Mouse Model Of Human Cancer Research Articles

Abstract 2839: The mouse models of human cancer database (MMHCdb)

Abstract The laboratory mouse plays a pivotal role as an experimental system for investigations into the genetic and genomic basis of cancer susceptibility, initiation, and progression and for preclinical research on novel treatment strategies for cancer. Advances in mouse models include humanized mice, transplant compliant mouse strains, and panels of genetically diverse mice (e.g., Diversity Outbred and Collaborative Cross). The distributed and heterogenous nature of information about these model systems presents a significant challenge to finding and aggregating information about mouse models and to identifying the most relevant models for a particular research question. The Mouse Models of Human Cancer database (http://tumor.informatics.jax.org) is an expertly curated FAIR-compliant knowledgebase that applies community annotation standards and nomenclature standards for genes, alleles, and strains to support accurate and comprehensive search results for mouse models of human cancer. The data in MMHCdb are curated from peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. A primary focus of the resource is to reflect the impact that genetic background has on the cancer-related characteristics of mouse models. The database includes information on spontaneous and genetically engineered cancer models as well as Patient Derived Xenografts and diversity panels. The database supports faceted searching for models by multiple criteria including, tumor type, genetic background of the mouse model, somatic mutations, and publication. Model descriptions include summaries of observed frequencies of tumors observed in the model and histopathology images. Information in MMHCdb is linked to cancer model data from other bioinformatics resources including the Patient Derived Cancer Models database (PDCM), PathBase, the Gene Expression Omnibus (GEO), and ArrayExpress. MMHCdb is supported by NCI R01 CA089713 Citation Format: Dale A. Begley, Debra M. Krupke, Emily Jocoy, Steven B. Neuhauser, Carol J. Bult. The mouse models of human cancer database (MMHCdb) [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 2839.

Abstract 2833: Validating cancer biomarker expression on mouse cell-derived xenograft models of human cancer

Abstract Background and Objective: The target antigen expression level is critical for the potency of immune therapies like ADC, mRNA-LNP, and CAR-T. Selecting an appropriate cancer model remains a challenge to the pre-clinical drug testing. HD Biosciences offers over 1000 cell lines and 150 CDX mouse models of human cancers. Furthermore, we have validated the expression of three therapeutic targets Nectin-4, Trop2, and PD-L1 in various CDX tumor tissues. This poster will highlight some recently established models as well as the antigen validation result. Our study provides a reference that guides the model selection of efficacy studies targeting Nectin-4, Trop2, or PD-L1. In addition, we offer a platform to validate the expression of target antigens in CDX mouse models covering numerous cancer types. Method and Result: Biomarker surface expression of Nectin-4, Trop2, and PD-L1 on xenograft tumors was validated by IHC staining and FACS analysis. We highlight these models with high expression of each marker. These models are available to support further efficacy studies of anti-cancer drugs targeting the marker. We also analyzed the biomarker surface expression in vitro using cell pellets via FACS analysis to compare with the in vivo expression level. Hence, the biomarker gene expression level was confirmed by FACS. Interestingly, the result indicates biomarker expression in mouse tumor tissues is often inconsistent with in vitro cell expression. For example, the A375 CDX model on humanized immunodeficient mice is commonly used for anti-PD-1/PD-L1 drug efficacy tests. However, the surface expression of PD-L1 is only detected in the A375 tumor tissues and is undetectable in the A375 cell pellet. This finding could explain the inconsistency of in vitro and in vivo drug test results. The in vivo CDX model-based biomarker would better predict the drug’s efficacy, as the model better mimics the clinical situation of tumor burden in patients. Conclusion: In vitro gene expression and protein expression of cell surface biomarkers may not be relevant to the in vivo tumor surface expression level, resulting in inconsistent efficacy data in vitro and in vivo. Thus, validating targeted biomarkers in vivo is crucial for choosing the best cancer tumor model with high target expression for drug efficacy validation. HD Biosciences provides validated 150 CDX models expressing Nectin-4, Trop2, and PD-L1 and have in vivo capability for target validation and drug efficacy study. Citation Format: Minqi Huang, Alyssa E. Wiggins, D Marroquin, Mengling Liu, Luke Tsai. Validating cancer biomarker expression on mouse cell-derived xenograft models of human 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 2833.

Blocking the functional domain of TIP1 by antibodies sensitizes cancer to radiation therapy

Non-small-cell lung cancer (NSCLC) and glioblastoma (GB) have poor prognoses. Discovery of new molecular targets is needed to improve therapy. Tax interacting protein 1 (TIP1), which plays a role in cancer progression, is overexpressed and radiation-inducible in NSCLC and GB. We evaluated the effect of an anti-TIP1 antibody alone and in combination with ionizing radiation (XRT) on NSCLC and GB in vitro and in vivo. NSCLC and GB cells were treated with anti-TIP1 antibodies and evaluated for proliferation, colony formation, endocytosis, and cell death. The efficacy of anti-TIP1 antibodies in combination with XRT on tumor growth was measured in mouse models of NSCLC and GB. mRNA sequencing was performed to understand the molecular mechanisms involved in the action of anti-TIP1 antibodies. We found that targeting the functional domain of TIP1 leads to endocytosis of the anti-TIP1 antibody followed by reduced proliferation and increased apoptosis-mediated cell death. Anti-TIP1 antibodies bound specifically (with high affinity) to cancer cells and synergized with XRT to significantly increase cytotoxicity in vitro and reduce tumor growth in mouse models of NSCLC and GB. Importantly, downregulation of cancer survival signaling pathways was found in vitro and in vivo following treatment with anti-TIP1 antibodies. TIP1 is a new therapeutic target for cancer treatment. Antibodies targeting the functional domain of TIP1 exhibited antitumor activity and enhanced the efficacy of radiation both in vitro and in vivo. Anti-TIP1 antibodies interrupt TIP1 function and are effective cancer therapy alone or in combination with XRT in mouse models of human cancer.

Monitoring the Cell Cycle of Tumor Cells in Mouse Models of Human Cancer.

Cell division is obligatory to tumor growth. However, both cancer cells and noncancer cells in tumors can be found in distinct stages of the cell cycle, which may inform the growth potential of these tumors, their propensity to metastasize, and their response to therapy. Hence, it is of utmost importance to monitor the cell cycle of tumor cells. Here we discuss well-established methods and new genetic advances to track the cell cycle of tumor cells in mouse models of human cancer. We also review recent genetic studies investigating the role of the cell-cycle machinery in the growth of tumors in vivo, with a focus on the machinery regulating the G1/S transition of the cell cycle.

A phase I/II trial investigating safety and efficacy of autologous TAC01-HER2 in relapsed or refractory solid tumors.

2519 Background: Despite recent therapeutic developments for patients with advanced, metastatic, unresectable HER2+ solid cancers, significant unmet medical needs still exist, especially in tumors other than breast and gastric. The T cell antigen coupler (TAC) technology is a novel approach to modifying T cells, allowing them to recognize and treat HER2+ solid tumors. The TAC receptor redirects T cells to tumor cells, and upon tumor cell recognition, co-opts the natural T cell receptor (TCR) to yield safer anti-tumor responses versus chimeric antigen receptor (CAR) T cells. In preclinical studies, TAC T cells led to complete tumor clearance in mouse models of human cancer, without any TAC-related toxicities. Methods: In the ongoing clinical trial (NCT04727151), TAC01-HER2 treatment of HER2+ solid tumors is hypothesized to result in safe and effective anti-tumor responses. Subjects undergo leukapheresis, bridging therapy (if needed) while their TAC01-HER2 are engineered, lymphodepletion chemotherapy (LDC), and finally TAC01-HER2 infusion. In phase I dose escalation, the primary objective is to evaluate the safety of TAC01-HER2 at increasing doses of 0.3, 0.8, 3, and 8 x 106 cells/kg in HER2+ solid tumors (1+, 2+ or 3+ as identified by immunohistochemistry) in adult subjects who have progressed after ≥2 lines of systemic therapy. Dose limiting toxicities (DLTs) are assessed up to 28 days from cell infusion. In Phase II, dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC01-HER2 dose in HER2+ breast and other solid tumor types. Results: As of 10 Feb 2023, 18 patients have been treated in Cohorts 1-4 with breast, colorectal, gall bladder, gastroesophageal junction, gastric, esophageal, lung, and ovarian cancers. One DLT event of grade 3 pneumonitis has been reported in one subject in Cohort 4 (8 x 106 cells/kg). No neurotoxicity has been reported. Most subjects treated at Cohorts 3 and 4 experienced Grade ≤2 CRS which resolved with standard therapy. Twelve subjects have reported a total of 21 serious adverse events, 17 unrelated to TAC01-HER2 except for one Grade 3 pneumonitis, one Grade 1 and two Grade 2 CRS. Most adverse events were related to LDC or the underlying malignancy. At Cohort 2 (0.8 x 106 cells/kg), a partial response was observed in a subject with refractory metastatic gastric adenocarcinoma (3+ HER2) at 1st scan, with a 35% reduction in measurable disease and clinical benefit was maintained for 4 months. A 55% disease control rate was observed at Cohorts 2-4 at 1st scan. Conclusions: Dose escalation of TAC01-HER2 is ongoing, with seven subjects treated and three more scheduled in Cohort 4. These results in a heavily pre-treated cancer population show manageable safety and promising clinical activity with a novel T cell therapy that may have broad clinical applicability in HER+ cancers. Clinical trial information: NCT04727151 .

If you give a mouse a mutation: comparing the therapeutic utility of renowned mouse models of human cancers

Cancers of the breast, prostate and intestinal tract account for most cancer-associated deaths in humans and represent several of the highest incidence human neoplasms. Therefore, understanding the underlying pathophysiology, including the formation and propagation of these cancers, is key to designing potential treatments. Over the last 50 years or more, genetically engineered mouse models (GEMMs) have been instrumental platforms to our discovery of neoplastic disease as many follow near-identical molecular and histological progression as human tumours. In this mini review, we summarize three key preclinical models and focus on some of the major findings in relation to clinical care. We discuss the MMTV-PyMT (polyomavirus middle T antigen) mouse, TRAMP (transgenic adenocarcinoma mouse prostate) mouse and APCMin (multiple intestinal neoplasm mutation of APC gene) mouse, which mimic breast, prostate and intestinal cancers, respectively. We aim to describe the significant contributions these GEMMs have made to our collective understanding of high-incidence cancers as well as briefly discuss the limitations of each model as a device for therapeutic discovery.

Abstract CT234: A phase I/II trial investigating safety and efficacy of autologous TAC01-HER2 in relapsed or refractory solid tumors

Abstract Background: Despite recent therapeutic developments for patients with advanced, metastatic, unresectable HER2+ solid tumors, significant unmet medical needs still exist, especially in tumors other than breast and gastric. The T cell antigen coupler (TAC) technology is a novel approach to modifying T cells, allowing them to recognize and treat HER2+ solid tumors. The TAC receptor redirects T cells to tumor cells, and upon tumor cell recognition, co-opts the natural T cell receptor (TCR) to yield safer anti-tumor responses versus chimeric antigen receptor (CAR) T cells. In preclinical studies, TAC T cells led to complete tumor clearance in mouse models of human cancer, without any TAC-related toxicities. In the ongoing clinical trial (NCT04727151), TAC01-HER2 treatment of HER2+ solid tumors is hypothesized to result in safe and effective anti-tumor responses. Subjects undergo leukapheresis, bridging therapy (if needed) while their TAC01-HER2 are engineered, lymphodepletion chemotherapy (LDC), and finally TAC01-HER2 infusion. Trial Design and Early Results: In phase I dose escalation, the primary objective is to evaluate the safety of TAC01-HER2 at increasing doses of 0.3, 0.8, 3, and 8 × 106 cells/kg in HER2+ solid tumors (1+, 2+ or 3+ as identified by immunohistochemistry) in adult subjects who have progressed after ≥2 lines of systemic therapy. Dose limiting toxicities (DLTs) are assessed up to 28 days from cell infusion. In Phase II, dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC01-HER2 dose in HER2+ breast and other solid tumor types. As of 12 Dec 2022, 12 patients have been treated in Cohorts 1-4 with breast, colorectal, gall bladder, gastro-esophageal junction, gastric and ovarian tumors. No DLTs or neurotoxicity events have been reported. All patients treated so far at Cohorts 3 and 4 (3 × 106 and 8 × 106 cells/kg, respectively) experienced Grade ≤2 CRS which were resolved with standard of care treatments. Eight subjects have reported a total of 15 serious adverse events, all unrelated to TAC01-HER2 except for a Grade 1 and a Grade 2 CRS, both resolved with standard of care. Most adverse events were related to LDC or the underlying neoplasm. At Cohort 2, a partial response was observed in a subject with refractory metastatic gastric adenocarcinoma (3+ HER2) at 1st scan, with a 36.5% reduction in measurable disease and clinical benefit was maintained for 6 months. A 71% disease control rate was observed at Cohorts 2 and 3 at 1st scan (0.8 × 106 and 3 × 106 cells/kg, respectively)). Dose escalation of TAC01-HER2 is ongoing, with the first subject treated at Cohort 4. These results in a heavily pre-treated cancer population show manageable safety and promising clinical activity with a novel T cell therapy that may have broad clinical applicability in HER+ cancers. Citation Format: Ecaterina Elena Dumbrava, Daniel Olson, Samuel Saibil, Brooke Pieke, Mridula A. George, Riemke Bouvier, Miriam Gavriliuc, Kelly Gruber, Kara Moss, Nathan Ternus, Maria Apostolopoulou, Deyaa Adib, Benjamin L. Schlechter. A phase I/II trial investigating safety and efficacy of autologous TAC01-HER2 in relapsed or refractory solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT234.

Abstract 14: The impact of genetic background on cancer phenotypes of mouse models

Abstract The laboratory mouse is the premier animal model system for in vivo studies of the genetic and genomic basis of cancer in humans. Although thousands of mouse models have been generated, finding relevant data and knowledge about these models is complicated by a general lack of compliance in the published literature with nomenclature and annotation standards for genes, alleles, mouse strains, and cancer types. The Mouse Models of Human Cancer database (MMHCdb; tumor.informatics.jax.org) is an expertly curated knowledgebase of cancer phenotypes reported for diverse types of mouse models of human cancer such as inbred mouse strains, genetically engineered mouse models (GEMMs), Patient Derived Xenografts (PDXs), and mouse genetic diversity panels (e.g., the Collaborative Cross). MMHCdb includes data on more than 60,000 mouse models for over 1200 tumor classifications curated from more than 25,000 peer-reviewed publications. One of the primary goals of the MMHCdb is to highlight the impact of genetic background on the incidence and presentation of different tumor types in mice. The same allele on different backgrounds can result in very different cancer characteristics and, therefore, impact the appropriateness of a model for a specific research application. In MMHCdb, users can review the impact of genetic background on the frequency of spontaneous tumors for inbred mouse strains using an interactive table generated from different published and unpublished data sources. In addition, color-coded tabular summaries of individual papers are available that allow researchers to quickly assess how genetic background affects cancer phenotypes in the mouse models reported in a specific publication. We will highlight examples of how genetic background can profoundly change the types and frequencies of tumor types that can be expected in mouse models of human cancer. MMHCdb is supported by NCI R01 CA089713 Citation Format: Dale A. Begley, Debra M. Krupke, Steven B. Neuhauser, Emily L. Jocoy, John P. Sundberg, Carol J. Bult. The impact of genetic background on cancer phenotypes of mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 14.

The Mouse Models of Human Cancer database (MMHCdb)

The laboratory mouse has served for decades as an informative animal model system for investigating the genetic and genomic basis of cancer in humans. Although thousands of mouse models have been generated, compiling and aggregating relevant data and knowledge about these models is hampered by a general lack of compliance, in the published literature, with nomenclature and annotation standards for genes, alleles, mouse strains and cancer types. The Mouse Models of Human Cancer database (MMHCdb) is an expertly curated, comprehensive knowledgebase of diverse types of mouse models of human cancer, including inbred mouse strains, genetically engineered mouse models, patient-derived xenografts, and mouse genetic diversity panels such as the Collaborative Cross. The MMHCdb is a FAIR-compliant knowledgebase that enforces nomenclature and annotation standards, and supports the completeness and accuracy of searches for mouse models of human cancer and associated data. The resource facilitates the analysis of the impact of genetic background on the incidence and presentation of different tumor types, and aids in the assessment of different mouse strains as models of human cancer biology and treatment response.

SB Digestor: a tailored driver gene identification tool for dissecting heterogeneous Sleeping Beauty transposon-induced tumors.

Sleeping Beauty (SB) insertional mutagenesis has been widely used for genome-wide functional screening in mouse models of human cancers, however, intertumor heterogeneity can be a major obstacle in identifying common insertion sites (CISs). Although previous algorithms have been successful in defining some CISs, they also miss CISs in certain situations. A major common characteristic of these previous methods is that they do not take tumor heterogeneity into account. However, intertumoral heterogeneity directly influences the sequence read number for different tumor samples and then affects CIS identification. To precisely detect and define cancer driver genes, we developed SB Digestor, a computational algorithm that overcomes biological heterogeneity to identify more potential driver genes. Specifically, we define the relationship between the sequenced read number and putative gene number to deduce the depth cutoff for each tumor, which can reduce tumor complexity and precisely reflect intertumoral heterogeneity. Using this new tool, we re-analyzed our previously published SB-based screening dataset and identified many additional potent drivers involved in Brca1-related tumorigenesis, including Arhgap42, Tcf12, and Fgfr2. SB Digestor not only greatly enhances our ability to identify and prioritize cancer drivers from SB tumors but also substantially deepens our understanding of the intrinsic genetic basis of cancer.

100 (PB090) - Synergy of the novel dual TTK/PLK1 mitotic checkpoint inhibitor (MCI) BAL0891 with paclitaxel and carboplatin in mouse models of human cancer

Background: BAL0891 is a first-in-class dual inhibitor of threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1). Both kinases collaborate in activating the spindle assembly checkpoint (SAC) to regulate chromosome alignment and segregation before the cell can exit mitosis. In vitro treatment of tumor cells with BAL0891 leads to rapid SAC disruption and accumulation of cells with aberrant chromosome numbers. The resultant genetic instability suggests a potential for combination effects with approved cytotoxic therapies, such as paclitaxel and carboplatin.

778TiP A phase I/II trial investigating safety and efficacy of autologous TAC T-cells targeting HER2 in relapsed or refractory solid tumors

Despite historic and recent therapeutic developments for patients with advanced, metastatic, unresectable HER2-positive (HER2+) solid tumors, significant unmet medical needs still exist, especially in tumors other than breast and gastric cancers. The T cell antigen coupler (TAC) technology is a novel approach to modifying T cells, allowing them to recognize and treat HER2+ solid tumors. Mechanistically, the TAC receptor redirects T cells to tumor cells, and upon tumor cell recognition, co-opts the natural T cell receptor (TCR) to yield safer anti-tumor responses versus chimeric antigen receptor (CAR) T cells. In preclinical studies, TAC T cells led to complete tumor clearance in various mouse models of human cancer, without any TAC-related toxicities, and potentially superior results to T cells engineered with a 2nd-generation CAR. In the ongoing clinical trial (NCT04727151), TAC T cell treatment in HER2+ solid tumors is hypothesized to result in safe and effective anti-tumor responses, with fewer cytokine release syndrome (CRS) and neurotoxicity events. Procedurally, subjects undergo leukapheresis, bridging therapy (if needed) while their TAC T cells are engineered, lymphodepletion chemotherapy, and finally TAC T cell infusion. Phase I dose escalation is investigating TAC T cells doses of 0.08, 0.3 (starting dose), 0.8, 3, 8 x 106 cells/kg in HER2+ solid tumors (1+, 2+ or 3+ by immunohistochemistry) in adult subjects who have progressed after ≥2 lines of systemic therapy. Dose limiting toxicities (DLTs) are assessed up to 28 days from engineered cell infusion. In Phase 2, dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC T cell dose in breast, lung, pancreatic, colorectal, gastric, endometrial, ovarian, and other tumor types. As of 13 Apr 2022, 3 patients have been treated in Cohort 1 (0.3 x 106 cells/kg): rectosigmoid, gastro-esophageal, and gastric adenocarcinoma. No DLTs, CRS, or neurotoxicity events have been reported, with the Data Safety Monitoring Committee recommending commencement of patient enrollment in Cohort 2. NCT04727151. The authors.

Abstract 1190: MMHCdb: A knowledgebase for the evolving landscape of mouse models of human cancer

Abstract The laboratory mouse is the premier mammalian model organism for interrogating the genetic and molecular basis of human cancer and for preclinical investigations into targets for the prevention and treatment of cancer. The distributed and heterogenous nature of information about these model systems makes it difficult for researchers to integrate and interpret the information to determine the state of the field and to identify the most relevant models for basic and preclinical research. The Mouse Models of Human Cancer database (http://tumor.informatics.jax.org) is an expertly curated knowledgebase about genetically defined mouse strains and Patient Derived Xenograft (PDX) models of human cancer. Data in MMHCdb are obtained from peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. MMHCdb is built on FAIR data management principles (Findable, Accessible, Interoperable, Reusable). The enforcement of metadata standards and official gene, allele and strain nomenclature ensure accurate and comprehensive search results for cancer models. MMHCdb has long represented data from spontaneous or endogenously induced tumors from genetically defined mice and for PDXs which have been the foundation of basic cancer research and preclinical studies for decades. MMHCdb has expanded to include cancer models such as Diversity Outbred and Collaborative Cross mice which are ideally suited for research into the relationship of genetic variation with cancer susceptibility and for modeling the genetics of variability in treatment responses. The MMHCdb contains over 109,266 curated tumor frequency records for over 8,275 mouse strains. Tumor types in the database have been indexed to over 21,000 literature citations. PDX models and data available in MMHCdb are also accessible from the Patient Derived Cancer Models resource at EMBL-EBI which currently provides information for over 4,000 PDXs (https://cancermodels.org).MMHCdb is supported by NCI R01 CA089713 Citation Format: Dale A. Begley, Debbie M. Krupke, Steven Neuhauser, John Sundberg, Carol J. Bult. MMHCdb: A knowledgebase for the evolving landscape of mouse models of human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1190.

Obesity-Associated Cancers: Evidence from Studies in Mouse Models.

Obesity, one of the major problems in modern human society, is correlated with various diseases, including type 2 diabetes mellitus (T2DM). In particular, epidemiological and experimental evidence indicates that obesity is closely linked to at least 13 different types of cancer. The mechanisms that potentially explain the link between obesity and cancer include hyperactivation of the IGF pathway, metabolic dysregulation, dysfunctional angiogenesis, chronic inflammation, and interaction between pro-inflammatory cytokines, endocrine hormones, and adipokines. However, how the largely uniform morbidity of obesity leads to different types of cancer still needs to be investigated. To study the link between obesity and cancer, researchers have commonly used preclinical animal models, particularly mouse models. These models include monogenic models of obesity (e.g., ob/ob and db/db mice) and genetically modified mouse models of human cancers (e.g., Kras-driven pancreatic cancer, Apc-mutated colorectal cancer, and Her2/neu-overexpressing breast cancer). The experimental results obtained using these mouse models revealed strong evidence of a link between obesity and cancer and suggested their underlying mechanisms.

Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents.

The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years. CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription. While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance. Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered. The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo. In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers. Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies. In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation.

Development of a Nanoscale Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agent That Measures pH.

AcidoCEST MRI can measure the extracellular pH (pHe) of the tumor microenvironment in mouse models of human cancers and in patients who have cancer. However, chemical exchange saturation transfer (CEST) is an insensitive magnetic resonance imaging (MRI) contrast mechanism, requiring a high concentration of small-molecule agent to be delivered to the tumor. Herein, we developed a nanoscale CEST agent that can measure pH using acidoCEST MRI, which may decrease the requirement for high delivery concentrations of agent. We also developed a monomer agent for comparison to the polymer. After optimizing CEST experimental conditions, we determined that the polymer agent could be used during acidoCEST MRI studies at 125-fold and 488-fold lower concentration than the monomer agent and iopamidol, respectively. We also determined that both agents can measure pH with negligible dependence on temperature. However, pH measurements with both agents were dependent on concentration, which may be due to concentration-dependent changes in hydrogen bonding and/or steric hindrance. We performed in vivo acidoCEST MRI studies using the three agents to study a xenograft MDA-MB-231 model of mammary carcinoma. The tumor pHe measurements were 6.33 ± 0.12, 6.70 ± 0.15, and 6.85 ± 0.15 units with iopamidol, the monomer agent, and polymer agent, respectively. The higher pHe measurements with the monomer and polymer agents were attributed to the concentration dependence of these agents. This study demonstrated that nanoscale agents have merit for CEST MRI studies, but consideration should be given to the dependence of CEST contrast on the concentration of these agents.

Low-Coverage Whole Genome Sequencing Using Laser Capture Microscopy with Combined Digital Droplet PCR: An Effective Tool to Study Copy Number and Kras Mutations in Early Lung Adenocarcinoma Development.

Defining detailed genomic characterization of early tumor progression is critical to identifying key regulators and pathways in carcinogenesis as potentially druggable targets. In human lung cancer, work to characterize early cancer development has mainly focused on squamous cancer, as the earliest lesions are more proximal in the airways and often accessible by repeated bronchoscopy. Adenocarcinomas are typically located distally in the lung, limiting accessibility for biopsy of pre-malignant and early stages. Mouse lung cancer models recapitulate many human genomic features and provide a model for tumorigenesis with pre-malignant atypical adenomatous hyperplasia and in situ adenocarcinomas often developing contemporaneously within the same animal. Here, we combined tissue characterization and collection by laser capture microscopy (LCM) with digital droplet PCR (ddPCR) and low-coverage whole genome sequencing (LC-WGS). ddPCR can be used to identify specific missense mutations in Kras (Kirsten rat sarcoma viral oncogene homolog, here focused on Kras Q61) and estimate the percentage of mutation predominance. LC-WGS is a cost-effective method to infer localized copy number alterations (CNAs) across the genome using low-input DNA. Combining these methods, the histological stage of lung cancer can be correlated with appearance of Kras mutations and CNAs. The utility of this approach is adaptable to other mouse models of human cancer.

Abstract 1238: Treating estrogen receptor (ER)-negative and triple-negative breast cancer by targeting STAT3 signaling with putative STAT3 inhibitors

Abstract Approximately 20% to a quarter of breast cancer cases are estrogen receptor (ER)-negative breast cancer (ENBC), including the most aggressive subtype, triple-negative breast cancer (TNBC), which spreads early and shows poor prognosis. ENBCs do not respond to selective ER modulators such as tamoxifen. Therefore, there is an urgent need for non-ER-based therapies for ENBC. Recently, STAT3 was found to play an important role in maintaining cancer stem cells in vitro and in mouse models of human cancers. In addition, during mammary carcinogenesis, STAT3 is highly activated in mammary epithelial cells involving in mammary epithelial cell transformation, tumor initiation, progression, and metastasis. STAT3 has been traditionally considered as non-targetable or undruggable, and there is currently a lack of FDA-approved STAT3 inhibitors for clinical use. We recently developed a putative STAT3 inhibitor, HJC0152, and a series of HJC0152-based analogues as orally bioavailable STAT3 inhibitors. These small molecules have been evaluated and a number of them showed low micro-molar potency in inhibiting the proliferation of a panel of breast cancer cell lines. Compound JMX0804 showed improved anti-proliferative effects against the highly aggressive TNBC cell line MDA-MB-231 and other ER+ and ER- breast cancer cell lines in comparison to HJC0152. JMX0804 inhibited STAT3 phosphorylation at the Tyr705 residue and induced apoptosis in MDA-MB-231 cells. In vivo, mice treated with JMX0804 at a 10 mg/kg dose via i.p. showed reduced growth of xenograft tumors arisen from MDA-MB-231 cells, with minimal impact on general health and body weight. Our current research supports the notion that JMX0804 suppresses breast cancer growth by inhibiting breast cancer cell proliferation and inducing apoptosis via mediating STAT3 signaling. JMX0804 is currently undergoing further characterization for breast cancer metastasis and mechanisms of action as well as optimization to improve drug properties including potency and safety profile. This work is supported by NIH/NCI grant R01 CA231150. Citation Format: Hyejin Kim, Doerte R. Fricke, Jimin Xu, Haiying Chen, Jia Zhou, Qiang Shen. Treating estrogen receptor (ER)-negative and triple-negative breast cancer by targeting STAT3 signaling with putative STAT3 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1238.

Laboratory Mice - A Driving Force in Immunopathology and Immunotherapy Studies of Human Multiple Myeloma.

Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on in vivo propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop de novo (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.

The Emerging Roles of RNA m6A Methylation and Demethylation as Critical Regulators of Tumorigenesis, Drug Sensitivity, and Resistance.

RNA N6 -methyladenosine (m6A) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA m6A is regulated by the RNA m6A methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1-2, YTHDF1-3, IGF2BP1-3, and SND1 (readers). These RNA m6A modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA m6A modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both in vitro and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA m6A modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA m6A modification protein expression or RNA m6A modification protein-induced resistance to cancer therapy.