tbuckley/cabot-search huggingface dataset:
Abstract LB376: Tirzepatide inhibits tumor growth in mice with diet-induced obesity
Authors: Michael N. Pollak, Jibin Zeng, Linxuan Huang, Ye Wang, Janane Rahbani, Lawrence Kazak
Journal: Cancer Research (2024)

Abstract Tirzepatide, a drug used in management of type II diabetes, is an activator of both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors. Tirzepatide treatment leads to weight loss in murine models of obesity, and clinical trials have shown the drug can achieve ∼ 20% weight loss in obese patients. Obesity has been shown to increase risk and/or to worsen prognosis of certain common cancers, including colon cancer, but the effect of tirzepatide on neoplasia has not been examined in detail. We studied the effects of this drug on mouse weight and energy balance and on the murine MC38 colon cancer model, which was previously shown to exhibit accelerated growth in hosts with diet-induced obesity. Tirzepatide led to substantial reductions in food intake, to reduced adipose tissue mass, and to significant decreases in circulating levels of insulin and leptin. Tirzepatide did not cause tumor regression, but reduced tumor growth rates by ∼ 50%. Tirzepatide had no effect on MC38 cancer cell proliferation in vitro, and the effect of tirzepatide on tumor growth in vivo could be phenocopied in placebo treated mice simply by restricting food intake to the amount consumed mice receiving the drug. This provides evidence that the drug acts indirectly to inhibit tumor growth. Our findings raise the possibility that use of tirzepatide or similar agents may benefit patients with obesity-related cancers. Citation Format: Michael N. Pollak, Jibin Zeng, Linxuan Huang, Ye Wang, Janane Rahbani, Lawrence Kazak. Tirzepatide inhibits tumor growth in mice with diet-induced obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB376.
Abstract LB332: Spatial transcriptomic and proteomic analysis of the treatment resistant slow cycling micro environment in GBM
Authors: Avirup Chakraborty, Diana Feier, Aryeh Silver, Changlin Yang, Miruna Anica, Avinash Pittu, Olusegun Sobanjo, Ethan Hodge, Mia Engelbart, Christina Von Roemeling, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane Mitchell, Loic Deleyrolle
Journal: Cancer Research (2024)

Abstract Within the Glioblastoma (GBM) microenvironment, there are micro-niches originating from independent lineages of cancer stem cells with distinct metabolic requirements that are characterized by Fast cycling cells (FCCs) and Slow cycling cells (SCC). The FCCs employ aerobic glycolysis for energy, while the treatment-resistant SCCs primarily rely on lipid metabolism. Our study allows for the molecular and spatial decoding of the heterogeneity within the GBM microenvironment, with a specific focus on decoding the dichotomy of the immune infiltrates and studying the interactions between the SCCs and the immune compartment in human GBM patients. Our research reveals a new paradigm of interaction within the tumor microenvironment (TME) of glioblastoma (GBM) patients, in which SCCs are instrumental in altering the tumor milieu to favor immune suppression. These SCCs actively recruit and harness sub-population of immune cells of myeloid origin that promote tumor growth and simultaneously provide metabolic aid to these treatment-resistant cells. Our research maps out the intricate metabolic dialogues within GBM and evaluates the potential therapeutic effect of disrupting this interaction to open up new treatment avenues. The findings based on our spatial transcriptomic and proteomic study on brain biopsies from human patients provide a deeper understanding of the critical links among the tumor's local environment, cellular metabolism, anti-tumor immunity, and potential treatment vulnerabilities. In summary, our investigation offers novel insights into how metabolic exchanges contribute to the evolution of GBM leading to the development of drug and immune resistant GBM. Our data is suggestive that therapies aimed at these metabolic interactions, especially those between SCCs and metabolically supporting immunosuppressive myeloid originating immune cells, hold potential as effective therapeutic strategy for GBM. Citation Format: Avirup Chakraborty, Diana Feier, Aryeh Silver, Changlin Yang, Miruna Anica, Avinash Pittu, Olusegun Sobanjo, Ethan Hodge, Mia Engelbart, Christina Von Roemeling, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane Mitchell, Loic Deleyrolle. Spatial transcriptomic and proteomic analysis of the treatment resistant slow cycling micro environment in GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB332.
Pyroptosis activates conventional type I dendritic cells to mediate the priming of highly functional anticancer T cells
Authors: Jordon M Inkol, Michael J Westerveld, Shayla G Verburg, Scott R Walsh, Jodi Morrison, Karen L Mossman, Sarah M Worfolk, Kaslyn LF Kallio, Noah J Phippen, Rebecca Burchett, Yonghong Wan, Jonathan Bramson, Samuel T Workenhe
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Initiation of antitumor immunity is reliant on the stimulation of dendritic cells (DCs) to present tumor antigens to naïve T cells and generate effector T cells that can kill cancer cells. Induction of immunogenic cell death after certain types of cytotoxic anticancer therapies can stimulate T cell-mediated immunity. However, cytotoxic therapies simultaneously activate multiple types of cellular stress and programmed cell death; hence, it remains unknown what types of cancer cell death confer superior antitumor immunity. Methods Murine cancer cells were engineered to activate apoptotic or pyroptotic cell death after Dox-induced expression of procell death proteins. Cell-free supernatants were collected to measure secreted danger signals, cytokines, and chemokines. Tumors were formed by transplanting engineered tumor cells to specifically activate apoptosis or pyroptosis in established tumors and the magnitude of immune response measured by flow cytometry. Tumor growth was measured using calipers to estimate end point tumor volumes for Kaplan-Meier survival analysis. Results We demonstrated that, unlike apoptosis, pyroptosis induces an immunostimulatory secretome signature. In established tumors pyroptosis preferentially activated CD103 + and XCR1 + type I conventional DCs (cDC1) along with a higher magnitude and functionality of tumor-specific CD8 + T cells and reduced number of regulatory T cells within the tumor. Depletion of cDC1 or CD4 + and CD8 + T cells ablated the antitumor response leaving mice susceptible to a tumor rechallenge. Conclusion Our study highlights that distinct types of cell death yield varying immunotherapeutic effect and selective activation of pyroptosis can be used to potentiate multiple aspects of the anticancer immunity cycle.
Abstract LB080: iOTarg screening platform reveals novel mechanisms of colorectal cancer evasion from antigen-specific tumor cell killing by T cells
Authors: Tillmann Michels, Valentina Volpin, Carmen Amerhauser, Claudia Tschulik, Leonie Majunke, Aleksandra Weglarz, Kilian Baritz, Kritika Sudan, Szilvia Bak-Kiss, Alina Huth, Carolin Strobl, Adriana Turqueti-Neves, Nisit Khandelwal
Journal: Cancer Research (2024)

Abstract While immune checkpoint therapies have revolutionized cancer treatment, their efficacy remains limited in colorectal cancer (CRC) and other malignancies. Tumors employ diverse strategies to evade immune-mediated destruction, hindering the success of immunotherapies. We introduce iOTarg, a robust high-throughput screening platform designed to uncover resistance pathways against T cell-mediated tumor killing within the tumor microenvironment. Focusing on CRC, we utilized iOTarg to dissect evasion mechanisms against antigen-specific T cell (TC) killing. In a representative CRC cell line co-culture system (SW480, HCT116 or COLO-678) with various TC sources, we gained key insights of tumor resistance towards killing. Survivin-specific TCs induce strong tumor lysis while tumor-infiltrating lymphocyte 412 (TIL412) represent a weaker basal killing representative of the situation in the tumor. Knockout of β₂-microglobulin abrogated TC-mediated killing, while c-FLIP knockout significantly enhanced tumor lysis. Intriguingly, PD-L1 blockade had no impact on TC activation or killing, underlining its lack of efficacy in CRC. Screening over 6000 druggable genes revealed several critical candidates, including anti-apoptotic BIRC family members (BIRC2, 3), apoptosis regulators (Bcl-xL, XIAP), TNF signaling regulators (TRAF2, MAP3K7), and genes recently described as sensitization mediators (B3GNT3, CHMP4B). Caspase-8 knockout prevented TC-mediated killing of CRC cells, confirming its crucial role in immune-mediated tumor cell clearance. Further validation in secondary screenings reinforced a subset of genes as strong regulators of tumor cell killing, uncovering an array of CRC resistance mechanisms. Our findings present a pioneering platform delineating resistance mechanisms against T cell-mediated colorectal tumor killing. We identify established and novel targets, offering prospects for novel therapeutics and expanding immune oncology treatment options. This platform holds promise for developing first-in-class therapies targeting the tumor microenvironment, potentially transforming CRC treatment paradigms. Citation Format: Tillmann Michels, Valentina Volpin, Carmen Amerhauser, Claudia Tschulik, Leonie Majunke, Aleksandra Weglarz, Kilian Baritz, Kritika Sudan, Szilvia Bak-Kiss, Alina Huth, Carolin Strobl, Adriana Turqueti-Neves, Nisit Khandelwal. iOTarg screening platform reveals novel mechanisms of colorectal cancer evasion from antigen-specific tumor cell killing by T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB080.
Abstract LB108: Specific plasma DNA end-motifs distinguish patients with lung adenocarcinoma versus benign nodules
Authors: Jason C. Hyun, Shun H. Yip, Neeti Swarup, Raghuraman Ramamurthy, Jordan C. Cheng, Irene Choi, Edmund Wong, Akanksha Arora, Denise Aberle, David T. Wong, Cheuk Y. Tang
Journal: Cancer Research (2024)

Abstract Background: Recent studies have identified blood plasma DNA as a rich source of biomarkers for non-invasive cancer detection. In particular, analysis of shorter DNA fragments or “fragmentomics” have shown promising results with numerous competing approaches such as those based on mutation calls, length distributions, or preferred fragmentation patterns. In this study, we assessed the potential of fragment end motif distributions in discriminating patients with lung adenocarcinoma versus benign tumors. Methods: Plasma samples from 37 patients (20 benign, 17 malignant) were subject to whole genome sequencing. For each sample, DNA fragments were grouped as short (30-99bp) and long (100-269bp) and end motif distributions were calculated by counting occurrences of 4-9bp sequences at either the 5’ or 3’ end of each fragment. A proprietary machine learning algorithm was employed to identify a minimal set of motifs capable of accurately distinguishing benign from malignant samples. Results: Just two 5’ end motifs in long fragments, CCAT and GACA, were sufficient for distinguishing malignant from benign samples in a two-step decision tree (89% accuracy with all samples, 86% accuracy in leave-one-out cross validation). Accuracy was significantly higher when compared to random guessing by shuffling labels (p=1.6*10−6, FWER &amp;lt; 0.05, Bonferroni correction, 351 tests). CCAT motif frequency was also significantly associated with cancer stage (p=0.04, Kruskal-Wallis test) and specifically elevated in early stage samples (I, II). Conclusions: These results suggest that plasma DNA end motif distributions are informative in discriminating patients with lung adenocarcinoma versus benign tumors. The two-motif model suggests that specific, rather than systemic changes in end motif distributions are more strongly associated with lung cancer patients and may point to specific mechanisms linked to cancer progression. Citation Format: Jason C. Hyun, Shun H. Yip, Neeti Swarup, Raghuraman Ramamurthy, Jordan C. Cheng, Irene Choi, Edmund Wong, Akanksha Arora, Denise Aberle, David T. Wong, Cheuk Y. Tang. Specific plasma DNA end-motifs distinguish patients with lung adenocarcinoma versus benign nodules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB108.
Abstract SY31-03: Cancer takes a nerve: Challenges and opportunities in cancer neuroscience
Authors: Moran Amit
Journal: Cancer Research (2024)

Abstract Neuronal reprogramming in cancer represents a groundbreaking frontier that intricately links the nervous system's plasticity to tumor progression and response to treatment. This process involves the aberrant activation or suppression of neuronal signals that can significantly influence cancer cell behavior, including proliferation, migration, and resistance to therapies. The concept of repurposing drugs originally designed to target the nervous system for use in clinical oncology offers a promising therapeutic strategy, potentially revolutionizing cancer treatment. By intercepting neuronal pathways that cancer cells exploit for their growth and survival, these drugs could modulate the tumor microenvironment, enhance the efficacy of conventional therapies, and potentially reverse drug resistance mechanisms. Moreover, targeting neuronal signaling in cancer could lead to improvements in patients' functional outcomes, mitigating cancer-related neurological deficits and improving quality of life. Importantly, this approach may also have profound implications for survival outcomes, as modulating the neuro-cancer interface could slow tumor progression and reduce metastatic spread. The repurposing of neuroactive drugs for cancer treatment thus opens a new avenue for personalized medicine, where the intricacies of neuronal reprogramming are leveraged to tailor therapy, improve response rates, and ultimately, enhance patient survival and well-being. Citation Format: Moran Amit. Cancer takes a nerve: Challenges and opportunities in cancer neuroscience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY31-03.
Abstract LB342: Potent Anti-Tumor Activity Demonstrated by Anti-AXL CAR T Cell Therapy and AXL-ADC in Lung Cancer and Breast Cancer Models
Authors: Zhongen Wu, Yang Gao, Jingpeng Pei, Enfeng Zhao, Shenglin Mei, Yuxiong Feng, Di Zhu
Journal: Cancer Research (2024)

Abstract AXL is over-expressed in various cancers. Its signaling pathway is related to tumor progress. We created a novel a novel AXL-ADC (Hu002-MMAE) based on humanized AXL-targeted antibody (Hu002). We also developed anti-AXL CAR T cells and AXL-CAR iNKT to evaluate anti-tumor effect. Methods: 1) Evaluate the cytotoxicity of Hu002-MMAE in 5 AXL-high-expressing cells. 2) in vivo efficacy validation of Hu002-MMAE into LCLC-103H-bearing Nude mice and U87MG-bearing nude mice. 3) Evaluate the cytotoxicity of anti-AXL CAR-T and AXL CAR-iNKT cells in cell lines with different AXL expression levels to validate the selectivity. 4) in vivo efficacy validation of anti-AXL CAR T cells into MDA-MB-231-bearing mice.Results: Hu002 demonstrates potent binding affinity significantly inhibited the migration of AXL-high tumor cells. The Hu002-MMAE showed potent cytotoxicity against AXL-high tumor cells (IC50 &amp;lt; 0.1 nmol/L) and had a longer-term therapeutic effect in a variety of NSCLC and glioma tumors in vivo (MED &amp;lt; 0.5 mg/kg). Anti-AXL CAR-T cells and AXL CAR-iNKT exhibited strong killing activity to AXL-high-expressed cell lines LCLC-103H and MDA-MB-231 in vitro, while shows minimum effect of anti-tumor effect in AXL-low-expressed cell lines H460 and MDA-MB-453. In in vivo models of MDA-MB-231, we observed increased infiltration of T cells in primary tumor and reduced lung metastasis after AXL CAR-T treamtment.Conclusion: Anti-AXL CAR T and AXL-ADC cells showed strong and selective killing activity, improved TME in primary tumor and mitigate lung metastasis, which makes it a potential strategy for cancers. Citation Format: Zhongen Wu, Yang Gao, Jingpeng Pei, Enfeng Zhao, Shenglin Mei, Yuxiong Feng, Di Zhu. Potent Anti-Tumor Activity Demonstrated by Anti-AXL CAR T Cell Therapy and AXL-ADC in Lung Cancer and Breast Cancer Models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB342.
Abstract LB175: Discovery of HP567, a highly potent, brain-penetrating, and H1047R-selective PI3Kα inhibitor for the treatment of tumors bearing H1047R mutation
Authors: Jing Li, Lei Fan, Chengcheng Liu, Yao Luo, Xiaohui Chu, Hua Yu, Fei Wang, Xinghai Li
Journal: Cancer Research (2024)

Abstract The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT) is one of the most altered pathways in human cancer and its hyperactivation promotes tumor growth and survival. H1047R increases kinase activity and is the most common PI3Kα mutation with a mutation rate of 7.8% in all cancers, and 21%, 5% and 3% in breast cancer, endometrium, and ovarian cancer, respectively. Alpelisib is an FDA approved PI3Kα inhibitor targeting both wild-type (WT) and mutant PI3Kα, yet its clinical benefit is limited by the toxicities including hyperglycemia and rash (which are considered on target effects of WT- PI3Kα inhibition). Here, we report an allosteric and brain-penetrating PI3Kα inhibitor, HP567 that is 14-fold selective for PI3Kα H1047R over PI3Kα WT and is 80-fold selective over other PI3K isoforms. HP567 strongly inhibits proliferation and p-AKT (S473) in H1047R mutant cell lines with an average IC50 of 138 nM and 8 nM, respectively, and has no activity against PI3Kα WT cell lines. HP567 strongly inhibits growth of tumors bearing H1047R in multiple CDX models including breast cancers (MDA-MB-453, T47D, and CAL-148), ovarian cancer (SK-OV-3), tongue squamous cell carcinoma (CAL-33), and a brain-metastatic breast cancer (MDA-MB-453), without causing hyperglycemia or increases in plasma insulin levels. In conclusion, HP567 is a novel, potent, and brain-penetrating PI3Kα H1047R selective inhibitor. The pre-clinical data supports the clinical development of HP567 for the treatment of tumors bearing PI3Kα H1047R mutations. Structure of HP567 will not be disclosed. Citation Format: Jing Li, Lei Fan, Chengcheng Liu, Yao Luo, Xiaohui Chu, Hua Yu, Fei Wang, Xinghai Li. Discovery of HP567, a highly potent, brain-penetrating, and H1047R-selective PI3Kα inhibitor for the treatment of tumors bearing H1047R mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB175.
Abstract LB340: Harnessing the gp70 endogenous retrovirus envelope protein as a universal tumor antigen for T cell therapy in mice
Authors: Sophie M. Lehar, Srirupa Roy, Lisa Liao, Haiyin Chen, Yongmei Chen, Mayra Cruz Tleugabulova, Eric Janezic, Azadeh Madjidi, Tamaki Jones, Vincent Javinal, James Ziai, Ira Mellman, Jill Schartner, Andrey Shaw
Journal: Cancer Research (2024)

Abstract FDA approval for chimeric antigen receptor (CAR) T cell therapies targeting hematological cancers has unleashed the potential of utilizing live T cells as therapeutics. However, CAR-mediated targeting of solid tumors is currently limited by a paucity of suitable tumor antigens that are both specific and highly expressed on the tumor cell surface. In this report we explore the possibility of harnessing tumor-specific expression of endogenous retroviruses (ERVs) as a universal target for CAR T cell therapy. We found that gp70, the envelope protein from a murine ERV, is highly expressed on the surface of tumor cell lines derived from a diverse array of murine tumor types. We utilized the B16 melanoma model as a representative poorly inflamed tumor that does not respond to existing immunotherapies to examine efficacy of gp70 CAR T cells. T cells engineered to express a gp70 CAR suppress tumor growth in vivo and recognize B16 tumor cells with improved sensitivity compared to T cells expressing two previously described dominant tumor antigens (gp100 or P15e) due to low expression of MHC-I on B16 tumors. Co-incubation of B16 tumor cells with gp70 CAR T cells results in upregulation of MHC-I on the tumor cell surface suggesting that in addition to killing tumor cells directly, gp70 CAR T cells could facilitate recognition of the tumor by endogenous T cells through local release T cell derived IFNγ. We postulate that utilization of CAR T cells specific for cell surface ERV envelope proteins offers a promising strategy that could be harnessed to achieve local release of T cell derived payloads specifically within the tumor microenvironment. Citation Format: Sophie M. Lehar, Srirupa Roy, Lisa Liao, Haiyin Chen, Yongmei Chen, Mayra Cruz Tleugabulova, Eric Janezic, Azadeh Madjidi, Tamaki Jones, Vincent Javinal, James Ziai, Ira Mellman, Jill Schartner, Andrey Shaw. Harnessing the gp70 endogenous retrovirus envelope protein as a universal tumor antigen for T cell therapy in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB340.