger sample sets is warranted for in-depth characterization and identification of unique immune based biomarkers for PDAC detection. Citation Format: Kevin D. Pavelko, Jose C. Villasboas, William R. Taylor, Karen A. Doering, John B. Kisiel, Shounak Majumder. Peripheral blood immune phenotypes in pancreatic ductal adenocarcinoma [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 2445.