tbuckley/cabot-search huggingface dataset:
Abstract IA06: Postpartum breast involution informs breast cancer metastasis to the liver
Authors: Pepper Schedin
Journal: Cancer Research (2024)

Abstract Young women with breast cancer have disproportionally higher rates of metastasis, and effective treatment strategies are lacking. Our lab has focused on investigating how normal reproductive changes in tissue biology interface with breast cancer metastasis in young patients. These studies identify weaning-induced involution of the breast as a tissue remodeling process similar to wound healing that promotes metastasis in rodent models. Relevance to women is suggested by the fact that a breast cancer diagnosis within 5 years of childbirth is a strong and independent risk factor for metastasis. Further, these studies find that up to 50% of all young onset breast cancer is diagnosed within this high risk postpartum window. This subset of common, young onset breast cancer is referred to as postpartum breast cancer (PPBC). We find that PPBC appears durably altered by involution, as PPBC tumors display involution, metastatic, and treatment resistant molecular signatures. PPBC also specifically associates with increased liver metastases, a metastatic site associated with very poor prognosis. In rodents, we identified a functional link between the mammary gland and the liver, including weaning-induced liver involution. Liver involution is characterized by hepatocyte cell death, fibroblast activation, ECM deposition, and an immune regulatory infiltrate similar to that found in the postpartum involuting breast. In rodent models of breast cancer liver metastasis (BCLM), the involuting liver supports outgrowth of circulating breast cancer cells more than the nulliparous host liver. Evidence for similar liver biology occurring in women is suggested by studies in healthy women, where we find liver volume increase during pregnancy and loss post wean, data consistent with liver involution. In our mouse models of BCLM, the involution metastatic advantage coincided with weaning-induced immune tolerance in the liver. We next targeted the pro-tumor, immune suppressed state of involution with the immune modulatory agent vitamin D. These studies revealed dramatic down regulation of liver metabolism with weaning, including liver cytochrome P450 enzymes, which effectively nullified the protective effect of vitamin D in involution hosts. Combined, these novel findings are anticipated to have implications for sex-specific liver diseases broadly, efficacy of pro-drugs in the postpartum window, and for breast cancer outcomes in young patients. Citation Format: Pepper Schedin. Postpartum breast involution informs breast cancer metastasis to the liver [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA06.
Abstract B028: Investigating immune activity caused by a novel anti-cancer cell penetrating peptide
Authors: Ryan Hecksel, Angelica Escoto, Joyce Schroeder
Journal: Cancer Research (2024)

Abstract Activating the immune system against cancerous cells represents a promising therapy against multiple cancer types, particularly breast cancer. The epidermal growth factor receptor (EGFR) represents an emerging target in immunotherapy. A novel anti-cancer cell penetrating peptide was recently discovered to affect immune recruitment and potentially function in a murine model of breast cancer. This peptide, termed cSNX1.3, is a targeted therapy to block the nuclear localization of the epidermal growth factor receptor (EGFR), a phenomenon thought to occur primarily in cancerous cells. This suggests that nuclear localized EGFR may play a role in suppressing an anti-cancer immune response. To gain a better understanding of this in vivo data, we used in vitro immune cell co-culture techniques, migration assays, and other techniques to investigate immune recruitment and function after cancer cells are treated with this novel peptide therapy. In addition, we are investigating the mechanism of cSNX1.3 mediated cell death to determine if it can induce immunogenic cell death. To determine if nuclear EGFR plays a role in immune cell suppression, we are using a CRISPR/Cas9 strategy to mutate the nuclear localization sequence. This will provide a valuable tool to better understand the seemingly cancer-specific trafficking phenomenon. Together, this work will expand our understanding of therapy induced immune cell recruitment and trafficking. Citation Format: Ryan Hecksel, Angelica Escoto, Joyce Schroeder. Investigating immune activity caused by a novel anti-cancer cell penetrating peptide [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B028.
Abstract B034: Order-of-mutation effects on cancer progression: Models for myeloproliferative neoplasm
Authors: Yue Wang, Tom Chou, Blerta Shtylla
Journal: Cancer Research (2024)

Abstract In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found, JAK2 V617F and one in the TET2 gene. Whether or not one mutation is present will influence how the other subsequent mutation affects the regulation of gene expression. When both mutations are present, the order of their occurrence has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation (ODE) model and a Moran process models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. These observations consistently shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models. Citation Format: Yue Wang, Tom Chou, Blerta Shtylla. Order-of-mutation effects on cancer progression: Models for myeloproliferative neoplasm [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B034.
Abstract IA004: Insights into lung cancer evolution and metastases in TRACERx and PEACE
Authors: Mariam Jamal-Hanjani
Journal: Cancer Research (2024)

Abstract TRACERx is a prospective longitudinal cancer evolution programme which investigates the relationship between intratumour heterogeneity and clinical outcomes in non-small cell lung cancer (NSCLC). In an interim cohort of 421 patients with extended follow up, matched primary and metastatic tumour analysis has demonstrated the impact of cancer evolution on patient outcomes. Large dominant subclones in primary tumours were associated with positive subclonal selection, and mutations in specific genes were found to be under significant subclonal, and not clonal, selection. Subclonal genome doubling was identified in 20% of tumours and multiple genome doubling events were identified in 10% of tumours. Patients with tumours containing large recent subclonal expansions had significantly shorter disease-free survival (DFS), and as previously demonstrated, chromosomal instability was associated with poor outcomes, in particular, extrathoracic disease relapse. Metastatic relapse was found to occur late in tumour evolution in 75% of tumours, and early divergence (25% of tumours) was found to occur at predicted tumour volumes below the threshold for further investigation using radiological imaging, suggesting potential implications for clinical intervention. Metastasis-seeding subclones in primary tumours were subject to subclonal expansion, likely reflective of the acquisition of subclonal driver mutations and somatic copy number alterations. ctDNA analyses in this larger cohort demonstrated the value of ctDNA to predict the likelihood of future relapse, but also its use in tracking tumour growth dynamics and emergence of relapse. Patients who develop relapsed disease in TRACERx after surgery are co-recruited into PEACE, a national research autopsy programme. Early findings from PEACE have demonstrated the genomic complexity of cancer relapse and metastatic heterogeneity and the different patterns of cellular migration that aid metastatic dissemination with both primary-to-metastasis and metastasis-to-metastasis seeding. Citation Format: Mariam Jamal-Hanjani. Insights into lung cancer evolution and metastases in TRACERx and PEACE [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA004.
Abstract B019: The bone microenvironment's impact on the heterogeneity of resistance to proteasome inhibitors in multiple myeloma
Authors: David Basanta, Ryan Bishop, Anna Miller, Conor C. Lynch, Matthew Froid, Ariosto S. Silva, Kenneth H. Shain
Journal: Cancer Research (2024)

Abstract Multiple myeloma (MM) is an osteolytic plasma cell malignancy that, despite being responsive to therapies such as proteasome inhibitors, frequently relapses. Understanding the mechanism and the niches where resistant disease evolves remains of major clinical importance. Cancer cell intrinsic mechanisms and bone ecosystem factors are known contributors to the evolution of resistant MM but the exact contribution of each is difficult to define with current in vitro and in vivo models. Using a novel bmathematical model that incorporates key cellular species of the bone ecosystem that control normal bone remodeling and, in MM, yields a protective environment we studied how, under therapy, the bone ecosystem contributes to the evolutionary dynamics of resistant MM under control and proteasome inhibitor treatment. Our results show that Environmentally-Mediated Drug Resistance (EMDR) might not be sufficient to explain resistant disease. But our results highlight the importance of EMDR in facilitating the emergence of resistance, and more importantly facilitating the survival of tolerant cells, allowing the tumor multiple routes for resistant disease. Our results also provide evidence that intervention with therapies targetting the bone ecosystem would significantly improve the ability of treatment to increase the time to progression for patients with multiple myeloma and, potentially, other diseases where EMDR plays a role. Citation Format: David Basanta, Ryan Bishop, Anna Miller, Conor C. Lynch, Matthew Froid, Ariosto S. Silva, Kenneth H. Shain. The bone microenvironment's impact on the heterogeneity of resistance to proteasome inhibitors in multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B019.
Abstract B066: PDGFR upregulation functions as a bypass mechanism contributing to FGFR inhibitor resistance in metastatic breast cancer
Authors: Mitchell Ayers, Michael Wendt
Journal: Cancer Research (2024)

Abstract Breast cancer (BC) is the most diagnosed cancer in females in the United States and the second leading cause of cancer related deaths among women. The fibroblast growth factor receptor (FGFR) signaling pathway is frequently activated in BC, making it an attractive therapeutic target, especially in metastatic disease. However, clinical trials using FGFR inhibitors in BC have been disappointing in comparison to other cancer types treated with these therapies. As a result, BC patients with activated FGFR do not have a targeted therapeutic option. Failure of FGFR inhibitors is indicative of intrinsic or acquired resistance mechanisms in metastatic BC. Herein we demonstrate significant efficacy of the FGFR inhibitor, pemigatinib, in the 4T07 murine model of BC utilizing a tail vein model to induce pulmonary tumors. Despite this initial response, pemigatinib fails to eliminate minimal residual disease (MRD) and allows for accelerated tumor return after pemigatinib cessation. Characterizing the MRD by IHC following pemigatinib treatment shows that expression of platelet-derived growth factor receptor (PDGFR) is significantly increased on tumor cells. This rise in PDGFR expression following pemigatinib treatment increases the responsiveness of 4T07 cells to platelet-derived growth factor ligand indicating PDGFR may act as an alternate signaling pathway bypassing FGFR signaling. Mechanistically, previous studies indicate that PDGFR protein expression is transcriptionally repressed by restriction of enhancer positioning by the CTCF insulator. DNA methylation surrounding CTCF causes its dissociation enhancing protein expression of PDGFR. Along these lines cotreatment with a DNA methyl transferase inhibitor prevents the increase of PDGFR protein expression induced by pemigatinib. Overall, our study determined that a highly potent FGFR inhibitor can inhibit tumor growth in a metastatic site, but it fails to eliminate MRD giving rise to tumor recurrence. Upregulation of PDGFR may act as a bypass mechanism of resistance allowing for tumor cell survival during pemigatinib treatment. Finally, our findings suggest that dual inhibition of DNA methylation and FGFR could improve patient response in metastatic BC. Citation Format: Mitchell Ayers, Michael Wendt. PDGFR upregulation functions as a bypass mechanism contributing to FGFR inhibitor resistance in metastatic breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B066.
Abstract PR014: Multiregion biopsies and corresponding neurosphere cultures reveal spatial divergence in glioblastoma evolution
Authors: Roberto Salatino, Ugoma Onubogu, Benjamin Oakes, Oszkar Szentirmai, Michalina Janiszewska
Journal: Cancer Research (2024)

Abstract Spatial organization of normal tissues is key for their function, yet the role of distribution of distinct clones of cancer cells in tumor in not usually studied as a potential vulnerability in cancer. This is of particular interest in glioblastoma (GBM), most aggressive brain tumor, in which extensive intratumor heterogeneity hampers effectiveness of treatment. Multiregion sampling has been used in multiple studies to uncover evolutionary trajectories of the tumor. To better understand tumor evolution and the complexity of cancer ecosystem in GBM, we performed profiling of biopsies collected from MRI-defined regions of the tumors, spanning the surface, tumor core and deep tumor margins, which drive local recurrence after surgery. To test how spatially distinct biopsies differ in their cancer cell composition and how heterogeneous the tumor microenvironment is in these samples, we took advantage of 5-ALA metabolite fluorescence, which accumulates in GBM cells. 5-ALA administration prior to the surgery allows the surgeon to visualize cancer under blue light. We used it to separate cancer cells (predominantly 5-ALAhigh) from tumor microenvironment (5-ALAlow) and subjected the fractions to bulk and single cell transcriptomics, respectively. We found a gradient of cellular states associated with location in the tumor, with the deep margin samples having more 5-ALAlow cancer cells and generally less defined phenotype. We have also developed neurosphere cultures from our collection of spatially distant biopsies. Despite the selection pressure of the in vitro culture conditions, cells from different regions of the tumor adopted different morphologies, suggesting retention of some of their differential features. The differences between cultures were reflected in metabolism, proliferation, and differential sensitivity to a drug panel. Whole exome sequencing and transcriptomic analysis were also performed to identify the selection bottleneck of culture conditions, establish evolutionary trajectory of the distinct regions and neurosphere cultures, and test how strongly our cultures represent both the 5-ALAhigh and 5-ALAlow subpopulations of GBM cells. Our study identified properties associated with different spatial locations within GBM tumors, which will help uncover the cellular and microenvironmental dependencies that could lead to novel therapeutic targets for this highly heterogeneous tumor. Citation Format: Roberto Salatino, Ugoma Onubogu, Benjamin Oakes, Oszkar Szentirmai, Michalina Janiszewska. Multiregion biopsies and corresponding neurosphere cultures reveal spatial divergence in glioblastoma evolution [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR014.
Abstract B086: Association of breast cancer-relevant DNA repair genes with postmenopausal breast cancer risk in UK Biobank
Authors: Carmen Smotherman, Brian Sprague, Dejana Braithwaite, Huaizhen Qin, Lusine Yaghjyan
Journal: Cancer Research (2024)

Abstract Purpose. Several polymorphisms have been described in DNA damage signaling and repair genes and some of the polymorphisms have been implicated in genetic susceptibility to breast cancer. However, there is no consensus result yet for most of these polymorphisms. In this study, we focused on evaluating selected SNPs in BRCA1, BRCA2, ATM, XRCC1, XRCC2, XRCC3, and XPD (ERCC2) genes that have been previously reported to be associated with breast cancer risk and are available in the UK Biobank. Methods. This study included 150,929 postmenopausal women (5,969 with BCa) from UK Biobank, a population-based prospective cohort. Cancer diagnoses were ascertained through the linkage to the UK National Health Service Central Registers. DNA was extracted from blood samples collected from participants at enrollment in UK Biobank. Samples were genotyped using the Applied Biosystems UK BiLEVE Axiom Array or the Applied Biosystems UK Biobank Axiom Array. The positions of markers in the data are in GRCh37 coordinates. SNPs with frequency &amp;lt; 1% in the study population were excluded from analyses. We included the following SNPs in the final analyses: XRCC3-rs861539, BRCA1-rs16942, BRCA1-rs4986852, XRCC1-rs25487, XRCC1-rs25489, XRCC1-rs1799782, XPD (ERCC2)-rs13181, XPD (ERCC2)-rs1799793, XRCC2-rs3218536, ATM-rs1800056, ATM-rs1800057, BRCA2-rs144848, BRCA2-rs4987117, and BRCA2-rs11571833. Information on breast cancer risk factors was collected at baseline. Cox proportional hazards regression models were used to analyze the association between each SNP and breast cancer risk while adjusting for known breast cancer risk factors. The risk estimates were presented as hazard rations (HRs) and their corresponding 95% confidence intervals (CIs). Results. The mean age of the study population at enrollment was 60.1 years (range 40-71 years). Heterozygous carriers of BRCA2-rs11571833 T allele were found to have an increased risk of breast cancer (HR=1.22, 95% CI 1.02, 1.46, p-trend = 0.033) compared to the homozygous carriers of the BRCA2-rs11571833 A allele. No other significant associations between other SNPs and breast cancer risk were found. Conclusions. We found a significant association between SNP BRCA2-rs11571833 and postmenopausal breast cancer risk. Our findings contribute to the existing evidence on the association of high-risk polymorphisms in DNA damage signaling and repair genes with postmenopausal breast cancer risk. Citation Format: Carmen Smotherman, Brian Sprague, Dejana Braithwaite, Huaizhen Qin, Lusine Yaghjyan. Association of breast cancer-relevant DNA repair genes with postmenopausal breast cancer risk in UK Biobank [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B086.
Abstract IA021: Digital patient avatars predict cancer evolution and personalised therapeutic strategies
Authors: Jasmin Fisher
Journal: Cancer Research (2024)

Abstract Tumour heterogeneity manifested by genetic diversity and interchangeable cell states poses considerable challenges for the design of therapeutic strategies to combat cancer. While many strategies have been proposed to address this problem, using combination treatments and sequential delivery of therapies, the scope of combinations and sequencing order of therapies is enormous and is beyond the capacity of exhaustive testing through experimental models. We therefore propose using computational models to rapidly identify effective therapeutic interventions supported by convincing mechanistic explanations. Digital cancer avatars are computational programs representing oncogenic signalling networks and mapping molecular interactions to cell phenotype, which can be interrogated in silico. These computational programs specify how molecular interactions and perturbations produce cellular responses, such as cell proliferation, cell survival or cell death, and as such are well-suited to provide novel mechanistic insights into cellular behaviours as well as to identify therapeutic strategies for targeting them. In this talk, I will demonstrate the utility of bespoke computational models for triple-negative breast cancer, non-small cell lung cancer and melanoma to study how genomic changes drive tumour evolution and therapeutic response, and how these models are used to identify personalised combination treatments to overcome resistance. I will also present an in silico method applied to these models, to screen tens of millions combinations for effective sequential treatments by mapping the evolution of a tumour in response to a single-agent treatment and determining the optimal second-line treatment that will overcome resistance. Together these studies demonstrate the utility of digital avatars to improve our understanding of the mechanisms driving tumour progression and pave the way for personalised therapeutic strategies for improved cancer patient outcomes. Citation Format: Jasmin Fisher. Digital patient avatars predict cancer evolution and personalised therapeutic strategies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA021.