tbuckley/cabot-search huggingface dataset:
Abstract 536: Breaking through ADCs resistance: Constructing preclinical enhertu-induced resistant model
Authors: Yuan Fang, Huiyi Wang, Jun Xing, Lu Yang, Jing Zhao, Xiang Gao, Cunxiang Ju
Journal: Cancer Research (2024)

Abstract Antibody-drug conjugates (ADCs) are compounds that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxic payload of toxic substances. In recent years, ADCs have rapidly developed in the field of cancer therapy, particularly in the treatment of HER2-positive breast cancer. One representative example is Trastuzumab deruxtecan (Enhertu), which has become a new benchmark for anti-HER2 ADCs due to its excellent performance in clinical trials. Despite the impressive clinical outcomes of ADCs, some tumors in patients may still develop resistance to these drugs. Therefore, it is crucial to understand the mechanisms of resistance and develop strategies to overcome ADCs resistance. To achieve these goals, it is essential to establish and utilize preclinical models to study these resistance mechanisms. Preclinical models of resistance to ADCs have mainly been generated using human cultured cell lines. JIMT-1 is a HER2-positive breast cancer cell line that exhibits primary resistance to the anti-HER2 antibody trastuzumab and also shows resistance to trastuzumab-derived ADC T-DM1. However, we found that Enhertu significantly inhibited tumor growth in JIMT-1 xenograft models. We subjected JIMT-1 tumor tissues to continuous passage in mice and administered long-term drug induction. The tumor growth rate gradually increased, and the drug sensitivity decreased, resulting in the acquisition of an Enhertu-resistant tumor model. The obtained resistant tumor tissues not only include tumor cells themselves but also comprise fibroblasts, extracellular matrix, and other cellular components, enabling a more comprehensive investigation into the interactions between different cells within the tumor microenvironment (TME). We believe that the establishment of preclinical Enhertu-resistant models helps predict resistance that has not yet emerged clinically and provides references for future drug development. Citation Format: Yuan Fang, Huiyi Wang, Jun Xing, Lu Yang, Jing Zhao, Xiang Gao, Cunxiang Ju. Breaking through ADCs resistance: Constructing preclinical enhertu-induced resistant model [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 536.
Abstract 5729: ADCK1 inhibition alters cell proliferation and cell cycle progression in liver cancer cells
Authors: Noel A. Jacquet, Yunfeng Zhao
Journal: Cancer Research (2024)

Abstract In 2020, there were over 830,000 reported liver cancer deaths. Incidence rates of liver cancer have tripled, and death rates have doubled since the 1980s; giving this disease one of the highest mortality rates when compared to its incidence rate. Hepatocellular carcinoma (HCC) is derived from hepatocytes and is the main type of liver cancer in adults, accounting for 75-85% of all primary liver cancers. Current treatment options for HCC like radiation therapy and chemotherapy are imperfect and cause significant side effects. Tumorigenesis is dependent on an organism’s cellular metabolism. Metabolic reprogramming is a promising area of focus for cancer therapeutics. Cancer cells thrive in nutrient-deficient environments by hijacking and reprogramming the cells existing cellular metabolism. Metabolic reprogramming is driven by genetic alterations and environmental cues. AarF Domain Containing Kinase 1 (ADCK1) is a protein-coding gene that acts as a mitochondrial protein with putative kinase activity. The role of ADCK1 has not been well studied, particularly in liver cancer. Our group has sought to study how ADCK1 impacts the metabolism and cellular environment of HCC cells to help establish a more effective drug target. Bioinformatics performed by our lab report that ADCK1 was highly expressed in HCC tumor cells. The expression levels of ADCK1 were also correlated with a decrease in patient survival. ADCK1 knockout clones were generated; these knockout cells showed decreased proliferation and altered cell cycle progression. Proteomics analysis demonstrated that loss of ADCK1 was also seen to alter the expression of proteins involved in several cellular processes related to the cell cycle and cellular metabolism. How ADCK1 regulates these processes will be studied in the future. Citation Format: Noel A. Jacquet, Yunfeng Zhao. ADCK1 inhibition alters cell proliferation and cell cycle progression in liver cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5729.
Abstract 6692: Intermittent fasting-remodeled gut microbiota improves anti-tumor immunity in pancreatic cancer
Authors: Le Li, Vidhi Chandra, Olivereen Le Roux, Rian Morgan Howell, Virginia Tahan, Nagireddy Putluri, Joseph Petrosino, Arun Sreekumar, Jay K. Kolls, James White, Florencia McAllister
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has become the third leading cause of cancer-related death in the United States with high resistance to therapies, presentation at late stages and aggressive biology. Immunotherapy has revolutionized cancer therapy by offering survival benefit in many solid malignancies, however, it is still not effective in pancreatic cancer. Host factors are crucial modulators of responses to immunotherapy. The roles of gut microbiome in modulating the immune system and determining cancer outcomes have been well established. Eating patterns can alter the gut microbiota and metabolic output, both of which affect anti-tumor immune responses. Intermittent fasting (IF), a form of dietary restriction which is characterized by limited feeding with unlimited calorie consumption during a certain time window. IF has been shown to affect gut microbiota composition, modulate immunity, and metabolic processes. Despite the well-known beneficial role of fasting in pancreatic conditions, including pancreatitis and diabetes, its effect in the treatment of pancreatic cancer has not been explored. Our study found that IF reverses immunotherapy resistance in PDAC. IF can reshape gut microbiota composition and reprogram the metabolism of host. We found that IF improves anti-tumor immunity through modulating gut microbiota. Depletion of gut microbiota can abrogate the beneficial effect of IF on anti-tumor response, while fecal microbiota transplantation from mice exposed to IF can sensitize the anti-tumor effects of immunotherapy. Using 16S rRNA sequencing, metabolic profiling and transcriptomic sequencing, our findings elucidate the mechanism of IF-remodeled gut bacteria influencing metabolic molecules which drive immune cells activation. Our study suggests that IF-based interventions have potential utility for the prevention and treatment of PDAC. Citation Format: Le Li, Vidhi Chandra, Olivereen Le Roux, Rian Morgan Howell, Virginia Tahan, Nagireddy Putluri, Joseph Petrosino, Arun Sreekumar, Jay K. Kolls, James White, Florencia McAllister. Intermittent fasting-remodeled gut microbiota improves anti-tumor immunity in pancreatic 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 6692.
Abstract 2592: New technologies and capabilities supporting the development of novel molecular radiotherapy agents
Authors: Sarah Belderbos, Celine Mothes, Claire Bernhard, Franck Denat, Pierre Adumeau, Merari Tumin Chevalier, Jordi Llop, Agnieszka Kownacka, Calmen Tihansky, Marie Ruch, Michael Claron, Mathieu Moreau, Cyril Berthet, Eftychia Koumarianou
Journal: Cancer Research (2024)

Abstract At Oncodesign-Services we aim to provide cutting-edge technologies and products to support the development of radiopharmaceuticals for theranostics. Starting from the optimization of lead compounds, the site-specific bioconjugation chemistry of a bifunctional chelator to large biological compounds, such as antibodies, can preserve the biological profile and the reliable batch production. Thanks to new technologies we can conjugate a variety of payloads (cytotoxins, radioactive chelates, fluorescent dyes) on antibodies at targeted lysine residues of the Fc region, independent of Fc glycosylation. Moreover, we aim to use relevant models for valuable translational results. In line with this, we established tumor spheroids to finely monitor the diffusion and subcellular distribution of novel fluorescent and radioactive probes in a 3D environment. Furthermore, we are currently generating two animal tumor models for optimal target expression levels and recapitulation of the human tumor microenvironment. Our first model is a PSMA+ expressing tumour model, in a non radiosensitive rodent strain allowing improved assessment of novel radiopharmaceuticals. Our second tumor model is under development to assess novel FAPI tracers. Finally, we present in partnership with ImaginAb 89Zr Crefmirlimab Berdoxam​, a minibody (human and murine analog) with high affinity to the CD8α glycoprotein, a valuable PET imaging tool for preclinical tracking and assessment of CD8 cells. This PET imaging can be used to evaluate immunoresponse following treatment, autoimmune, inflammatory and/or infectious diseases models. To conclude, our continuous efforts aim at expanding our service portfolio to fulfil the needs of our various projects, as presented herein. Our experience and expertise allow us to suggest alternatives based on the latest technological progresses to facilitate and expedite the drug discovery progress from bench to bedside. Citation Format: Sarah Belderbos, Celine Mothes, Claire Bernhard, Franck Denat, Pierre Adumeau, Merari Tumin Chevalier, Jordi Llop, Agnieszka Kownacka, Calmen Tihansky, Marie Ruch, Michael Claron, Mathieu Moreau, Cyril Berthet, Eftychia Koumarianou. New technologies and capabilities supporting the development of novel molecular radiotherapy agents [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 2592.
Abstract 486: Paclitaxel nanoformulation attenuates pancreatic tumor desmoplasia and alter tumor immune responses
Authors: Vivek K. Kashyap, Godwin P. Darkwah, Neeraj Chauhan, Mohammed Sikander, Eswara N. Ghali, Meghana Kolli, Bilal B. Hafeez, Murali M. Yallapu, Subhash C. Chauhan
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with a 5-year survival rate of less than 13% due to the lack of effective diagnostic/therapeutic modalities. Paclitaxel (PTX) has been tested in pancreatic cancer (PanCa) therapy with marginally better clinical outcomes, but remains limited by its poor hemocompatibility, biodistribution, and intracellular accumulation in tumor cells. Gemcitabine (GEM) is the most effective therapy for PanCa. However, it shows only a marginal survival benefit of 6 months. The poor therapy response is attributed to high desmoplasia, unfavorable tumor microenvironment (TME), and excessive recruitment of immune suppressive cells. We have recently engineered a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated paclitaxel loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PPNPs), which effectively inhibits pancreatic tumor. In this study, we demonstrate that PPNPs effectively sensitize tumor cells to GEM via attenuation of tumor desmoplasia. Our findings also show that PPNPs synergize GEM therapy response in cell lines and in vivo mouse models. Mechanistically, PPNPs target the TME via inhibition of the sonic hedgehog (SHH) pathway and other oncogenic signaling axis that inhibits bidirectional tumor-stromal cell interaction as determined by qPCR and Western blot analyses. In addition, PPNPs effectively target tumor-associated macrophages (TAM) by repolarizing M2 into M1 phenotype via inhibiting expression of M2 markers and an increase in M1 markers in mouse macrophage cell line RAW264.7. M2 polarization of RAW264.7 cells were induced by culture with IL-4 (20 ng/mL) in the presence of PPNPs or vehicle control. Furthermore, PPNPs effectively increase phagocytic capacity in murine macrophages as determined by phagocytosis assay (Vybrant Phagocytosis Assay Kit). In conclusion, we observed that our novel PPNP nano formulation effectively targets TME, and facilitates GEM uptake by inhibiting the activation of SHH signaling and reprograming the tumor immune surveillance mechanisms. This study suggests that PPNPs have great potential for future clinical use in management of pancreatic cancer. Citation Format: Vivek K. Kashyap, Godwin P. Darkwah, Neeraj Chauhan, Mohammed Sikander, Eswara N. Ghali, Meghana Kolli, Bilal B. Hafeez, Murali M. Yallapu, Subhash C. Chauhan. Paclitaxel nanoformulation attenuates pancreatic tumor desmoplasia and alter tumor immune responses [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 486.
Abstract 669: Interrogating circadian clock compounds as an adjuvant to chemoradiation against GBM
Authors: Priscilla Chan, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Gevorg Karapetyan, Khalid Shah, Hiroaki Wakimoto, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Tsuyoshi Hirota, Rex A. Moats, Jeremy N. Rich, Steve A. Kay
Journal: Cancer Research (2024)

Abstract Despite the extensive efforts of researchers and physicians over the past two decades, glioblastoma (GBM) remains the most prevalent brain tumor type with a grim average survival time of 8 months following diagnosis irrespective of treatment. Additionally, the current standard-of-care has not changed from maximal surgical resection followed by concurrent chemoradiation from its establishment in 2005. One of the major challenges that limits progress in treating GBM is the presence of GBM stem cells (GSCs) that are highly invasive, reaching far past the tumor margins, are resistant to both chemotherapy and radiation, and can recapitulate the primary tumor following resection. Recent studies have found that GSCs, however, are highly sensitive to targeting of core circadian clock components, particularly positive regulators of the clock Brain and Muscle ARNTL-Like 1 (BMAL1) and Circadian Locomoter Output Cycles Protein Kaput (CLOCK). Here we employ the use of small molecule compounds that upregulate the activity of the negative regulators of the clock in order to suppress BMAL1::CLOCK transcriptional activity or repress BMAL1 transcription. We find that these compounds not only have a much more potent effect against GSCs compared to temozolomide (TMZ) chemotherapy but also, they display combination effect against both GSCs and differentiated GSCs (DGCs) when combined with TMZ. These results suggest that the blood brain barrier (BBB) penetrant circadian clock compounds can be utilized as an adjuvant to current GBM therapies as they can effectively target both the primary tumor cells and GSCs. Citation Format: Priscilla Chan, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Gevorg Karapetyan, Khalid Shah, Hiroaki Wakimoto, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Tsuyoshi Hirota, Rex A. Moats, Jeremy N. Rich, Steve A. Kay. Interrogating circadian clock compounds as an adjuvant to chemoradiation against GBM [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 669.
Abstract 5696: Exploring the association between miR-9-5p levels and the mTORC1/mTORC2 pathway in laryngeal cancer cell lines
Authors: Christina Gobin, Matthew Chang, Chayil C. Lattimore, Kristianna M. Fredenburg
Journal: Cancer Research (2024)

Abstract Background: We previously demonstrated that differing levels of miR-9-5p could predict chemosensitivity to cisplatin, and that miR-9-5p is a regulator of potential chemotherapeutic target MAP1B. As the mTOR/PIK3CA pathway has been implicated in the pathogenesis of laryngeal squamous cell carcinoma (LSCC), we sought to determine an association between differing miR-9-5p levels, mTOR pathway mediators including MAP1B, and methylation. Methods: UM-SCC-98, UM-SCC-12, UM-SCC-11A, UM-SCC-10A (obtained from the University of Michigan) laryngeal cancer cell lines were used in this study. We previously showed UM-SCC-98 and UM-SCC-12 to have significantly lower miR-9-5p levels as compared to UM-SCC-11A and UM-SCC-10A (Northern blot analysis). The IC50 of an mTORC1 inhibitor (Rapamycin) and an mTORC1/C2 inhibitor (AZD-8055) were evaluated using the Cell Titer Blue Viability assay. Cells were treated with the de-methylating agent, 5-Azacytidine (1μM). Gene expression of mTOR pathway mediators- miR-9-5p, PTEN, EGFR, PIK3CA, and MAP1B- were determined in each cell line pre-and post-treatment via qPCR. Results: All cell lines were resistant to treatment with Rapamycin (IC50 &amp;gt; 60μM) with the UM-SCC-12 cell line yielding the highest IC50 (&amp;gt; 150μM). Conversely, decreased cell proliferation was detected with AZD-8055. This was significantly associated with their miR-9-5p levels– a higher AZD-8055 IC50 was associated with cell lines UM-SCC-98 (~40μM) and UM-SCC-12 (~23μM) compared to UM-SCC-10A (~16μM) and UM-SCC-11A (~8μM). Following demethylation treatment, miR-9-5p levels were significantly increased in UM-SCC-12 only (2-fold), and this corresponded to a significant decrease in MAP1B gene expression (2-fold) but not with EGFR, PIK3CA, and PTEN gene expression. Conclusion: In conclusion, our study suggests that miR-9-5p may regulate MAP1B gene expression via the mTORC2 pathway. In addition, methylation may play a role in the regulation of the miR-9-5p gene and its downstream targets in laryngeal cancer tumorigenesis. Future studies will involve exploring epigenetic mechanisms of miR-9-5p inhibition and defining the role of key mediators of the mTOR pathway in LSCC. Citation Format: Christina Gobin, Matthew Chang, Chayil C. Lattimore, Kristianna M. Fredenburg. Exploring the association between miR-9-5p levels and the mTORC1/mTORC2 pathway in laryngeal cancer cell lines [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 5696.
Abstract 6673: Tumor microbial burden is regulated by mast cells and determines immunotherapy responses
Authors: Hajar Rajaei, Jeong-Hoon Jang, Haoyue Liu, Erika Y. Faraoni, Olivia Le Roux, Vidhi Chandra, Virginia Tahan, Le Li, Erick Riquelme, James Robert White, Luis A. Diaz, Florencia McAllister
Journal: Cancer Research (2024)

Abstract Immune checkpoint inhibitors (ICI) have notably improved overall survival rates across various cancers, particularly in cases of mismatch repair deficient cancer (MMRd). However, numerous factors influence patient response following ICI treatment. Beyond genetic factors, mutations, and levels of immune cell infiltration, several studies highlight the correlation between the gut microbiome and treatment response rates. Furthermore, specific bacterial compositions have been observed to shift during therapeutic interventions. Notably, studies have demonstrated that patients who used antibiotics before and during ICI treatment exhibited lower progression-free survival and overall survival, serving as evidence for this association. Our previous investigations elucidated the impact of distinct tumor microbial burdens on modulating immune activation. Consequently, our hypothesis posits the substantive involvement of the interplay between tumor microbial burden and the immune system response to ICI treatment. We evaluated the presence of intra-tumoral microbes within Colorectal cancers (CRC) by examining TCGA data. Patients with elevated microbial levels demonstrated heightened immune activity and better survival rates. Using cybersport analysis, we validated increased mast cell infiltration in CRC patients with abundant microbes. Quantification involved assessing bacterial burden through 16s rRNA via FISH staining and mast cell counts using tryptase via IHC staining. Reducing bacterial load in MC38 cancer model, achieved by locally administering antibiotics, led to a diminished immune response when PD-1 was introduced to these mice. Cross-referencing TCGA data, we identified upregulated genes in CRC patients with high microbial burden and downregulated genes in mice receiving local antibiotics after MC38 cell implantation. The common genes were associated with immune responses, suggesting a strong correlation between bacterial burden and immune activity in CRCs. In conclusion, the high burden of bacteria in CRC improves immune response to ICI and increases the infiltration of mast cells, which all contribute to better survival rates. Citation Format: Hajar Rajaei, Jeong-Hoon Jang, Haoyue Liu, Erika Y. Faraoni, Olivia Le Roux, Vidhi Chandra, Virginia Tahan, Le Li, Erick Riquelme, James Robert White, Luis A. Diaz Jr., Florencia McAllister. Tumor microbial burden is regulated by mast cells and determines immunotherapy responses [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 6673.