tbuckley/cabot-search huggingface dataset:
Abstract 3735: Combinatorial targeting of tumor-microenvironment together with antigen vaccination using innovative nano-immuno-gel for enhanced cancer-immunotherapy
Authors: Anjali Kozhissery Sunilkumar, Margaux Salvi, Saira Nujoom Mohammed, Zahara Thaivalappil Zakkariya, Alejandra Gomez Cadena, Shalin Chappan, Sreedevi Panachithanathu Radhakrishnan, Maneesh Manohar, Pavithran Keechilat, Shantikumar Nair, Pedro Romero, Camilla Jandus, Manzoor Koyakutty
Journal: Cancer Research (2024)

Abstract Successful cancer-immunotherapy need to address three critical factors: a) Relieving the immuno-suppressive tumor microenvironment (TME) b) expanding antigen specific, functionally avid effector T cells, c) triggering systemic immunity with a balanced innate-adaptive response for continued effector cell-feeder supply-chain and memory generation. Combinatorial engagement of such multi-elemental components demands smart, engineered immunotherapy systems compared to conventional vaccines. Here, we report an injectable Nano-Immuno-Gel (NIG) that can neutralize immunosuppressive components (e.g., myeloid derived suppressor cells (MDSCs), M2 macrophages (Mϕ) in TME, together with generating strong effector T cells by nano-vaccination, and sustained release of cytokines to enhance systemic immunity against tumor. In a proof-of-concept study, we show that sustained-release of myeloid-suppressive drug from NIG depot efficiently inhibited MDSCs and M2 Mϕ, not only in TME, but also in the circulation and in peripheral systems, thus creating a conducive, hot TME infiltrated with CD8 effector cells. Follow-up antigen vaccination with novel nano-adjuvant enhanced DC-T cell engagement and sustained IL15 release from NIG provided systemic NK/T cell activation, rendering significant control of the tumor growth. Our data demonstrate the potential of rationally engineered multi-functional nano-immuno-gels (NIG) to combine sequential neutralization of the suppressive TME, antigen vaccination, and concurrent systemic immune activation for highly effective combinatorial cancer immunotherapy. Citation Format: Anjali Kozhissery Sunilkumar, Margaux Salvi, Saira Nujoom Mohammed, Zahara Thaivalappil Zakkariya, Alejandra Gomez Cadena, Shalin Chappan, Sreedevi Panachithanathu Radhakrishnan, Maneesh Manohar, Pavithran Keechilat, Shantikumar Nair, Pedro Romero, Camilla Jandus, Manzoor Koyakutty. Combinatorial targeting of tumor-microenvironment together with antigen vaccination using innovative nano-immuno-gel for enhanced cancer-immunotherapy [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 3735.
Authors’ correction for Euro Surveill. 2024;29(11)
Journal: Eurosurveillance (2024)

© This work is licensed under a Creative Commons Attribution 4.0 International License. Closure This is a corrected article applying to the following content: Ongoing mpox outbreak in Kamituga, South Kivu province, associated with monkeypox virus of a novel Clade I sub-lineage, Democratic Republic of the Congo, 2024
Abstract 2077: Exploring the multifaceted efficacy of de novo lipogenesis inhibitor in cancer therapy
Authors: Dallin Lowder, Jin Na Shin, Maria E. Ruiz-Echartea, Jenny Deng, Aleksandra Rusin, Darlene Skapura, Michael Ittmann, Salma Kaochar
Journal: Cancer Research (2024)

Abstract Cancer cells frequently exhibit altered lipid metabolism to sustain their rapid growth and proliferation.Sterol Regulatory Element-Binding Proteins (SREBPs) are key transcription factors that orchestratelipid biosynthesis and uptake in cells. Dysregulation of SREBPs is a common feature of many cancertypes, making them attractive targets for therapeutic intervention. In this study, we present acomprehensive exploration of the potential and rationale for targeting lipid metabolism in cancerthrough the use of a small molecule inhibitor that targets activation of SREBP. We illustrate that oursmall molecule inhibitor (SMI) exhibits potent anticancer activity and effectively targets SREBPsignaling in a variety of prostate cancer models as well as in non-prostate cancer models that arelipogenesis driven. Our novel SMI induces apoptosis and reduces PCa cell proliferation, suppressescell invasion and migration. Furthermore, we illustrate that in addition to suppressing the transcriptionfactor activity of SREBPs, these novel SMIs are highly effective in suppressing both the full length andvariant androgen receptor and their signaling in prostate cancer cells. Notably, in cell and organoidmodels, these novel inhibitors exhibit synergistic anticancer activity in combination with the ARsignaling inhibitor, Enzalutamide. The anticancer activity of these inhibitors extend beyond ARdependent prostate cancer and are also effective in organoid models of neuroendocrine PCa, aparticularly drug-resistant and aggressive PC subtype. Lastly, we illustrate excellent pharmacokineticsand potent anti-tumor effects of these novel SREBP activation inhibitors using in vivo castration-resistant prostate cancer CDX tumors. Given the urgent need for novel targets in PCa, our first-in-class inhibitor represents a promising therapeutic strategy with the potential to effectively targetdysregulated lipogenesis in cancer patients. Citation Format: Dallin Lowder, Jin Na Shin, Maria E. Ruiz-Echartea, Jenny Deng, Aleksandra Rusin, Darlene Skapura, Michael Ittmann, Salma Kaochar. Exploring the multifaceted efficacy of de novo lipogenesis inhibitor in cancer therapy [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 2077.
Abstract 6592: Deciphering the effects of age on T cell immunity and immunotherapy
Authors: SeongJun Han, Peter Georgiev, Jaime Schneider, Amy Huang, Zhanel Nugmanova, Thao H. Nguyen, Conghui Yao, Sheila Johnson, Shakchhi Joshi, Ishita Dhiman, Jefte M. Drijvers, Megan Fung, Jared H. Rowe, Brian C. Miller, Gordon J. Freeman, Alison E. Ringel, Marcia C. Haigis, Arlene H. Sharpe
Journal: Cancer Research (2024)

Abstract Aging induces profound alterations in host biology and correlates with unfavorable clinical outcomes in age-related diseases such as cancer. While the pivotal role of the immune system in regulating tumor progression is well-acknowledged, the precise mechanisms through which aging influences anti-tumor T cell immunity and responsiveness to immune checkpoint blockade (ICB) remain elusive. In this study, we employed syngeneic murine tumor models (B16, MC38, and E0771) in young (2-4 months) and aged (20-24 months) cohorts to elucidate the early impacts of aging on tumor development and T cell responses. Our findings demonstrate that aged mice exhibit accelerated tumor growth across various models. In-depth analysis of tumor-infiltrating lymphocytes (TILs) uncovered distinct alterations in the CD8+ T cell population, characterized by decreased activation status and diminished tumor specificity in aged mice. Correspondingly, aged mice exhibited resistance to anti-PD-1 immunotherapy. To unravel the underlying environmental factors contributing to compromised anti-tumor T cell responses and ICB resistance, we characterized the immune and metabolic landscapes of the aged tumor-draining lymph nodes and tumors. Furthermore, we established a genetically engineered mouse model of lung adenocarcinoma in both young and aged mice, unveiling novel functions and mechanisms associated with age-related T cells actively impeding effective tumor control. In the context of increasing average life expectancy, comprehending the intricate interplay between age-related T cell dysfunction and cancer assumes paramount importance. Such insights hold the key to the development of innovative therapeutic strategies tailored for the growing population of older patients. Citation Format: SeongJun Han, Peter Georgiev, Jaime Schneider, Amy Huang, Zhanel Nugmanova, Thao H. Nguyen, Conghui Yao, Sheila Johnson, Shakchhi Joshi, Ishita Dhiman, Jefte M. Drijvers, Megan Fung, Jared H. Rowe, Brian C. Miller, Gordon J. Freeman, Alison E. Ringel, Marcia C. Haigis, Arlene H. Sharpe. Deciphering the effects of age on T cell immunity and immunotherapy [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 6592.
Abstract 7222: Antiandrogen equipped with HDAC inhibitors activates autophagy-mediated growth inhibition in castrate-resistant prostate cancer
Authors: Balaji Chandrasekaran, Kiran Kumar Yalla, Ashish Tyagi, Vaibhav Shukla, Neha Tyagi, Bhawna Tyagi, Mohit Vashishta, Adegboyega K Oyelere, Chendil Damodaran
Journal: Cancer Research (2024)

Abstract Targeting androgen receptor (AR) by pharmacologic intervention is one of the practical approaches for the treatment of castration-resistant prostate cancer (CRPC). Hence, this study aimed to develop novel molecules that employ multiple mechanisms to inhibit AR expression and curtail the growth of CRPC. The target antiandrogen-equipped histone deacetylase inhibitors were synthesized, adapting the convergent chemistry we used to synthesize the first-generation compounds. The final compounds were characterized using 1H-NMR, 13C-NMR, and high-resolution mass spectrometry. We synthesized and analyzed several compounds, in which KK62 emerged as the lead compound. KK62 significantly inhibits a panel of CRPC cell lines in nanomolar concentrations without causing toxicity to healthy prostate epithelial cells. The molecular analysis suggested that inhibition of AR and AR-splice variants was evident, followed by downregulation of PSA expression in AR-positive CRPC cell lines. Further analysis confirmed that KK62 overcomes dihydrotestosterone (DHT) induced AR signaling and enzalutamide-resistant CRPC cells by downregulating AR and AR-splice variants in CRPC cells. Subsequent analysis confirmed that KK62 induces autophagy signaling by upregulating autophagosome (LC3B) and lysosome (LAMP1) markers expression and facilitating the autophagosome and lysosome fusion, which resulted in the induction of apoptosis in all AR-positive CRPC cell lines. The pro-apoptotic markers, such as BAX and cleaved caspase, were upregulated, whereas the downregulation of pro-survival markers was evident in KK62-treated CRPC cells. Our ongoing castrated and non-castrated xenotransplanted CRPC tumors and Patient-derived xenograft in vivo studies would validate our in vitro findings and confirm that KK62 is a potent compound that may improve therapeutic advances in treating CRPC. Citation Format: Balaji Chandrasekaran, Kiran Kumar Yalla, Ashish Tyagi, Vaibhav Shukla, Neha Tyagi, Bhawna Tyagi, Mohit Vashishta, Adegboyega K Oyelere, Chendil Damodaran. Antiandrogen equipped with HDAC inhibitors activates autophagy-mediated growth inhibition in castrate-resistant prostate 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 7222.
Abstract 2956: Chemotherapy-induced adipocyte senescence triggers bone loss through osteoclast activation
Authors: Ganesh Kumar Raut, Taylor Malachowski, Taylor Holt, Renata Oliveira, Xianmin Luo, Douglas Faget, Qihao Ren, Sheila Stewart
Journal: Cancer Research (2024)

Abstract Despite breakthroughs in cancer treatment, chemotherapy-induced osteo-toxicity is a major problem that compromises the quality of life and overall survival of cancer patients regardless of cancer type. Recently we demonstrated that chemotherapy-induced senescence drives bone loss by both limiting mineralization of new bone and increasing bone resorption. However, the underlying mechanism of action remains elusive. Therefore, it is critical that we understand the mechanisms that drive these toxicities and develop approaches to mitigate their severity. To establish whether senescent bone resident cells or systemic responses to chemotherapy drove therapy-induced bone loss, we used a vertebral body transplant (vossicle) model. Using this approach, we found that the specific elimination of senescent cells in L4 and L5 donor vossicles (INK-ATTAC) implanted into wildtype mice, protects from chemotherapy-induced bone loss within the vossicles but not the femur of the recipient mice. This demonstrated that chemotherapy-induced senescence in resident bone cells is responsible for bone loss. To determine which bone resident cell(s) underwent senescence in response to chemotherapy and how their gene expression was impacted, we used the p16-CreERT2-tdTomato mouse model and found that chemotherapy triggers senescence in bone marrow adipocytes. Subsequently, we observed that postnatal fat ablation in adipoqCre-inducible DTR transgenic mice (iDTRADQ) prevented chemotherapy-induced bone loss, indicating senescent adipocytes trigger bone loss. Furthermore, we observed chemotherapy-induced bone loss is attributed to RANKL-mediated high osteoclasts activity. Collectively, our data demonstrate that chemotherapy causes senescence in marrow adipocytes which in turn triggers bone loss via RANKL-mediated osteoclasts activation and bone loss can be protected by eliminating senescent cells. Citation Format: Ganesh Kumar Raut, Taylor Malachowski, Taylor Holt, Renata Oliveira, Xianmin Luo, Douglas Faget, Qihao Ren, Sheila Stewart. Chemotherapy-induced adipocyte senescence triggers bone loss through osteoclast activation [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 2956.
Abstract 92: Assessment of an in vitro potency assay for evaluation of immune cell-mediated cytotoxicity using the Omni Pro 12 automated imaging platform
Authors: Denise Sullivan, Lieke Stemkens, Inge Thijssen, Svenja Meiler, Danielle Califano, Stacie Chvatal, Daniel Millard
Journal: Cancer Research (2024)

Abstract The development of immunotherapies relies on the use of in vitro potency assays—which are key for understanding complex interactions between immune cells and cancer cells. Immune effector T-cells are a promising cancer therapy due to their innate cytotoxicity. In particular, CAR T-cell therapy uses genetically engineered T-cells that express a chimeric antigen receptor that binds to a specific antigen on tumor cells. Assessing the efficacy and potency of CAR T-cell therapies in vitro and at high throughputs is vital for the preclinical development of these promising therapies. Here, we describe an in vitro potency assay that uses an automated imaging platform to quantify immune cell-mediated cytotoxicity of cancer target cells by immune effector cells. A GFP fluorescent and HER-2 expressing lung cancer cell line, A549, was seeded into a 96-well cell culture plate. Then, HER-2 CAR T-cells were added at 24 hours post target cell seeding at various E:T ratios (1:10, 1:5, 1:2, 1:1, and 5:1). Fluorescent images of the target cells were captured every 6 hours by the Omni Pro 12, an automated, high-throughput, live-cell analysis platform designed for continuous multi-well imaging inside an incubator. Automated image analysis was performed using the Confluency Module in the Axion Portal to view attachment and proliferation and quantify cytolysis of fluorescent A549 target cells. Percent cytolysis of the target cells was calculated by comparing the green fluorescent confluency of treated wells to no treatment control wells. A549-GFP cells showed a dose-dependent decrease in confluency over time that correlated with increasing amounts of CAR T-cells. At 92 hours post HER-2 CAR T-cell addition, the 5:1 ET group demonstrated approximately 91.8% +/- 2.0% cytolysis of A549-GFP cells, while the 1:10 group demonstrated approximately 69.2% +/- 3.0% cytolysis. Future work will evaluate differences in CAR T-cell potency when co-cultured with target cells that express different levels of HER-2. Overall, the Omni Pro 12 platform enables continuous quantification of the potency and kinetics of immune cell-mediated cytolysis. Citation Format: Denise Sullivan, Lieke Stemkens, Inge Thijssen, Svenja Meiler, Danielle Califano, Stacie Chvatal, Daniel Millard. Assessment of an in vitro potency assay for evaluation of immune cell-mediated cytotoxicity using the Omni Pro 12 automated imaging platform [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 92.
Abstract 6047: Discovery and characterization of PVTX-321, an estrogen receptor heterobifunctional degrader 
Authors: Courtney G. Havens, Guozhang Xu, Cass Lowenstein, Debangshu Samanta, Brian Vidal, Elham Behshad, Rakesh Nagilla, Mike Russell, Peter Orth, Winston Wu, Larry Jolivette, Scott Priestley, Helai Mohammad, Zhihua Sui
Journal: Cancer Research (2024)

Abstract The estrogen receptor α (ERα) is a clinically validated target for the treatment of estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. However, resistance to early line endocrine treatments due to mutations of the ESR1 gene encoding ERα is associated with poor prognosis and remains an area of unmet clinical need. ERα degradation using heterobifunctional degraders has emerged as a promising approach to tackle endocrine resistance through proteasome mediated degradation of the receptor. Here, we present the preclinical results for the development candidate, PVTX-321, an ERα heterobifunctional degrader. PVTX-321 is a rapid and potent ER heterobifunctional degrader as well as a full ERα antagonist. Both properties translate into potent antiproliferative activity across multiple ER+ breast cancer cell lines bearing either wild-type or clinically relevant ERα mutations (E380Q, Y537S and D538G). PVTX-321 demonstrates favorable oral bioavailability across different species and effectively induces dose-dependent degradation of ERα in vivo. Moreover, PVTX-321 achieves tumor regression as an oral agent at 10 mg/kg in MCF-7 mouse xenograft model. Furthermore, PVTX-321 possesses excellent in vitro and in vivo safety profiles and warrants further development for the treatment of ER+/HER2- breast cancer. Citation Format: Courtney G. Havens, Guozhang Xu, Cass Lowenstein, Debangshu Samanta, Brian Vidal, Elham Behshad, Rakesh Nagilla, Mike Russell, Peter Orth, Winston Wu, Larry Jolivette, Scott Priestley, Helai Mohammad, Zhihua Sui. Discovery and characterization of PVTX-321, an estrogen receptor heterobifunctional degrader [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 6047.
Abstract 436: Extracellular glutathione catabolism as an alternative cyst(e)ine source in cancer
Authors: Fabio Hecht, Marco Zocchi, Emily Tuttle, Gloria Asantewaa, TashJaé Scales, Fatemeh Alimohammadi, Nathan Ward, Gina DeNicola, Isaac Harris
Journal: Cancer Research (2024)

Abstract Glutathione (GSH) is the most abundant antioxidant in the human body and plays essential roles in physiology and disease. Unchecked oxidative stress is involved in tumor initiation and progression. Paradoxically, clinical and laboratory data show that ROS-scavenging molecules such as glutathione not only fail to impede tumor growth but, in many cases, accelerate it. Still, preliminary data from our lab show that genetically ablating tumors’ ability to synthesize GSH does not affect their growth. This finding suggests that the favorable influence of glutathione on tumor growth may arise from external sources. Yet, the mechanism cancer cells employ to take advantage of extracellular glutathione in this context is unknown. Here, we show that γ-glutamyl-transpeptidase 1 (GGT1), an enzyme that localizes on the outer side of the cell’s membrane, can break down extracellular GSH, yielding glutamate and the dipeptide cysteinylglycine. Cysteinylglycine can be further metabolized, generating cysteine and glycine to the cells. We found that the addition of exogenous GSH, as well as cysteinylglycine, can mitigate cell death, proliferation arrest, and oxidative stress caused by cystine depletion. The overexpression of human GGT1 in cancer cells significantly reduces the amount of glutathione needed to rescue cell fitness. Accordingly, pharmacologic inhibition of GGT1 activity prevented GSH's ability to rescue cell proliferation. Moreover, an unbiased pharmacological screening revealed that GGT1-mediated cysteine acquisition renders cancer cells resistant to inhibitors of cystine uptake and utilization, supporting the role of GGT1 as a source of cyst(e)ine. Our findings reveal that cancer cells can access cysteine, a vital yet scarce amino acid, through GGT1's ability to break down glutathione, which is present in remarkably high concentrations within the tumor microenvironment. Although the downstream proteins involved in the transport and utilization of GSH breakdown products are yet to be identified, we anticipate this pathway has the potential to uncover novel therapeutic avenues for cancer treatment by targeting alternative pathways of nutrient acquisition that are potentially implicated in cancer progression and therapy resistance. Citation Format: Fabio Hecht, Marco Zocchi, Emily Tuttle, Gloria Asantewaa, TashJaé Scales, Fatemeh Alimohammadi, Nathan Ward, Gina DeNicola, Isaac Harris. Extracellular glutathione catabolism as an alternative cyst(e)ine source in 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 436.