tbuckley/cabot-search huggingface dataset:
Abstract 24: Utilizing T cell receptor-based therapy to treat anaplastic thyroid cancer
Authors: Shao-Hsi Hung, Ying C. Henderson, Pan Ke, Yulun Chiu, Shailbala Singh, Yunyun Chen, Stephen Y. Lai, Cassian Yee
Journal: Cancer Research (2024)

Abstract Anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumor in thyroid tissue, with a 6-month medium overall survival. The effectiveness of conventional treatments in extending the survival of patients is limited. Therefore, there is an urgent need to develop novel systemic therapeutic interventions. Adoptive cell therapy has revolutionized cancer immunotherapy by successfully treating B-cell malignancies through chimeric antigen receptor-based approaches. For solid tumors, there is a need to identify a broader spectrum of tumor target antigens, and the field has now shifted towards leveraging T cell receptors (TCRs) which can recognize both intracellular and extracellular antigen-derived epitopes. Our team has established an immunogenic epitope discovery pipeline, followed by a specialized protocol for empiric validation of candidate epitopes. We characterized immunogenic epitopes by coupling tandem mass spectrometry of MHC-eluted peptides with tumor proteome and MHC-peptide binding prediction databases. By integrating multi-omics data (genomics, transcriptomics, and immunopeptidomics) from both in-house and publicly available ATC databases, we find that ATC exhibits significant upregulation of pathways associated with microtubule-based movement, chromosome segregation, and kinetochore complex components. We have identified several HLA-A2- and A24-restricted immunogenic peptides representing these pathway-associated proteins that covered more than 60% of the patient population. These immunogenic peptides were subsequently utilized to isolate antigen-specific T cells from peripheral blood and identify cognate TCR. These peptide-specific T lymphocytes elicit cytotoxicity toward multiple HLA-matched ATC cell lines and tumor samples in vitro and in vivo. In conclusion, our studies contribute to the development of a new treatment paradigm for treating ATC. Citation Format: Shao-Hsi Hung, Ying C. Henderson, Pan Ke, Yulun Chiu, Shailbala Singh, Yunyun Chen, Stephen Y. Lai, Cassian Yee. Utilizing T cell receptor-based therapy to treat anaplastic thyroid 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 24.
Abstract 5303: A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation
Authors: Wonjun Son, Yangsoon Lee, Yelim Park, Jonghwa Won
Journal: Cancer Research (2024)

Abstract T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an immune checkpoint molecule responsible for delivering inhibitory signals that suppress immune activation. Due to its inhibitory role in the immune response, TIGIT has emerged as a potential therapeutic target for various malignancies, with several clinical trials exploring the use of anti-TIGIT blocking antibodies with anti-PD-(L)1 therapies. Recent reports have indicated elevated expression of 4-1BB within intra-tumoral Tregs. Therefore, we hypothesized that a dual targeting approach involving both TIGIT and 4-1BB could effectively enhance intra-tumoral immunity. ABL112, a First-in-Class bispecific antibody targeting TIGIT and 4-1BB, demonstrated the induction of T cell activation by blocking the TIGIT signaling and TIGIT dependent 4-1BB clustering. By having intact Fc, ABL112 bound to FcγRI and its crosslinking with 4-1BB also induced 4-1BB activation. ABL112 selectively depleted Treg cells but not other T cells in vitro, potentially through antibody-dependent cell-mediated cytotoxicity. ABL112 demonstrated superior efficacy in tumor regression compared to anti-TIGIT monoclonal antibody across various mouse tumor models. Additionally, combining ABL112 with pembrolizumab significantly inhibited tumor growth better than combining anti-TIGIT monoclonal antibody with pembrolizumab. According to immune cell depletion assay, ABL112-mediated tumor suppressive activity was predominantly driven by CD8+ T cells, with a partial tumor reduction by CD4+ T cell or NK cell depletion. Mice with complete remission (CR) were further protected from the tumor re-challenge after 3 months of cessation of ABL112 treatment, and the proportion of tumor-specific memory T cells in the blood increased, suggesting long-term immunological memory has been established. In conclusion, ABL112 exhibited potent in vitro and in vivo anti-tumor activity through multiple mode of action including TIGIT inhibition and 4-1BB activation. These results strongly suggest that ABL112 is an innovative and promising therapeutic option with the combination of anti-PD-(L)1 therapies for cancer patients. Citation Format: Wonjun Son, Yangsoon Lee, Yelim Park, Jonghwa Won. A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation [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 5303.
Abstract 2401: Changes in skeletal muscle mass after gastrointestinal cancer surgery by body composition
Authors: Yuto Maeda, Yuji Miyamoto, Mayuko Ohuchi, Yukiharu Hiyoshi, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2024)

Abstract Background: Previous studies have extensively explored the correlation between preoperative skeletal muscle mass and long-term survival in gastrointestinal cancers. However, investigations into postoperative skeletal muscle mass alterations are limited. In gastrointestinal cancers, factors such as the tumor and surgical interventions can significantly impact dietary intake, nutritional status, and skeletal muscle mass, affecting postoperative body composition. This study aimed to examine these postoperative changes in skeletal muscle mass across different gastrointestinal cancers, including esophageal, gastric, and colorectum. Methods: This study encompassed 969 patients with Stage I-III esophageal (307 cases), gastric (278 cases), and colorectal (384 cases) cancers who underwent radical resection between 2005 and 2019. Skeletal muscle mass was quantified as the total psoas volume (TPV), measured using Ziostation2® imaging software from preoperative and postoperative CT scans at 1, 2, and 3 years. The study compared postoperative TPV trends across the different cancer types. Results: The study cohort comprised patients with esophageal (median age 66 years, 85% male), gastric (65 years, 60%), and colorectal cancers (67 years, 55%). Median BMIs were 21.5, 19.4, and 22.6 kg/m2, and median TPVs were 352.0, 305.8, and 309.5 cm3 for esophageal, gastric, and colorectal cancers, respectively. Esophageal cancer patients had significantly higher TPV and male predominance, while gastric cancer patients had notably lower BMI. Relative to preoperative TPV, the postoperative TPV at three years was 0.92, 0.91, and 0.96 for esophageal, gastric, and colorectal cancers, respectively. A year-by-year decrease in TPV was observed for each cancer type, with colorectal cancer demonstrating a less pronounced decrease compared to esophageal and gastric cancers (p&amp;lt;0.01). Stage-wise analysis revealed no significant differences among the cancer types. Regarding gender, no significant differences were noted between gastric and colorectal cancers, but esophageal cancer showed a more marked decrease in TPV in males compared to females. In recurrent cases, no significant TPV differences were observed in esophageal cancer, while recurrent gastric and colorectal cancers exhibited significant TPV decreases. Conclusions: The study indicates a general decline in TPV following gastrointestinal cancer surgery, with the extent of reduction varying according to the type of tumor and treatment. Citation Format: Yuto Maeda, Yuji Miyamoto, Mayuko Ohuchi, Yukiharu Hiyoshi, Naoya Yoshida, Hideo Baba. Changes in skeletal muscle mass after gastrointestinal cancer surgery by body composition [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 2401.
Abstract 7220: Emerging combination strategy: FANCI suppression induces PARP1 redistribution to enhance efficacy of PARP inhibitors in breast cancer
Authors: Yu-zhou Huang, Ming-Yi Sang, Pei-Wen Xi, Ruo-Xi Xu, Meng-Yuan Cai, Zi-Wen Wang, Jian-Yi Zhao, Yi-Han Li, Ji-Fu Wei, Qiang Ding
Journal: Cancer Research (2024)

Abstract While polyADP-ribose polymerase (PARP) inhibitors have made advancements in the treatment of breast cancer, challenges such as chemotherapy resistance and limited application persist. Fanconi AnemiaComplementation Group I (FANCI), a DNA repair protein associated with breast cancer development, represents a potential target for novel combination therapeutic strategies. However, the role of FANCI in breast cancer and its impact on the efficacy of PARP inhibitors require further investigation. In our study, we analyzed FANCI expression in breast cancer tissues and cell lines, and its correlation with clinical parameters and patient prognosis. Lentiviral vectors were utilized and functional assays were performed to evaluate the effects of FANCI modulation on breast cancer cell growth and migration. Co-immunoprecipitation assays and protein interaction analysis were conducted to identify the interaction between FANCI and PARP1 and determine the specific binding region. The functionality and nuclear distribution of PARP1 were assessed upon FANCI modulation. Finally, the sensitivity of breast cancer cells to the PARP inhibitor talazoparib upon FANCI knockdown was evaluated in vitro and in vivo. Our findings demonstrated that FANCI was overexpressed in breast cancer and associated with poor prognosis. FANCI significantly promoted breast cancer cell proliferation both in vitro and in vivo. We identified the interaction between FANCI and PARP1, specifically at the FANCI helical domain 2 binding site. FANCI knockdown led to reduced nuclear localization of PARP1 and decreased PARP1 activity. Importantly, combination treatment with FANCI knockdown and talazoparib significantly inhibited cancer growth in vitro and in vivo. Additionally, we found that the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib, which effectively suppresses FANCI protein expression, exhibited a robust synergistic effect with talazoparib both in vitro and in vivo. In conclusion, FANCI is a novel therapeutic target for breast cancer. Suppression of FANCI regulates PARP1 redistribution and activity, making breast cancer cells more responsive to PARP inhibitors. This combination therapeutic strategy shows potential in enhancing the effectiveness of PARP inhibitors for breast cancer treatment, regardless of BRCA mutations. Citation Format: Yu-zhou Huang, Ming-Yi Sang, Pei-Wen Xi, Ruo-Xi Xu, Meng-Yuan Cai, Zi-Wen Wang, Jian-Yi Zhao, Yi-Han Li, Ji-Fu Wei, Qiang Ding. Emerging combination strategy: FANCI suppression induces PARP1 redistribution to enhance efficacy of PARP inhibitors in breast 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 7220.
Abstract 5995: How FDA-approved drug, Aprepitant, induces immunogenic death of cancer cells
Authors: Xinyi Dai, Junyao Zhu, Sofia Perry, Qianjin Jiang, David J. Shapiro
Journal: Cancer Research (2024)

Abstract Aprepitant is a long-standing FDA approved anti-nausea drug, recently re-purposed as an early-stage anticancer agent; how aprepitant kills cancer cells was not well studied. We find that aprepitant kills human and mouse cancer cells by hyperactivating the stress response pathway, the anticipatory unfolded protein response (a-UPR), thereby inducing immune cell activating necrotic cell death. Aprepitant is a small molecule neurokinin-1 receptor (NK-1R) antagonist widely used to prevent nausea and vomiting in cancer patients undergoing chemotherapy. Recently aprepitant has shown promise in mouse xenograft studies of colon, lung and pancreatic cancer and melanoma. Since aprepitant was thought to trigger release of calcium stored in the lumen of the endoplasmic reticulum, the step that we showed triggers hyperactivation of the a-UPR by ErSO family anticancer agents, we explored the role of the a-UPR in aprepitant action. Aprepitatnt robustly activates the PERK arm of the UPR increasing p-PERK and peIF2α, inhibiting protein synthesis. Notably, aprepitant treatment results in ATP depletion and activation of AMPK. Aprepitant induced rapid cell death was not blocked by apoptosis inhibitors or necroptosis inhibitors. In both standard 2-dimensional cell culture and 3-dimensional organoid culture aprepitant-treated breast cancer cells displayed typical features of necrotic cell death, including cell swelling, membrane rupture, and cytoplasmic vacuolization. Cell death by necrosis and membrane rupture leads to release of immune cell activating cell contents termed damage-associated molecular patterns (DAMPs). Aprepitant treatment induces release of the classic DAMPs, HMGB1 and ATP and medium from aprepitant-treated breast cancer cells enhances migration of differentiated human THP-1 macrophage. Thus aprepitant and other necrosis inducing therapies elicit immunogenic cell death (ICD) and may have the potential to enhance adjuvant immunotherapy. Genome-wide CRISPR screens with negative selection against aprepitant and other studies are being used to explore the pathways of aprepitant induced cell death and evaluate its therapeutic efficacy. Since FDA-approved aprepitant has been widely used for many years, identifying its pathway of action will both accelerate its clinical transition as an anticancer agent and help identify patients whose genetic profiles make them most likely to benefit from aprepitant therapy. Citation Format: Xinyi Dai, Junyao Zhu, Sofia Perry, Qianjin Jiang, David J. Shapiro. How FDA-approved drug, Aprepitant, induces immunogenic death of 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 5995.
Abstract 5313: CB307: A dual targeting costimulatory Humabody® VH therapeutic for treating PSMA-positive tumors
Authors: Sophie Archer, Phillip M. Brailey, Minjung Song, Phillip D. Bartlett, Ines Figueiredo, Bora Gurel, Christina Guo, Verena Brucklacher-Waldert, H. Lorraine Thompson, Jude Akinwale, Samantha E. Boyle, Christine Rossant, Neil R. Birkett, Julia Pizzey, Mark Maginn, James Legg, Richard Williams, Colette M. Johnston, Philip Bland-Ward, Johann S. de Bono, Andrew J. Pierce
Journal: Cancer Research (2024)

Abstract INTRODUCTION: CD137 is a T and NK cell costimulatory receptor involved in consolidating immunological responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumour toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumour cells, could bring effective immunotherapy to this immunologically challenging to address disease. EXPERIMENTAL PROCEDURES: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody® VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumour microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse anti-tumour pharmacology studies. Non-clinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with anti-tumour activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 immunohistochemistry (IHC) assay demonstrated a higher prevalence of CD137-postive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in non-human primates and exhibited a plasma half-life supporting weekly clinical administration. CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T cell activation thereby alleviating toxicological concerns against unrestricted CD137 agonism. Citation Format: Sophie Archer, Phillip M. Brailey, Minjung Song, Phillip D. Bartlett, Ines Figueiredo, Bora Gurel, Christina Guo, Verena Brucklacher-Waldert, H. Lorraine Thompson, Jude Akinwale, Samantha E. Boyle, Christine Rossant, Neil R. Birkett, Julia Pizzey, Mark Maginn, James Legg, Richard Williams, Colette M. Johnston, Philip Bland-Ward, Johann S. de Bono, Andrew J. Pierce. CB307: A dual targeting costimulatory Humabody® VH therapeutic for treating PSMA-positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5313.
Abstract 7218: Venetoclax triggers apoptosis and augments the effectiveness of doxorubicin against acute myeloid leukemia cells
Authors: Osama Aloudat, Omar S. Al Odat, Tulin Budak-Alpdogan, Subash Jonnalagadda, Yong Chen, Manoj Pandey
Journal: Cancer Research (2024)

Abstract Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the clonal proliferation of immature blast cells in the peripheral blood and bone marrow. AML is the second most common type of childhood leukemia, and 50% to 60% of relapses occur within the first year of diagnosis. Chemotherapy side effects and resistance are becoming major clinical issues. Although anthracyclines are one of the most commonly used induction regimens for children with AML in the United States, clinicians avoid them due to adverse effects and clinical resistance issues. To address this clinical issue, we are looking for a novel AML approach to boost the usage of anthracyclines. Since Bcl-2 protein overexpression in AML is related to uncontrolled growth, poor prognosis, and chemoresistance. Multiple clinical trials have suggested combining venetoclax (a selective Bcl-2 inhibitor) with well-established medicines to boost efficacy and overcome resistance. We suggest that inhibiting Bcl-2 is a feasible strategy for increasing the use of anthracycline medicines. We proposed combining doxorubicin and venetoclax as an alternative approach for AML patients. In a panel of three AML cell lines, Kusami-1, U937, and THP-1, our western blot revealed that Kusami-1 had the highest expression of Bcl-2 proteins. Surprisingly, venetoclax causes Kusami-1 cell death and increases the efficacy of doxorubicin in a dose-dependent manner, suggesting that utilizing a lower clinical standard dose may avoid major adverse effects such as cardiotoxicity. Furthermore, the Annexin V Apoptosis Detection Kit indicated that venetoclax coupled with doxorubicin synergistically promoted total apoptosis in Kusami-1 cells. The combination medication shown promising and synergistic in vitro anti-leukemic action against AML cell lines and represents a potentially viable treatment option for AML patients. Future research will use the combination approach in AML cell lines, as well as in patient samples and in vivo experiments. Citation Format: Osama Aloudat, Omar S. Al Odat, Tulin Budak-Alpdogan, Subash Jonnalagadda, Yong Chen, Manoj Pandey. Venetoclax triggers apoptosis and augments the effectiveness of doxorubicin against acute myeloid leukemia 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 7218.
Abstract 5124: A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics
Authors: William C. Wright, Paul Geeleher
Journal: Cancer Research (2024)

Abstract Combination chemotherapy is crucial for successfully treating cancer. However, the enormous number of possible drug combinations means discovering safe and effective combinations remains a significant challenge. To improve this process, we conduct large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritize neuroblastoma, the most common extracranial pediatric solid tumor, where ~50% of high-risk patients do not survive. Our screen examines all druggable gene knockouts in 18 cell lines (10 neuroblastoma, 8 others) treated with 8 widely used drugs, resulting in 94,320 unique combination-cell line perturbations, which is comparable to the largest existing drug combination screens. Using dense drug-drug rescreening, we find that the top CRISPR-nominated drug combinations are more synergistic than standard-of-care combinations, suggesting existing combinations could be improved. As proof of principle, we discover that inhibition of PRKDC, a component of the non-homologous end-joining pathway, sensitizes high-risk neuroblastoma cells to the standard-of-care drug doxorubicin in vitro and in vivo using patient-derived xenograft (PDX) models. Our findings provide a valuable resource and demonstrate the feasibility of using targeted CRISPR knockout to discover combinations with common chemotherapeutics, a methodology with application across all cancers. Citation Format: William C. Wright, Paul Geeleher. A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics [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 5124.