tbuckley/cabot-search huggingface dataset:
Abstract 1903: Zenocutuzumab, a HER2xHER3 bispecific antibody, is effective in cancer models with high NRG1 expression
Authors: Marie N. O'Connor, Ron C. Schackmann, Igor Odintsov, Szabolcs Fatrai, Arie B. Brinkman, Sidney Walker, Jeroen J. Lammerts van Bueren, Cecile A. Geuijen
Journal: Cancer Research (2024)

Abstract Neuregulin 1 (NRG1) is a ligand that binds to HER3, promotes HER2/HER3 dimerization and PI3K/AKT/mTOR signaling, and causes malignant transformation. Zenocutuzumab (Zeno, MCLA-128) is a humanized IgG1 bispecific antibody that docks on HER2, preventing heterodimerization with HER3, while also blocking NRG1 interaction with HER3, and potently inhibiting NRG1-induced HER2:HER3 proliferation and survival signaling of cancer cells. High NRG1 expression arising from autocrine signaling or gene amplification is associated with poor prognosis in certain cancers, and resistance to standard therapies. The clinical efficacy and safety of Zeno in patients with NRG1 fusion-driven cancer who were enrolled in the ongoing global multicenter eNRGy study and Early Access Program were recently presented. Treatment with Zeno led to durable responses across multiple different previously treated NRG1 fusion tumor types. Zeno utilizes the Merus Dock &amp; Block® mechanism to inhibit HER2/HER3 dimerization and the NRG1/HER3 tumor-signaling pathway and is effective at high NRG1 concentrations. Here, we examined the efficacy of Zeno in preclinical models representing different tumor types expressing high NRG1 levels. Zeno treatment of the lung cancer cell line HCC95, which harbors an NRG1 gene amplification, effectively inhibited signaling pathways involved in the regulation of proliferation and survival, including the PI3K/AKT/mTOR pathway and inhibited cell proliferation. The anti-tumor efficacy of Zeno in vivo against a panel of 28 patient-derived xenograft (PDX) models representing different tumor types was examined. Zeno significantly inhibited tumor growth in seven high-NRG1-expressing PDX models. These results show that Zeno is effective in tumor cell killing in vitro and in vivo in high NRG1-expressing cancer models representing multiple different tumor types. Citation Format: Marie N. O'Connor, Ron C. Schackmann, Igor Odintsov, Szabolcs Fatrai, Arie B. Brinkman, Sidney Walker, Jeroen J. Lammerts van Bueren, Cecile A. Geuijen. Zenocutuzumab, a HER2xHER3 bispecific antibody, is effective in cancer models with high NRG1 expression [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 1903.
Abstract 6280: Vitamin D enhances luminal differentiation of prostate organoids more than androgens
Authors: Oscar Fernando Cerna, Larisa Nonn, Mike Schlicht, Kirty Krieger
Journal: Cancer Research (2024)

Abstract Background: Prostate Cancer (PCa) is a prevalent disease affecting over two million men worldwide. Vitamin D is a fat-soluble hormone that is well-known for its role in the maintenance of strong bones and has anti-cancer effects in prostate cancer. Vitamin D is synthesized in the skin in response to sun exposure and may be supplemented with diet. However, since melanin hinders this synthesis many African Americans are deficient in vitamin D. Vitamin D circulates as 25-hydroxyvitamin D3 (25D) and 25-dihydroxyvitamin D3 (1,25D). Hydroxylation of 25D by the kidney or within tissues forms the active hormone 1,25D. 1,25D binds the vitamin D receptor (VDR), a steroid transcription factor. Androgens are the main regulatory hormones involved in prostate growth and differentiation. Epithelial differentiation is the process in which progenitor or stem cells become specialized cells, such as basal or luminal. In the prostate, luminal epithelial cells are the most differentiated and are the origin of PCa. We used mouse prostate organoids to replicate the differentiation process in vitro and to help identify the role of 1,25D on epithelial differentiation in the presence and absence of other androgens. Methods: Primary mouse prostate cells were isolated from dorsal lateral lobes and grown as organoids. Over two weeks, we treated these organoids with concentrations of 1,25D and androgen (dihydrotestosterone, DHT). The four treatment groups were control, 1,25D only, DHT only and 1,25D+DHT. Organoids were imaged and analyzed for number, size and phenotype. Phenotypes were identified as luminal, acinar, or solid. Results: Luminal phenotypes were more prevalent in 1,25D conditions compared to control or DHT alone. The number, size and percent of luminal organoids was highest in 1,25D + DHT compared to all other groups. Ongoing studies include examination of prostate organoids from mice with a vitamin D-deficient diet and staining of the organoids for differentiation markers. Conclusions/Significance: We observed that 1,25D enhanced luminal epithelial differentiation in mouse prostate organoids. These findings suggest that chronic vitamin D deficiency may increase risk of aggressive prostate cancer, due to decreased epithelial differentiation. This has implications for the disparity of aggressive PCa observed in African American men who have lower vitamin D levels compared to their white counterparts. Citation Format: Oscar Fernando Cerna, Larisa Nonn, Mike Schlicht, Kirty Krieger. Vitamin D enhances luminal differentiation of prostate organoids more than androgens [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 6280.
Abstract 7603: Targeting MTAP-deleted tumor via synthetic lethality with a combination of a PRMT5i and an MAT2Ai
Authors: Guiping Zhang, Jiapeng Li, Jie Jack Li
Journal: Cancer Research (2024)

Abstract MTAP (methylthioadenosine phosphorylase) is located adjacent to the tumor-suppressor gene CDKN2A (cyclin-dependent kinase inhibitor 2A) and sometimes co-deleted in 10-15% of all cancers, especially in glioblastoma, mesothelioma, and pancreatic cancers. Recent studies shown that MTAP deletions in cancer create vulnerability to synthetic lethal with the MAT2A/PRMT5/RIOK1 axis. Herein, we report the discovery of a PRMT5 inhibitor GH56, and an MAT2A inhibitor GH31, both showed promising single agent efficacy and synergy in MTAP loss tumor models. GH56 is an MTA-Cooperative PRMT5 inhibitor. In vitro, GH56 showed potent SDMA inhibition in MTAP-deleted cancer cells with an IC50 from 0.8‒3 nM. It also showed excellent selectivity with more than 100-folds in MTAP-WT cells. In a cell panel with more than 100 cell-lines, GH56 selectively inhibited the growth of cells with MTAP-deletion while separated the cells with MTAP-WT. In the safety panel and kinase panel, GH56 all showed good selectivity. In addition, GH56 had an IC50 &amp;gt; 10 μM for hERG. In vivo, GH56 showed dose-dependent efficacy in a series MTAP-deleted models and were well tolerated. In U87MG glioblastoma CDX model, NCI-H838 NSCLC CDX model, BXPC-3/HupT4 PDAC CDX models and RT112-84 BLCA model, TGI for GH56 at high dose were all &amp;gt;100%. On the other hand, GH31 is a potent and selective MAT2A inhibitor. GH31 also showed excellent selectivity with MTAP-deleted and MTAP-WT cell lines. The combination of GH56 and GH31 showed synergy both in vitro and in vivo. The low dose GH31 combination with low-dose GH56 achieved the similar efficacy as high dose GH56 and a more rapid tumor regression. In view of the delayed onset of the tumor response and high dose needed by PRMT5 inhibitor (reported by clinic stage compounds), the combination of PRMT5i and MAT2Ai will be advantageous. Furthermore, both GH56 and GH31 are brain penetrant, especially for GH31, with a Kpuu &amp;gt; 0.6 and B/P &amp;gt; 2. The combination of GH56 and GH31 in a brain metastasis model and a glioblastoma in situ model all showed strong synergy, demonstrated the potential for the treatment of glioblastoma and other cancer with brain metastasis. In summary, we discovered potent, selective and brain penetrant PRMT5 inhibitor GH56 and MAT2A inhibitor GH31. Both compounds are currently under evaluation in IND-enabling studies and will provide more options for MTAP-deleted cancers. Citation Format: Guiping Zhang, Jiapeng Li, Jie Jack Li. Targeting MTAP-deleted tumor via synthetic lethality with a combination of a PRMT5i and an MAT2Ai [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 7603.
Abstract 4423: Cholesterol and arachidonic acid promote the tumor growth of epithelial ovarian cancer via MAPK signaling pathway
Authors: Hitomi Sakaguchi-Mukaida, Kosuke Hiramatsu, Mamoru Kakuda, Satoshi Nakagawa, Toshihiro Kimura, Yutaka Ueda, Tadashi Kimura
Journal: Cancer Research (2024)

Abstract Introduction: Previously, we reported that VLDL promoted cell proliferation of epithelial ovarian cancer (EOC) cells in vitro. In vivo, we also confirmed that High-Fat Diet (HFD) strongly promoted the tumor growth of EOC. These results suggest that lipid molecules in HFD might contribute to cell proliferation of EOC cell. In this study, we performed metabolome analysis and analyzed the metabolomic profile of lipid molecules of HFD fed mouse serum. Finally, we demonstrated that some lipid molecules promoted the cell proliferation of EOC cells in vitro and vivo. Methods: We obtained the serum of HFD and normal diet (ND) fed mouse (non-tumor bearing) and performed metabolome analysis to identify the lipid molecules which associate with cell proliferation. In addition, we demonstrated that the lipid molecules promoted cell proliferation and activated signaling pathway of EOC cells in vitro. Moreover, we evaluated that the lipid molecules-rich diet promoted the tumor growth of EOC in vivo. Results: The tumor growth of EOC (EOC cell line; KURAMOCHI and RMG-I) was significantly promoted by HFD compared to ND in vivo (p &amp;lt; 0.05, respectively). Metabolome analysis using the serum of HFD and ND fed mouse (non-tumor bearing) detected 210 metabolites, and principal component analysis showed obvious different metabolic profiles of HFD fed mouse serum compared to ND. Partial least squares-discriminant analysis revealed cholesterol and arachidonic acid (AA) as the lipid molecules with high VIP score in the serum of HFD fed mouse. In vitro, cholesterol and AA significantly promoted cell proliferation, respectively (p &amp;lt; 0.05) through the activation of MAPK signaling pathway. In vivo, we also confirmed that cholesterol and AA-rich feed promoted the tumor growth of EOC, respectively (p &amp;lt; 0.05). Conclusions: Cholesterol and AA significantly promoted the tumor growth of epithelial ovarian cancer through the activation of MAPK signaling pathway. Citation Format: Hitomi Sakaguchi-Mukaida, Kosuke Hiramatsu, Mamoru Kakuda, Satoshi Nakagawa, Toshihiro Kimura, Yutaka Ueda, Tadashi Kimura. Cholesterol and arachidonic acid promote the tumor growth of epithelial ovarian cancer via MAPK signaling pathway [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 4423.
Abstract 4430: Metabolic reprogramming by ASPSCR1::TFE3 and VCP
Authors: Rahi Patel, Amir Pozner, Kyle Dunlap, Lara Carroll, Jeff Brown, Greg Ducker, Kevin Jones
Journal: Cancer Research (2024)

Abstract Alveolar soft part sarcoma (ASPS) is a lethal soft tissue malignancy typically incident among adolescents and young adults, distinguished by the t(X;17) ASPSCR1::TFE3 fusion gene (AT3). Conventional chemotherapy has shown limited efficacy against ASPS, necessitating exploration of alternative strategies. Previous investigations have shown the pivotal role of the fusion gene in sarcomagenesis in mice, particularly in lactate-rich environments. This study aims to elucidate the metabolic alterations actuated by the AT3 fusion gene, both in vitro and in vivo. To model in vitro metabolic profiles, ASPS (ASPS-1) and renal cell carcinoma (FU-UR1) cell lines, each expressing AT3, were employed. Utilizing siRNA-mediated gene silencing, AT3 and VCP, a cofactor, were targeted in vitro. Metabolomic profiling through GC-MS analyzed the impact of depletion of AT3 or its transcriptional co-factor, VCP. C13-labeled metabolites were introduced and traced in vitro and in vivo to enhance comprehension of carbon utilization in aerobic respiration. While metabolic activity and O2 consumption differed between cell lines, inhibition of AT3 and VCP led to similar metabolite alterations. Significant changes in amino acid metabolism, notably glutamate, aspartate, and alanine were observed in both cell lines. There was notable diversion of glucose carbon utilization away from typical entry into the tricarboxylic acid (TCA) cycle, with minimal carbon incorporation beyond alpha-ketoglutarate. Despite prior data indicating heightened mitophagy activity in AT3 driven cells, inhibition of lysosomal activity did not yield significant changes in cellular respiration or O2 consumption. Citation Format: Rahi Patel, Amir Pozner, Kyle Dunlap, Lara Carroll, Jeff Brown, Greg Ducker, Kevin Jones. Metabolic reprogramming by ASPSCR1::TFE3 and VCP [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 4430.
Abstract 6886: Orion™: 17-plex single-step stain and imaging of normal lung section adjacent to non-small cell lung carcinoma
Authors: Selena Larkin, Tad George, Eric Kaldjian
Journal: Cancer Research (2024)

Abstract Background: The ability to image tissue microenvironments (TME) at high-plex over a whole slide without requiring multiple staining steps allows for unprecedented ability to study tissue architecture and molecular mechanisms of immune and disease processes. Here we investigate a sample of normal lung section adjacent to non-small cell lung carcinoma using whole slide, single-step stain and imaging at single-cell resolution. Methods: These images profiled a whole slide tissue section of normal lung section adjacent to non-small cell lung carcinoma, stained with a 17-plex immuno-oncology biomarker panel. In this profile, we designed a high-plex panel of 17 biomarkers where the tissue autofluorescence was imaged and isolated as an additional fluorescence channel. All markers were stained in a single staining procedure and imaged in a single scan. Whole slide spatial staining and imaging was conducted on the Orion spatial biology platform. The full protocol is quick and simple, using standard histology tools: •Mount sections on glass slides•De-paraffinize and perform antigen retrieval•Quench autofluorescence•Stain slides with a panel of ArgoFluor™ conjugated antibodies•Coverslip with ArgoFluor Mounting Medium and cure overnight•Image whole slides at 20X magnification using the Orion instrument•Process to ome.TIFF and analyze. Results: Data revealed intact normal lung alveolar architecture, with scattered immune cell infiltrates. Multiplexed imaging revealed epithelial cells, which make up alveoli, and endothelial vasculature as well as immune cells infiltrates in the alveolar space. Various immune cell populations were observed to be present (T cells, B cells, macrophages) and immune cell activation could be distinguished using PCNA and/or Ki-67 markers. Various T cell subsets could also be identified among the infiltrate using markers for CD4, CD8 and T-regulatory marker FOXP3. Through the use of multiplex staining, immune cell activity could also be characterized with respect to bronchiolar, artery, and capillary tissue architecture. Conclusions: High-quality subcellular imaging of TME can lead to greater spatial investigation and more in-depth understanding of immune function in normal and diseased tissue. Here, multiplexed imaging identified distinct immune cell collections among cancer-adjacent normal lung tissue, providing validation of instrumentation and methods to obtain benchmarks for spatial quantitation of immune cells in control regions adjacent to cancer tissue. Citation Format: Selena Larkin, Tad George, Eric Kaldjian. Orion™: 17-plex single-step stain and imaging of normal lung section adjacent to non-small cell lung carcinoma [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 6886.
Abstract 7620: Immuno-transcriptomic profiling of blood and tumor tissue identifies gene signatures associated with immunotherapy response in metastatic bladder cancer
Authors: Pedro J. Romero, Emma Desponds, Davide Croci, Victoria Wosika, Noushin Hadadi, Sara Fonseca Cost, Laura Ciarloni, Marco Ongaro, Hana Zdimerova, Marine M. Leblond, Sahar Hosseinian-Ehrensberger, Grégory Verdeil
Journal: Cancer Research (2024)

Abstract Muscle-invasive bladder cancer (MIBC) accounts for 25% of bladder cancer cases. Despite the broader usage of immune checkpoint blockade targeting the PD-1/PD-L1 axis, the response rate and survival of patients remain low for this disease. Redirecting swiftly these patients toward alternative therapeutic strategies upon immunotherapy failure should be a priority. So far, no marker allows to precisely determine early outcome to the treatment.Blood-based biomarkers represent ideal candidates for the development of non-invasive immuno-oncology-based assays. However, to date, no blood biomarker has been validated to predict clinical response to immunotherapy. In this study, we used next generation sequencing (RNAseq) on bulk RNA extracted from whole blood and tumor samples in a pre-clinical MIBC mouse model. We aimed at identifying biomarkers associated with immunotherapy response and to assess the potential application of simple non-invasive blood biomarkers as therapeutic decision-making assay compared to tissue-based biomarkers. We established that circulating immune cells and the tumor microenvironment (TME) display highly organ-specific transcriptional responses to ICI. Interestingly, a common lymphocytic activation signature can be identified in both compartments associated with the efficient response to immunotherapy, including a blood specific CD8+ T cell activation/proliferation signature which predicts immunotherapy response. Citation Format: Pedro J. Romero, Emma Desponds, Davide Croci, Victoria Wosika, Noushin Hadadi, Sara Fonseca Cost, Laura Ciarloni, Marco Ongaro, Hana Zdimerova, Marine M. Leblond, Sahar Hosseinian-Ehrensberger, Grégory Verdeil. Immuno-transcriptomic profiling of blood and tumor tissue identifies gene signatures associated with immunotherapy response in metastatic bladder 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 7620.
Abstract 3229: IACS-16559, a CBP/P300 bromodomain inhibitor for the treatment of specific AML subsets
Authors: Ciro Zanca, Michael Soth, Guang Gao, Jason Gay, Ningping Feng, Christopher Bristow, Kang Le, Quanyun Xu, Phuong Nguyen, Yongying Jiang, Teresa Perry, Faika Mseeh, Paul Leonard, Jason Cross, Virginia Giuliani, Joe Marszalek, Philip Jones, Tim Heffernan
Journal: Cancer Research (2024)

Abstract Block in differentiation and accumulation of undifferentiated blasts are hallmarks of Acute Myeloid Leukemia (AML) and epigenetic processes have been shown to play a critical role in hematological malignancies. Paralogs CREBBP and EP300, in association with co-factors, are hijacked during leukemogenesis by aberrant transcriptional factors, thus driving blast proliferation and maintaining the undifferentiated phenotype. Here, we introduce IACS-16559, a bromodomain inhibitor targeting CREBBP/EP300. IACS-16559 is highly selective for the bromodomains of CBP and EP300 versus BRD4, showing a dose-dependent inhibition of H3K27 acetylation residue in vivo and in vitro. In addition, IACS-16559 pharmacokinetic properties show low clearances, high oral exposures and predicted QD dosing in human. We screened AML cell lines in vitro for their response to IACS-16559 and identified specific subtypes of AML that exhibit heightened sensitivity to CBP/EP300 inhibition, specifically AML with AML1-ETO and MLL-AF9 rearrangements, and AML featuring mutations in the nucleophosmin (NPM1c) gene. IACS-16559 inhibited proliferation of AML responder cell lines in vitro, halted cell cycle progression, with an accumulation of cells in G1 and a decrease of cells in S phase. IACS-16559 did not induce apoptosis across a panel of AML cell lines, indicating that induction of apoptosis is not a major mechanism of action of CBP/EP300 inhibition. To augment the anti-tumor effects of IACS-16559, we prioritized the pharmacological combination of CBP/EP300 and MLL-Menin inhibitors. This combination synergistically impeded cell proliferation and potently triggered apoptosis in vitro and in vivo, whereas none of the individual agents alone had this effect. The changes in gene and surface marker expression produced by these treatments, as single agents and in combination with synergistic effects, were in line with an induced myeloid differentiation phenotype. Collectively, our findings provide a compelling basis for further exploring the use of a CBP/EP300 bromodomain inhibitor in conjunction with an inhibitor of the MLL-Menin interaction in a subset of AML patients with MLL rearrangements or NPM1 mutations. Citation Format: Ciro Zanca, Michael Soth, Guang Gao, Jason Gay, Ningping Feng, Christopher Bristow, Kang Le, Quanyun Xu, Phuong Nguyen, Yongying Jiang, Teresa Perry, Faika Mseeh, Paul Leonard, Jason Cross, Virginia Giuliani, Joe Marszalek, Philip Jones, Tim Heffernan. IACS-16559, a CBP/P300 bromodomain inhibitor for the treatment of specific AML subsets [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 3229.