tbuckley/cabot-search huggingface dataset:
Abstract 6070: Identification of a molecular glue degrader that engages a cancer-specific E3 ligase
Authors: Yuan Liu, Mads Larsen, Bo Lin, Irene A. Cardenal, Jason R. Kennerdell, Toren Finkel, Bill B. Chen
Journal: Cancer Research (2024)

Abstract To date, most successful molecular glues have leveraged ubiquitously expressed E3 ligases, most notably Cereblon in the case of the thalidomide derivatives. However, a number of specific E3 ligases are highly over-expressed in certain tumors. Compounds that engage such tumor-specific E3 ligases might provide a unique opportunity to develop molecular glues with higher therapeutic indexes. One such tumor-specific E3 ligase is FBXO5, a member of the F-box family of E3 ligases. Expression analysis suggests this E3 ligase is highly expressed in a wide array of tumor tissues when compared to the corresponding normal tissue, and that within a given tumor type, higher FBXO5 expression correlates with advanced tumor stage and worse disease-free survival. Here, we describe a small molecule (MW~400 Daltons) that uses FBXO5 to function as a molecular glue degrader. This compound, CL-200, exerts cytotoxicity in the nanomolar range across a number of diverse tumor types. The cytotoxicity of CL-200 is abrogated when FBXO5 is knockdown using siRNA. We have further determined that CL-200 induces the FBXO5-dependent proteasomal degradation of at least two critical neosubstrates. One identified neosubstrate is the p150 isoform of ADAR1, an enzyme that catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA). Evidence suggests that ADAR1p150 is the isoform that confers oncogenic and immune modulating effects in many tumors. Another neosubstrate targeted by CL-200 is c-myc, a critical transcription factor linked to a wide array of tumors. Of note, both p150 ADAR1 or c-myc have been viewed as difficult-to-drug if not undruggable targets. As such, these data suggests that CL-200 functions as a novel molecular glue degrader that engages the cancer-specific E3 ligase FBXO5 to degrade both p150 ADAR1 and c-myc. Structural alteration of CL-200 suggest that chemical modifications can be made that retain the engagement with FBXO5 while altering the neosubstrate profile. Together, these results demonstrate the possibility of leveraging cancer-specific E3 ligases to develop novel molecular glues. Citation Format: Yuan Liu, Mads Larsen, Bo Lin, Irene A. Cardenal, Jason R. Kennerdell, Toren Finkel, Bill B. Chen. Identification of a molecular glue degrader that engages a cancer-specific E3 ligase [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 6070.
Abstract 723: Reduction of immunosuppressive function of regulatory T cells enhances antigen-specific T cell mediated cytotoxicity against tumor cells
Authors: Arif Azam Khan, Jaehyung Park, Nate LaVoy, Chris Tompkins, Jeff Bellinder, Tisha San Miguel, Neal Lawrence, Brianna Schoen
Journal: Cancer Research (2024)

Abstract Regulatory T cells (Tregs) maintain immune homeostasis by suppressing abnormal immune response to self and non-self-antigens. Tregs are also involved in tumor development and progression by inhibiting anti-tumor immunity. Infiltration of Tregs in the tumor microenvironment (TME) inhibit anti-tumor immunity by suppressing tumor antigen-specific T cell responses. This results in tumor progression and poor prognosis in patients with various types of cancers. Therefore, depletion of Tregs could be a promising immunotherapy target to augment the anti-tumor immune response. Molecules highly expressed by Tregs such as CD25, immune checkpoint molecules, and chemokine receptors have been targeted by antibodies or small molecules to deplete Tregs and its immunosuppressive function has been tested in the clinic. However, a thin line exists between augmenting effective immunity and inducing autoimmunity, posing difficulties in harnessing Tregs modulation in cancer treatment. Thus, additional strategies to selectively control Tregs are urgently needed for the effective treatment of cancer. In this study we evaluated the role of Tregs in suppressing the effector function of antigen-specific T cells and targeted killing of cancer cells in vitro. We observed Tregs mediated suppression of antigen-specific cytotoxicity against cancer cells. When Tregs were treated with cyclophosphamide, CD25 depleting antibody and anti-CTLA4 antibody alone or in combination, we observed enhanced killing of cancer cells in vitro as a result of potentiated effector function of antigen-specific T cells. This study provides a path forward to fine-tune and optimize strategies to target various molecules that are highly expressed on Tregs and augment anti-tumor immunity by antigen-specific T cells to achieve therapeutic outcome. Citation Format: Arif Azam Khan, Jaehyung Park, Nate LaVoy, Chris Tompkins, Jeff Bellinder, Tisha San Miguel, Neal Lawrence, Brianna Schoen. Reduction of immunosuppressive function of regulatory T cells enhances antigen-specific T cell mediated cytotoxicity against tumor 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 723.
Abstract 3189: A novel monoclonal antibody targeting TM4SF4 enhances antitumor activity through regulation of cellular levels of immune checkpoint ligands and antibody dependent cellular cytotoxicity
Authors: Rae Kwon Kim, Chang-Kyu Heo, Yeon-jee Kahm, Uhee Jung, Byung-Chul Shin, Won-Yong Kim, Bum-Jin Kim, Sung-Chul Kim, Chun-jeih Ryu, Eun-Wie Cho, In-Gyu Kim
Journal: Cancer Research (2024)

Abstract Transmembrane 4 super family member 4(TM4SF4) protein has been shown to be involved in EMT-associated stemness through autocrine of insulin-like growth factor 1(IGF1) and osteopontin(OPN) in non-small cell lung cancer(NSCLC) cells. However, its potential as a therapeutic target has not been evaluated. In this study, anti-human TM4SF4 monoclonal antibodies(anti-hTM4SF4 mAbs) were prepared in mouse as part of a strategy for developing anticancer drug using humanized antibody. A synthetic peptide(15 mer, 126-140th AA) derived from the extracellular loop(ECL) 2 of human TM4SF4 exposed on outer cell surface was used as an immunization antigen. Among the selected anti-hTM4SF4 mAbs, ECL-2B7 and ECL-12A8 showed the best affinity for the antigen(Kd), approximately 2.66 nM and 8.34 nM, as determined by surface plasmon resonance analysis. Using mouse xenograft of NSCLC cell line, it was confirmed that ECL-2B7 was superior to ECL-12A8 in producing humanized antibody. ECL-2B7 inhibited EMT-associated stemness of TM4SF4 positive cancer cells by blocking cellular signaling events such as IGF1Rβ and CD44 and their downstream signals, PI3K/AKT/GSK3β/NF-κB and JAK2/STAT3 pathways. ECL-2B7 also enhanced antitumor activity by downregulating cellular and exosomal level of PD-L1 and B7-H4, immune-checkpoint ligands that elicit immunosuppression of T cell, and by mediating antibody-dependent cellular cytotoxicity. Treatment with OPN- and IGF1-neutralizing antibodies suppressed intracellular PD-L1 and B7-H4 level. It means that the regulation of PD-L1 and B7-H4 levels by TM4SF4 is closely related to the autocrine action of OPN and IGF1 induced by TM4SF4. Using patient-derived xenograft model, it was confirmed that the ECL-2B7 has excellent antitumor activity that effectively inhibits tumor progress. These results strongly suggest that it is necessary to construct humanized antibody based on ECL-2B7 to confirm its potential as a novel anticancer drug. Citation Format: Rae Kwon Kim, Chang-Kyu Heo, Yeon-jee Kahm, Uhee Jung, Byung-Chul Shin, Won-Yong Kim, Bum-Jin Kim, Sung-Chul Kim, Chun-jeih Ryu, Eun-Wie Cho, In-Gyu Kim. A novel monoclonal antibody targeting TM4SF4 enhances antitumor activity through regulation of cellular levels of immune checkpoint ligands and antibody dependent cellular cytotoxicity [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 3189.
Abstract 7160: Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE
Authors: Fei Shen, Guanglong Jiang, Santosh Philips, Erica Cantor, Laura Gardner, Gloria Xue, Geneva Cunningham, Nawal Kassem, Anne Oneil, David Cameron, Thomas Suter, Kathy Miller, George Sledge, Bryan Schneider
Journal: Cancer Research (2024)

Abstract Introduction: Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions. Methods: We performed post-hoc analyses to evaluate the association in 3,124 patients from two phase III adjuvant breast cancer trials, E5103 and BEATRICE. Differences in invasive disease-free survival (IDFS) and overall survival (OS) between patients with hypertension and those without were compared. Hypertension was defined as systolic blood pressure (SBP) ≥ 160 mmHg (n=346) and SBP ≥ 180 mmHg (hypertensive crisis) (n=69). Genomic analyses were performed to evaluate germline genetic predictors for the hypertensive crisis. Results: Hypertensive crisis was significantly associated with superior IDFS (p = 0.015) and OS (p = 0.042), but only IDFS (p = 0.029; HR = 0.28) remained significant after correction for prognostic factors. SBP ≥ 160 mmHg was not associated with either IDFS or OS. A common single-nucleotide polymorphism, rs6486785, was significantly associated with hypertensive crisis (p = 8.4 × 10−9; OR = 5.2). Conclusion: Bevacizumab-induced hypertensive crisis is associated with superior outcomes and rs6486785 predicted an increased risk of this key toxicity. Citation Format: Fei Shen, Guanglong Jiang, Santosh Philips, Erica Cantor, Laura Gardner, Gloria Xue, Geneva Cunningham, Nawal Kassem, Anne Oneil, David Cameron, Thomas Suter, Kathy Miller, George Sledge, Bryan Schneider. Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE [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 7160.
Abstract 6947: Exploring the single-cell dynamics of FOXM1 under cell cycle perturbations
Authors: Tooba Jawwad, Maliwan Kamkaew, Kriengkrai Phongkitkarun, Porncheera Chusorn, Somponnat Sampattavanich
Journal: Cancer Research (2024)

Abstract The cell cycle plays a critical role in maintaining normal cellular functions and preventing abnormal cell growth. The transcription factor FOXM1 has emerged as a crucial regulator of cell cycle progression and has been implicated in various physiological and pathological processes. Notably, FOXM1 overexpression has been observed in numerous cancer types, including liver, prostate, breast, lung, and colon cancer. Despite its significance, our understanding of how FOXM1 dynamic behaves at the single-cell level under different cell cycle perturbations and its link to cell behavior heterogeneity remains limited. Here, we investigated the dynamic behavior of FOXM1 in individual cells exposed to various cell cycle perturbations, focusing on understanding heterogeneity in cell behavior and improving disease treatment. At the single-cell level, our investigation reveals six distinct dynamic features of FOXM1 in response to various therapeutic interventions, each of which corresponds to a unique cell phenotype. Our result further demonstrates that for cells exhibiting a high FOXM1 pattern, targeting aurora kinase and PLK1 may hold promise as a therapeutic approach for cancer suggesting that FOXM1 is a strong biomarker, and its pattern can be predictive of drug response, especially in cases with G1 checkpoint defects like Rb1 loss or p53 deficiency. Citation Format: Tooba Jawwad, Maliwan Kamkaew, Kriengkrai Phongkitkarun, Porncheera Chusorn, Somponnat Sampattavanich. Exploring the single-cell dynamics of FOXM1 under cell cycle perturbations [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 6947.
Abstract 7230: A novel platform for identifying therapeutic index in pancreatic cancer
Authors: Vasiliki Pantazopoulou, Dannielle Engle
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDA) remains highly aggressive with a mere 12% 5-year survival rate, which underscores the urgent need for improved therapeutic approaches. The current standard of care primarily includes surgery and chemotherapy. However, existing therapies often result in severe side effects and offer limited success. The limitations are not only due to the development of treatment resistance but also due to the killing of normal cells, and as such a low therapeutic index. Targeted therapies aimed at the primary drivers of PDA, such as the KRASG12D mutation or the activated ErbB pathway, have shown promise in providing novel treatment options. We have previously demonstrated that combining targeted therapies, specifically KRASG12D and EGFR inhibitors, results in reduced tumor growth in both human and murine PDA organoid models in vitro. However, less is known about how these targeted therapies affect normal cells. Here, we are using co-cultures of normal pancreas and PDA organoids to create a platform that allows us to identify combinations of targeted therapies that can achieve a higher therapeutic index. Our goal is to identify treatment combinations that allow for the use of lower individual drug dose, while exhibiting enhanced anti-tumor efficacy and minimizing toxicities to normal organoids. This approach holds significant promise for improving patient outcomes and addressing the challenges associated with current PDA treatments. Citation Format: Vasiliki Pantazopoulou, Dannielle Engle. A novel platform for identifying therapeutic index 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 7230.
Abstract 91: Comprehensive 27-marker standard panel for immune monitoring of pre-clinical tumor mouse models using spectral analyzer technology
Authors: Jonas F. Hummel, Philipp Metzger, Roland Sonntag, Dennis Borrero-Wolff, Cynthia Obodozie, Holger Weber
Journal: Cancer Research (2024)

Abstract Within the last decade, major technological advances in flow cytometry and (single cell) RNA-sequencing have deepened our understanding of complex anti-tumoral immune responses. This allows a comprehensive immune monitoring of novel therapies in pre-clinical models. Conventional flow cytometry is reaching its technical limitation. The emitted fluorescence signal of the target population stained with antibodies is evaluated with simple bandpass filters, which leads to spectral overlap and thus the number of parameters that can be analyzed simultaneously is limited. The spectral analyzer technology combines both methods, providing great flexibility in evaluating different immune cell populations. This provides the opportunity to obtain target information by measuring the entire fluorescence spectrum measuring each wavelength individually and thus evaluating the true signal of each fluorochrome unaffected by autofluorescence or spillover. Our standard all-in-one flow cytometry panel uses the full capacity of a conventional BD Fortessa flow cytometer and enables the differentiation of important immune cell populations in tumors, such as T cells (CD4+, CD8+, regulatory T cells), B and NK cells as well as macrophages (M1/M2), MDSCs (granulocytes and monocytes) and dendritic cells. However, it would be of great advantage to gain further insights into activation and effector functions of the immune cells using markers like CD44 &amp; CD62L, CD69, PD-1, Lag-3, Tim-3 and PDL-1, CD80, CD86, CD40 and Ki-67. The Sony ID7000 spectral analyzer enables the simultaneous assessment of 27 markers to evaluate immune phenotypes, with the ability to include up to 4 individual target antibodies. Flow cytometry data from various tumor models are presented, demonstrating the enormous utility and potential of the spectral analyzer, especially with limited and precious tumor sample material, by evaluating different immune cell populations simultaneously without reaching its technical limits. The spectral analyzer technology enables us to mechanistically investigate differences in tumor therapies such as PD-1 treatment or other immune cell modulators not only phenotypically but also with regard to activation and differentiation of immune cell populations. Citation Format: Jonas F. Hummel, Philipp Metzger, Roland Sonntag, Dennis Borrero-Wolff, Cynthia Obodozie, Holger Weber. Comprehensive 27-marker standard panel for immune monitoring of pre-clinical tumor mouse models using spectral analyzer technology [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 91.
Abstract 7242: Immunostimulatory gene therapy co-expressing immune activators TMZ-CD40L and 4-1BBL with a PD-L1-targeting Affibody molecule to reactivate T cell immunity
Authors: Luke Adam White, Iris Vaask, Jonas Härdin, Emma Eriksson, Anna Sandegren, Fredrik Y. Frejd, Tanja Lövgren, Angelica Loskog
Journal: Cancer Research (2024)

Abstract Immunotherapy has been used to make great strides in helping cancer patients, and new approaches to reactivate patient immunity are constantly being developed. We are developing immunostimulatory gene therapy using adenoviruses as gene vehicles to inflame the tumor microenvironment and drive anti-tumor immunity. One consequence of immune activation is PD-L1 upregulation, so to optimize our treatment, we are using a novel gene therapy vehicle expressing both immune activators and a PD-L1-blocking Affibody molecule. Affibody molecules are tri-helical proteins engineered to bind specific target molecules with high affinity. These molecules have successfully been used to image cancer cells in the body and can block target proteins. Affibody molecules are advantageous over other affinity molecules due to their small size, averaging about 6 kDa, and their high stability. The small size makes an Affibody molecule an ideal candidate for use in viral vectors, where genetic space is limited. In the present study, we tested the biological activity of a PD-L1 targeted Affibody molecule expressed from a viral vehicle compared to the synthetic protein, using a Bio-IC in vitro luciferase assay. Further, the capacity of the PD-L1-binding Affibody molecule to prevent inhibitory signaling was evaluated in an ovarian cancer/immune cell co-culture assay. Our results demonstrate that cell lines infected with viral gene vehicles successfully express and release the Affibody molecule as demonstrated with PCR and ELISA. Furthermore, the supernatants containing the Affibody molecule and synthetic Affibody molecule inhibited the activity of PD-L1 in the BioIC assay. Next, an adenovirus vector containing trimerized-CD40L and 4-1BBL (LOAd703), known to upregulate PD-L1 in stimulated dendritic cells, was modified to co-express the anti-PD-L1 Affibody molecule (LOAd724). Gene expression was confirmed using PCR, flow cytometry (CD40L, 4-1BBL) and ELISA (anti-PD-L1 Affibody molecule). The tumor/immune cell co-culture is underway. In summary, Affibody molecules can be expressed from adenoviral gene vehicles alone or in combination with immunostimulatory genes. Further studies are warranted to understand the role of local PD-L1 blockade in the tumor microenvironment following LOAd724 therapy. Citation Format: Luke Adam White, Iris Vaask, Jonas Härdin, Emma Eriksson, Anna Sandegren, Fredrik Y. Frejd, Tanja Lövgren, Angelica Loskog. Immunostimulatory gene therapy co-expressing immune activators TMZ-CD40L and 4-1BBL with a PD-L1-targeting Affibody molecule to reactivate T cell immunity [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 7242.
Abstract 449: Catabolism of GSH by GGT supports cancer cell survival
Authors: Marco Zocchi, Fabio Hecht Castro Medeiros, Fatemeh Alimohammadi, Emily Tuttle, Gloria Asantewaa, TashJae Scales, Isaac S. Harris
Journal: Cancer Research (2024)

Abstract Cancer metabolism depends on amino acid sources to fuel tumor growth and drug resistance. Using amino acid restriction to treat tumors can enhance existing therapeutic techniques. The tripeptide Glutathione (GSH), which contains cysteine, glutamate, and glycine, is often considered an antioxidant, and its potential as an amino acid pool has been overlooked. GSH is ubiquitous in the tumor microenvironment and could provide a ready source of amino acids to tumor cells through its catabolism by the enzyme γ-Glutamyl transpeptidase (GGT), which has been shown to cleave GSH and its’ conjugates in the extracellular space. It is unclear if the cleavage of GSH by GGT supports cancers in vivo. We find that inhibiting GGT with the pharmacologic agent GGsTop blocks GSH catabolism and decreases tumor growth. We show that cultured cells can be rescued from a lethal depletion of cystine upon supplementation with GSH or its catabolic product cysteinylglycine, but not under the conditions of GGT inhibition. Through pharmacokinetic methods, we identify a usable systemic dose of GGsTop and show GGT inhibition in tumor tissue. Further, we demonstrate that systemic GGT inhibition in vivo decreases tumor mass and volume. These findings support the hypothesis that GSH catabolism by GGT1 is a non-canonical source of amino acids for tumor metabolism. Understanding GSH catabolism by GGT could elucidate new metabolic pathways in tumors. Inhibiting GSH catabolism could provide new therapeutic approaches to inhibit tumor growth. Citation Format: Marco Zocchi, Fabio Hecht Castro Medeiros, Fatemeh Alimohammadi, Emily Tuttle, Gloria Asantewaa, TashJae Scales, Isaac S. Harris. Catabolism of GSH by GGT supports cancer cell survival [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 449.