tbuckley/cabot-search huggingface dataset:
Abstract 2378: The triple-specific antibody KA-3003, targeting PSMA, CD28, and 4-1BB, is developed for the treatment of prostate cancer by enhancing T cell activity within the tumor
Authors: Guojin Wu, Zhengcheng Guo, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning
Journal: Cancer Research (2024)

Abstract Immunotherapy, revolutionizing the treatment of advanced solid tumors by blocking PD1 signaling, has encountered a challenge in prostate cancer, exhibiting a low response ratio to anti-PD-1 therapy. Furthermore, cancer immunotherapy using 4-1BB agonists faces limited clinical development due to dose-limiting toxicity. Here, we developed a tri-specific antibody, KA-3003, targeting PSMA, CD28, and 4-1BB, with the goal of enhancing T cell activation in the tumor microenvironment. This antibody was created using our common light chain bispecific antibody discovery platform and nanobody antibody discovery platform with knob-into-hole technology. KA-3003, in IgG1 format, features mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. It contains two identical nanobodies at the C-terminal against 4-1BB, while binding to PSMA and CD28 with two Fabs at the N-terminal, sharing an identical light chain. KA-3003 exhibits high affinity for PSMA and relatively lower affinity for CD28 and CD137. In the presence of a low concentration of CD3 antibody to stimulate T cell activation, co-culture of tumor cells expressing PSMA with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3003 effectively suppresses the growth of 22Rv1 tumors with or without a PD1 antagonist antibody. Additionally, KA-3003 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature. KA-3003 shows neither aggregation nor degradation. In conclusion, the tri-specific antibody KA-3003, developed with our common light chain antibody discovery platform, stands out as a promising pre-clinical candidate drug for the treatment of prostate cancer. Citation Format: Guojin Wu, Zhengcheng Guo, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The triple-specific antibody KA-3003, targeting PSMA, CD28, and 4-1BB, is developed for the treatment of prostate cancer by enhancing T cell activity within the tumor [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 2378.
Abstract 3332: Kalkitoxin thiol amide suppresses the breast cancer metastasis to bone and brain
Authors: Yunjo Soh, Saroj Kumar Shrestha, Se woong Kim
Journal: Cancer Research (2024)

Abstract Introduction: Breast cancer is the primary frequently diagnosed cancer worldwide, with a high fatality rate. Metastasis resulting from advanced breast cancer increases mortality in patients. MDA-MB-231 is triple-negative breast cancer that does not have any of the receptors that are commonly found in breast cancer. The lipopeptide toxin kalkitoxin thiol amide (KTA), generated from the marine cyanobacterium Moorena producens (formerly Lyngbya majuscule), has a wide range of biological and pharmacological effects. Its promise as a therapeutic agent for treating bone metastases from breast cancer is still uncertain. This study aimed to determine whether KTA could prevent breast cancer from metastasis to mice's bones and to elucidate any potential mechanisms causing this inhibition. Experimental Procedures: MDA-MB-231 cells were transfected with pGL4.50 (Luc2/CMV/Hygro) vector using LipofectamineTM 2000. Positive clones of MDA-MB-231 cells were selected after treatment with 300 µg/ml hygromycin for one week. After cancer implantation to the heart, bioluminescent imaging of femurs was measured upto 5 weeks and signal intensity of KTA-treated groups was compared with the vehicle group. Summary: KTA decreased breast cancer cell proliferation, migration, and invasion. KTA prevented MDA-MB-231 cells from breast cancer metastasizing to the bone and brain via inhibiting MAPK and STAT signaling. The epithelial-mesenchymal transition markers, which are responsible for distant metastasis, are highly opposed by KTA. Compared to mice in the control group, mice receiving KTA displayed considerably less bone and brain metastasis, a lower tumor burden, and less bone destruction in the murine breast cancer bone metastasis model. Conclusion: KTA has new inhibitory effects on cancer cell invasion and migration both in vitro and in vivo. From these findings, KTA may have therapeutic promise for treating breast cancer patients with distant metastases. Citation Format: Yunjo Soh, Saroj Kumar Shrestha, Se woong Kim. Kalkitoxin thiol amide suppresses the breast cancer metastasis to bone and brain [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 3332.
Abstract 3334: Combined treatment with PG3 and Nelfinavir induced synergistic apoptosis though sustained activation of integrated stress response
Authors: Xiaobing Tian, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract Integrated stress response (ISR) activation has been linked to many human diseases, including cancer and neurological diseases. The ISR controls protein synthesis and proteostasis. ISR main effector ATF4 transcriptional factor regulates the balance between survival and cell death. Under acute ISR, ATF4 promotes cell adaptation and survival. Sustained ISR leads to ATF4-mediated apoptosis. In many cancers, mutations or overexpression of oncogenes, results in enhanced cell proliferation and increased protein synthesis, which activate the ISR. Therefore, protein translation is reduced to maintain proteostasis. In other words, many cancers are primed by the ISR. Therefore, additional push by small molecule ISR-inducers will disrupt the balance and force cancer cells to enter apoptosis. Nelfinavir activates ATF4 through inhibition of eIF2α specific phosphatases CReP and GADD34. PG3 upregulates ATF4 through the HRI/eIF2α/ATF4 pathway. We hypothesize that combined treatment of PG3 and Nelfinavir will sustain upregulation of ATF4, and lead to ATF4-mediated cell apoptosis. Cell viability assays indicated that the combined treatment potently and synergistically inhibited cell viability in colorectal cancer cell lines HT29, SW480 and HCT116 p53−/−, osteosarcoma cell line U2OS and breast cancer cell lines MCF7 and T47D. The combined treatment sustained the induction of ATF4 and enhanced the expression of its proapoptotic target genes, CHOP and PUMA, and cell apoptosis. We confirmed that the enhanced induction of ATF4, CHOP and PUMA is through the ISR because ISRIB (ISR inhibitor) blocked the combined treatment-induced upregulation of ATF4, CHOP and PUMA. Citation Format: Xiaobing Tian, Wafik S. El-Deiry. Combined treatment with PG3 and Nelfinavir induced synergistic apoptosis though sustained activation of integrated stress response [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 3334.
Abstract 2681: Blockade of SIRPα in glioblastoma cells inhibits mitochondrial fatty acid β-oxidation and increase immune cell mediated cytotoxicity
Authors: Yu-Ting Tsai, Glenn J. Lesser, David R. Soto-Pantoja
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most malignant brain tumor with limited immunotherapeutic options, likely due to significant GBM-associated systemic and intra-tumoral immunosuppression. The binding of SIRPα on myeloid cells to CD47 on cancer cells restricts immuno-phagocytosis against cancer cells. However, less attention has been given to SIRPα is also expressed in cancer cells, and the role of SIRPα on cancer cells is still unclear. Immunohistochemistry (IHC) staining was used to examine the expression of SIRPα in normal brain tissues and GBM. A single-cell database on the Broad Institute Portal was utilized to analyze the SIRPα expression in different cell types. SIRPα antisense morpholino was applied for gene knockdown. Established stable SIRPα overexpressed GBM cell lines were used to examine the mitochondrial function through the Seahorse Mito Stress test. In vitro, immune cell-mediated cytotoxicity was measured by Agilent xCELLigence Real-Time Cell Analysis. Patient biopsies show a 2-fold increase in SIRPα expression in GBM tumors compared to the normal adjacent (n=14-21; p &amp;lt; 0.01). Single-cell RNA-seq data on GBM tumors shows that SIRPα is expressed not only in the myeloid compartment but also in malignant cells. Studies have shown that mitochondrial function and fatty acid β-oxidation (FAO) play a critical role in GBM progression. Respirometry data revealed that blocking SIRPα in murine GBM cell line (CT2A) decreases mitochondrial ATP production. Seahorse Mito Stress test combined with fuel inhibitors showed that SIRPα expression mainly affects the usage of FAO (approximately 50%). In addition, stably, the GFP-tagged SIRPα overexpressed GBM cell line showed an increase of mitochondrial respiration with enhanced FAO ratio compared to the GFP control cell line. These suggested that SIRPα regulates mitochondrial FAO. Studies have shown that tumor-intrinsic FAO confers cell resistance to immune cell-mediated cytotoxicity. Interestingly, by coculturing with microglia, the innate immune population in the brain, our data showed that SIRPα blockade on GBM enhanced microglia-mediated cytotoxicity. Our data showed that targeting SIRPα on GBM may be a prospective therapeutic option by inhibiting FAO in mitochondria and increasing immune cell-mediated cytotoxicity. Citation Format: Yu-Ting Tsai, Glenn J. Lesser, David R. Soto-Pantoja. Blockade of SIRPα in glioblastoma cells inhibits mitochondrial fatty acid β-oxidation and increase immune cell mediated 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 2681.
Abstract 2649: A new role for the aryl hydrocarbon receptor (AhR) as a proximal mediator of immune checkpoints (PD-L1/2 and IDO1) in non-small cell lung cancer: Insights into an interferon-induced, LncRNA-and JAK/STAT-mediated signaling pathway
Authors: Brian Lara, Megan Snyder, Zhongyan Wang, Jocelyn Fimbres, Eric Yang, David H. Sherr
Journal: Cancer Research (2024)

Abstract Non-small cell lung cancer (NSCLC) is the second most common cancer and accounts for ~127,000 deaths/year in the U.S. Its current ~30% five-year survival rate is an improvement from a decade ago thanks in part to the introduction of immune checkpoint inhibitors including PD1- and PD-L1-specific monoclonal antibodies. While PD-1/PD-L1-targeted immunotherapy is effective in many cases, not all patients respond and complete remissions still only occur in a minority of patients. Therefore, a greater understanding of immune checkpoint regulation in human NSCLC is needed. Here, we investigated a novel role for the aryl hydrocarbon receptor (AhR), an environmental carcinogen receptor previously associated with smoking-induced lung cancers, in the regulation of immune checkpoints PD-L1, PD-L2, and IDO1. Computational analyses of existing databases for protein-protein interactions linked to the AhR signaling pathway suggested crosstalk between the AhR, type I and type II Interferon (IFN), and JAK/STAT signaling pathways. AhR deletion from human lung A549 adenocarcinoma cells significantly reduced expression of JAK2, STAT1, STAT2, and the JAK/STAT signaling targets IRF1 and IRF9. Type II IFNγ significantly increased expression of those genes as well as the immune checkpoints IDO1, PD-L1, and PD-L2 in an AhR-dependent fashion. Interestingly, AhR deletion also eliminated IFNγ-mediated induction of a recently described long non-coding RNA, INCR1, which is encoded across the CD274/CD273 locus, and which facilitates JAK2, CD274/PD-L1, and IDO1 translation. Concomitantly, AhR knockout increased baseline expression of an RNA-binding protein, HNRNPH1, known to sequester JAK2 and CD274 mRNA thereby reducing IDO, PD-L1 and PD-L2 expression. Similarly, the AhR was shown to regulate Type I IFNα-mediated induction of STAT1, STAT2, CD274/PD-L1, and CD273/PD-L2. The data indicate that IFN induction of key immune checkpoints in lung adenocarcinoma cells is dependent on the AhR through its control of a conventional JAK/STAT pathway and an unconventional lncRNA (INCR1) and RNA-binding protein (HNRNPH1) pathway. Citation Format: Brian Lara, Megan Snyder, Zhongyan Wang, Jocelyn Fimbres, Eric Yang, David H. Sherr. A new role for the aryl hydrocarbon receptor (AhR) as a proximal mediator of immune checkpoints (PD-L1/2 and IDO1) in non-small cell lung cancer: Insights into an interferon-induced, LncRNA-and JAK/STAT-mediated 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 2649.
Abstract 3330: BPP, a dual functional inhibitor, targets MLL-rearranged acute myeloid leukemia: Unraveling mechanisms and expanding therapeutic horizons
Authors: Tai-Lin Chen, Tsann-Long Su, Te-Chang Lee
Journal: Cancer Research (2024)

Abstract Refractory/recurrent acute myeloid leukemia (AML) poses a formidable clinical challenge, with MLL translocations implicated in approximately 10% of AML cases and a staggering 75% in infant leukemia, bearing an unfavorable prognosis. Our investigation focuses on BPP, a dual-functional inhibitor capable of inducing DNA cross-linking and suppressing angiogenesis. In a diverse panel of solid tumor and leukemic cells, BPP exhibited exceptional sensitivity against MLL-rearranged AML cell types. In MOLM13 and MV4-11 xenograft models, BPP showcased outstanding tumor suppression, with some tumors even achieving complete remission. In-house acute toxicity testing, BPP treated group showed excellent safety margin in both blood chemistry and pathological examination. Remarkably, BPP demonstrated significant cytotoxicity not only in FLT3-WT AML but also in FLT3-ITD AML. Delving into the mechanism, BPP was found to induce FLT3-ITD and MLL degradation by triggering DNA damage and ER stress. Comet assays revealed a dose-dependent accumulation of DNA fragments in MLL cells upon BPP exposure.The involvement of the KMT2A gene in chromosomal translocation in THP1 cells was highlighted, with BPP treatment resulting in a significant increase in Heat-shock protein. Notably, the combination of ganetespib, an FDA-approved HSP90 inhibitor, with BPP exhibited synergistic effects in both in vitro and in vivo models, inducing synthetic lethality and inhibiting HR repair. Furthermore, BPP not only reduced leukemic stem cells in colony formation assays but also demonstrated sensitivity in relapsed/refractory (R/R) and multiple drug-resistant patient samples. These findings collectively position BPP as a promising candidate for the treatment of MLL-rearranged AML, offering multifaceted therapeutic potential. Citation Format: Tai-Lin Chen, Tsann-Long Su, Te-Chang Lee. BPP, a dual functional inhibitor, targets MLL-rearranged acute myeloid leukemia: Unraveling mechanisms and expanding therapeutic horizons [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 3330.
Abstract 2064: Unveiling the correlation between gemtuzumab-ozogamicin efficacy and CD33+ expression in AML primary samples using the novel AML vitroscreen
Authors: Mara Gilardi, Garima Kaushik, Brandon Walling, Paolo Schiavini, Stefano Cairo, Marianna Zipeto
Journal: Cancer Research (2024)

Abstract Acute myeloid leukemia (AML) poses a significant therapeutic challenge, with a rising incidence in recent times. This clonal hematopoietic disorder of progenitor and stem cells exhibits aggressive behavior, and despite initial remission, recurrence is common1. The conventional shift from chemotherapy to monoclonal antibodies and antibody-drug conjugates (ADCs) has been hindered by the absence of AML-specific antigens. Notably, CD33, expressed strongly in 80-90% of AML cells, has become a target for gemtuzumab-ozogamicin (Mylotarg), the sole FDA approved ADC for AML treatment2. While advancements in understanding AML molecular mechanisms have influenced clinical approaches, the lack of clinically representative models hinders therapeutic progress. Existing models, both in vivo and ex vivo, struggle to capture the heterogeneity and complexity of AML3. Addressing this, we present our proprietary assay, Champions AML VitroScreen®4, designed for testing therapeutic candidates in primary AML samples. Our diverse bank of deeply characterized AML samples encompasses multiple subtypes, allowing evaluation of therapeutic responses through cell viability, proliferation, and clonal composition analyses. To validate our novel assay, we employed the VitroScreen platform to test Mylotarg across various AML subtypes, considering CD33 expression levels. By assessing more than 20 AML models, we determined the IC50 for Mylotarg and observed dose-dependent responses, where sensitivity to the drugh correlated with CD33 expression. Through multiple endpoints, including viability, proliferation, apoptosis, and phenotyping, we categorized primary AML models as responders, low responders, or resistant, establishing a strong positive correlation between Mylotarg sensitivity and CD33 expression. Our innovative approach, utilizing deeply characterized AML patient samples in the AML VitroScreen® platform, facilitates high-throughput drug testing. This system, serving as an ideal clinical translational setting in preclinical research, holds promise for developing tailored therapeutic strategies. Ultimately, this approach could significantly impact patient outcomes by offering improved strategies for both primary and recurrent AML cases. Citation Format: Mara Gilardi, Garima Kaushik, Brandon Walling, Paolo Schiavini, Stefano Cairo, Marianna Zipeto. Unveiling the correlation between gemtuzumab-ozogamicin efficacy and CD33+ expression in AML primary samples using the novel AML vitroscreen [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 2064.
Abstract 1874: Common vulnerabilities of stem cells along the Barrett's-dysplasia-adenocarcinoma sequence
Authors: Wa Xian, Frank McKeon, Christopher Crum, Jaffer Ajani, Peter Davies, Matthew Vincent, William Bachovchin, Hung-Sen Lai, Shuang Pan, Amber Su, Ashley Hoffman, Raul Caballero Montes, Melina Khorrami, Melika Khorrami, Yusuke Yamamoto
Journal: Cancer Research (2024)

Abstract Barrett's esophagus (BE) is an early precursor of esophageal adenocarcinoma and therefore a relevant target of preemptive therapeutics. Using robust stem cell cloning technologies, we have cloned stem cells from patient-matched biopsies of BE, low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC) from multiple patients. Whole exome sequencing of these stem cells reveals the mutational maturation along the sequence of BE, LGD, HGD, and EAC at unprecedented resolution of both copy number and single nucleotide variation. In vitro differentiation and xenografting of these clones recapitulates their original histology and shows that only the EAC stem cells yield robust tumors in immunodeficient mice. Leveraging the intrinsic immortality of these stem cells, we have performed high-throughput screens for small molecules that selectively kill BE stem cells without harming patient-matched normal esophageal stem cells. These screening efforts evolved into synthetic lethal strategies that identified drug combinations that selectively eliminate, in vitro, BE stem cells from 20 of 23 cases. Remarkably, this same synthetic lethal drug combination also eliminated in vitro stem cells of LGD, HGD, and EAC that were not components of the original screens. We have used synthetic chemistry to generate a series of novel molecules based on the identified drug combination that significantly improved the in vitro efficacy to sub-nanomolar levels. These novel molecules directed to the stem cell component of BE, LGD, HGD, and EAC also show potent effects against tumors generated from EAC stem cells in immunodeficient mice. We anticipate that these synthetically lethal drug combinations will have potential utility against precursor lesions to preempt EAC as well as against EAC itself. Citation Format: Wa Xian, Frank McKeon, Christopher Crum, Jaffer Ajani, Peter Davies, Matthew Vincent, William Bachovchin, Hung-Sen Lai, Shuang Pan, Amber Su, Ashley Hoffman, Raul Caballero Montes, Melina Khorrami, Melika Khorrami, Yusuke Yamamoto. Common vulnerabilities of stem cells along the Barrett's-dysplasia-adenocarcinoma sequence [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 1874.