tbuckley/cabot-search huggingface dataset:
Abstract 2459: ADT-030 is a novel dual-acting RAS/β-catenin inhibitor that potentiates antitumor immunity
Authors: Md Yeashin Gazi, Ogacheko Okoko, Xin Wang, Caitlin Brandle, Xi Chen, Khalda Fadlalla, Adam Keeton, Yulia Maxuitenko, Catherine Hedrick, Huidong Shi, Gary Piazza, Gang Zhou
Journal: Cancer Research (2024)

Abstract ADT-030 is a novel indene identified from a screening campaign and chemically optimized for drug-like properties that acts as a dual inhibitor of RAS and β-catenin signaling. Here we demonstrate that ADT-030 binds RAS with high affinity and inhibits MAPK/AKT signaling with high potency and selectivity in KRAS mutant cells to inhibit proliferation and induce apoptosis. ADT-030 also inhibits phosphodiesterase 10A (PDE10) that is overexpressed in cancer cells to selectively activate cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling, which induces phosphorylation and degradation of the oncogenic pool of β-catenin. ADT-030 exhibited cytotoxicity to a variety of murine cancer cell lines in vitro, and inhibited tumor growth in syngeneic immunocompetent mice when orally administered. The antitumor activity of ADT-030 was diminished in mice that were immunodeficient or depleted of CD8+ T cells, indicating a critical role of the host immune system. In a metastatic breast tumor mouse model (4T1), ADT-030 not only delayed the growth of the primary tumor but also reduced tumor colonization in the lungs, leading to increased survival. CyTOF and scRNAseq analyses provided a plethora of information revealing the impact of ADT-030 on the immune milieu in the tumor microenvironment. Notably, ADT-030 selectively induced apoptosis of myeloid-derived suppressor cells (MDSCs) while CD8+ T cells were not affected. Consequently, ADT-030 treatment resulted in a marked reduction of MDSCs, which was accompanied by increased tumor infiltration of effector CD8+ T cells. ADT-030 treatment of cancer cells led to immunogenic cell death and enhanced dendritic cell activation. Furthermore, the ability of ADT-030 to augment the antitumor activity of immune checkpoint blockade therapy underlines its potential as a desirable immune-potentiating agent to improve the outcome of cancer immunotherapy. ADT-030 represents a development candidate ready for IND-enabling safety assessment. Citation Format: Md Yeashin Gazi, Ogacheko Okoko, Xin Wang, Caitlin Brandle, Xi Chen, Khalda Fadlalla, Adam Keeton, Yulia Maxuitenko, Catherine Hedrick, Huidong Shi, Gary Piazza, Gang Zhou. ADT-030 is a novel dual-acting RAS/β-catenin inhibitor that potentiates antitumor 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 2459.
Abstract 3193: Utilizing a pH sensitive peptide (pHLIP) for antigen-directed T cell therapy
Authors: Annali M. Yurkevicz, Yanfeng Liu, Peter M. Glazer
Journal: Cancer Research (2024)

Abstract Many targeted therapies, such as antibody drug conjugates (ADCs) and chimeric antigen receptor (CAR) T cell therapies, rely on the identification of an optimal antigen as the cell marker for targeting cancer cells. However, there is a paucity of antigen candidates that are sufficiently specific to epithelial cancers. Therefore, technologies that can mark tumor cells for immune recognition could prove beneficial in the treatment of these solid cancers. pH low insertion peptides (pHLIPs) act as a unique delivery platform that can specifically target the acidic microenvironment of tumors, sparing healthy tissue in the process. We developed a pHLIP-peptide conjugate (pHLIP-SIINFEKL) to deliver the SIINFEKL peptide, an immunogenic fragment of ovalbumin, to investigate antigen delivery and recognition to tumors in vivo. When processed intracellularly, SIINFEKL is presented for immune recognition through the major histocompatibility complex (MHC) class I pathway. We observed selective delivery of pHLIP-SIINFEKL both in vitro and in vivo using fluorescently labeled constructs. In vitro, treatment of melanoma tumor cells with pHLIP-SIINFEKL resulted in recognition by SIINFEKL-specific T cells (OT1), leading to T cell activation and effector function. Mechanistically, we show that this recognition by OT1 cells was abrogated by siRNA knockdown of the β2 microglobulin (β2m) component of MHC class I in the target tumor cells, indicating that an intact antigen processing pathway in the cancer cells is necessary to mediate the effect of pHLIP-directed SIINFEKL delivery. In vivo, pHLIP-SIINFEKL treatment of tumor-bearing mice resulted in recruitment of OT1 T cells and suppression of tumor growth in two syngeneic tumor models in immunocompetent mice, with no effect when mutating either the pHLIP or SIINFEKL components of the conjugate. These results suggest that pHLIP-mediated peptide delivery can provide a novel approach to decorate solid tumors with engineered antigens for enhanced immune recognition and anti-tumor efficacy. Citation Format: Annali M. Yurkevicz, Yanfeng Liu, Peter M. Glazer. Utilizing a pH sensitive peptide (pHLIP) for antigen-directed T cell 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 3193.
Abstract 7198: A small molecule Notch1 inhibitor (ASR490) restores chemosensitivity in triple-negative breast cancer
Authors: Neha Tyagi, Balaji Chandrasekaran, Ashish Tyagi, Balpreet Singh, Megha Chandran, Amandeep Singh, Arun Sharma, Chendil Damodaran
Journal: Cancer Research (2024)

Abstract Metastatic triple-negative Breast cancer (mTNBC) is an aggressive and often a chemo resistant disease for which no effective druggable target has yet been identified. We and others reported that the aberrant expression of neurogenic locus Notch homolog protein 1 (Notch1) serves as a molecular signature for TNBC. Hence, we postulated that pharmacologically targeting Notch1 in conjunction with a standard chemotherapeutic agent (Doxorubicin: DXR) may completely eradicate TNBC growth and overcome systemic and debilitating toxicity. Hence, this study aims to elucidate the role of our recently discovered notch1 inhibitor ASR490 and its ability to chemosensitize TNBC without significant systemic toxicity. In our results, pretreatment of 1/10 th of the inhibitory concentration of ASR490 combined with 1/10 th or 1/20th of DXR significantly inhibited the growth of TNBC cells (MDA-MB-231 and BT549). Notably, DXR treatment induced Notch1 activation which led to chemoresistance in TNBC; however, co-treatment with the Notch1 inhibitor ASR490, led to the downregulation of Notch1 activation and eradication of the cell viability and clonogenicity of the TNBC cells. Further, molecular analysis suggested that pretreatment of 1/10th of ASR490 facilitates DXR-mediated sensitivity, by inhibiting the DNA repair pathway and upregulating (cleaved) caspase 3, (cleaved) caspase-9 and poly (ADP-Ribose) polymerase (PARP)-mediated apoptosis. Similarly, the combination effectively blocked the epithelial and mesenchymal transition (EMT) regulators and suppressed metastatic properties of MDA-MB231 and BT-549 cells. Moreover, combining ASR490(1/10th) and DXR (1/20th) significantly eradicated xenotransplanted TNBC tumors compared to ASR490 or DXR alone. In addition to being effective at inhibiting tumor growth, the significantly lower dose requirements of DXR and ASR490 in combination makes it a highly safe therapeutic modality. These findings suggest that aberrant activation of Notch1 is responsible for TNBC chemoresistance and concomitantly inhibiting Notch1 activation is an effective therapeutic strategy to restore chemosensitivity in TNBC. Citation Format: Neha Tyagi, Balaji Chandrasekaran, Ashish Tyagi, Balpreet Singh, Megha Chandran, Amandeep Singh, Arun Sharma, Chendil Damodaran. A small molecule Notch1 inhibitor (ASR490) restores chemosensitivity in triple-negative breast 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 7198.
Abstract 2334: Computational methods for optimizing marker selection, clonal lineage reconstruction, and longitudinal tracking of clonal dynamics via circulating tumor DNA (ctDNA)
Authors: Xuecong Fu, Yueqian Deng, Zhicheng Luo, William Laframboise, David Bartlett, Russell Schwartz
Journal: Cancer Research (2024)

Abstract Background: Technologies for blood-based profiling of tumor DNA (“liquid biopsy”) have offered great prospects for non-invasive early cancer diagnosis, treatment monitoring, and clinical guidance, but further advances in computational models and data analysis to optimize monitoring protocols and develop liquid biopsy as a robust quantitative assay of tumor clonal evolution. Methods: We propose new computational methods to improve our ability to characterize tumor clonal dynamics from circulating tumor DNA (ctDNA). Our methods address how to apply ctDNA assays most effectively to two distinct questions in profiling tumor clonal dynamics: 1) How to apply longitudinal ctDNA data to refine phylogenetic tree models of clonal evolution, and 2) how to most effectively characterize changes in clonal frequencies that may be indicative of treatment response or tumor progression. We pose these questions computationally in terms of a probabilistic framework for optimally identifying maximum likelihood markers for the preceding tasks and applying measured marker concentrations to their solution. We apply this framework by first evaluating the distribution of plausible clonal lineage models using bootstrap samples over pre-treatment tissue-based genetic variation data, then refining these lineage models and the clonal frequencies we can infer from them over successive longitudinal samples of selected markers. Results: We tested our method on synthetic data under various model assumptions and showed the method to be effective at refining distribution tree models and clonal frequencies over longitudinal samples so as to minimize measures of tree distance relative to the ground truth. We further apply the methods to a real ovarian cancer case and show their ability to develop and refine a clonal lineage model and assess clonal frequencies. Conclusion: Our methods show the power of ctDNA assays in conjunction with computational optimization to lead to improved marker selection, clonal lineage reconstruction, and tracking of clonal dynamics, with potential for more precise and quantitative profiling of tumor progression enabling improved clinical decision-making. Citation Format: Xuecong Fu, Yueqian Deng, Zhicheng Luo, William Laframboise, David Bartlett, Russell Schwartz. Computational methods for optimizing marker selection, clonal lineage reconstruction, and longitudinal tracking of clonal dynamics via circulating tumor DNA (ctDNA) [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 2334.
Abstract 2447: Identification of tumor marker gangliosides for early cancer detection: A mass spectrometry approach
Authors: Rachel Culp-Hill, Collin Hill, Adele Blackler, William Ricketts
Journal: Cancer Research (2024)

Abstract Tumor-marker gangliosides (TMGs) have enormous potential for early-stage cancer detection as diagnostic biomarkers despite being relatively understudied in this context. AOA Dx is focused on the development of a mass spectrometry platform for the quantitation of TMGs in human serum, particularly disialogangliosides GD2 and GD3. The development of a mass spectrometry platform for TMG quantitation may allow for the identification of diagnostic signatures for early-stage cancer detection. Briefly, we monitored fragment moieties characteristic of gangliosides in an untargeted fashion by mass spectrometry. We then identified those differentially altered in cancerous groups compared to normal, and subsequently performed targeted MRM analysis. Through these investigations, we have identified multiple TMGs, specifically multiple types of GD2 and GD3 species characterized by unique lipid tails across different cancer types in human serum from confirmed cancer diagnoses. Other ganglioside classes including GMs and relatively understudied GTs were also identified in this study. Notably, the serum of melanoma and ovarian cancer patients exhibited significantly increased levels of several ganglioside species compared to age-matched healthy serum, highlighting the potential of TMGs as a promising avenue for cancer diagnosis. Further experiments will focus on refining this mass spectrometry method and expand demographic representation to confirm our initial findings and identify additional TMGs of interest. In addition, we intend to apply immune-based platforms such as thin-layer chromatography and ELISA, which have already shown promising results in the detection and quantitation of these compounds. Taken together, AOA Dx is advancing the development of a high-throughput mass spectrometry platform designed for the detection of TMGs, with a primary focus on GD2 and GD3. Our objective is the identification of a diagnostic disease signature for early-stage cancer detection. The validation of this type of diagnostic panel would allow for expedited diagnosis and treatment of cancers currently diagnosed at late stages, ultimately reducing healthcare costs and increasing survival rates. Future research will aim to validate these biomarkers in independent prospective studies. Citation Format: Rachel Culp-Hill, Collin Hill, Adele Blackler, William Ricketts. Identification of tumor marker gangliosides for early cancer detection: A mass spectrometry approach [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 2447.
Abstract 4538: Brigatinib induces synergy with PARP inhibitors through dual inhibition of FAK and EphA2 in high-grade serous ovarian carcinoma
Authors: Julie R. Duffield, Xiaonan Hou, Iman K. McKeon-Makki, Amelia M. Huehls, Benjamin W. Wilson, Anjali Prasad, Xinyan Wu, Scott H. Kaufmann, Larry M. Karnitz, John J. Weroha, Arun Kanakkanthara
Journal: Cancer Research (2024)

Abstract PARP inhibitors (PARPis) have now become a standard of care for high-grade serous ovarian cancer (HGSOC), especially for those with defects in homologous recombination (HR) DNA repair. However, the innate and acquired PARPi resistance in HGSOC poses a significant concern, necessitating the exploration of novel treatment options and strategies. Here we investigated the potential of combining brigatinib—a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved for treating lung cancer—with PARPis as way to enhance PARPi activity in HGSOC. Clonogenic cell survival assays revealed that brigatinib synergizes with PARPis in HR-proficient and -deficient HGSOC cell lines. In subsequent proteomics approaches and cell-based confirmatory studies, we found that brigatnib suppressed tyrosine kinases FAK and EphA2 with reduction in downstream signaling. Follow-up pharmacologic and gene-silencing techniques demonstrated that dual FAK and EphA2 inhibition additively reduces PI3K/Akt and MAPK/ERK cell survival signaling to levels conferring PARPi sensitivity. Additionally, the efficacy of this therapeutic approach on tumor size reduction was assessed in HGSOC patient-derived xenograft (PDX) models, with combination treatment inducing tumor regression more effectively than either agent alone. Overall, our studies unveil a beneficial ALK-independent effect of brigatinib that may offer new avenues for considering its repurposing as a HGSOC therapy. Citation Format: Julie R. Duffield, Xiaonan Hou, Iman K. McKeon-Makki, Amelia M. Huehls, Benjamin W. Wilson, Anjali Prasad, Xinyan Wu, Scott H. Kaufmann, Larry M. Karnitz, John J. Weroha, Arun Kanakkanthara. Brigatinib induces synergy with PARP inhibitors through dual inhibition of FAK and EphA2 in high-grade serous ovarian 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 4538.
Abstract 670: Preclinical candidate LAE120, a novel selective USP1 inhibitor shows effective anticancer and combination activity with PARP inhibitor
Authors: Jintao Wang, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Chaojun Cai, Minhua Zhang, Ming Li, Justin Gu
Journal: Cancer Research (2024)

Abstract The Fanconi anemia (FA) and translesion synthesis (TLS) are DNA damage tolerance and repair pathways that have been found to be regulated by reversible ubiquitination in which ubiquitin-specific protease 1 (USP1) plays a key role. Numerous studies have indicated that USP1 inhibitors have therapeutic effects on tumors with homologous recombination deficiency (HRD), including mutations in BRCA1/2. Due to the emergence of resistance to PARP inhibitors in clinical applications, new strategies are needed to address this issue. Here we present LAE120, a novel, allosteric and highly potent USP1 inhibitor, displayed monotherapy potency and combination activity with PARP inhibitor in HRD cancers. LAE120 has a unique tail group distinct from all the published USP1 inhibitors and is predicted to induce a different conformational change at the USP1 allosteric site. In the biochemical assay, LAE120 strongly inhibited USP1 enzymatic activity with IC50 of 5.6 nM. LAE120 potently inhibited proliferation of BRCA-mutated MDA-MB-436 breast cancer cell (IC50:19 nM) and exhibited anti-proliferative activity in NCI-H1792 (IC50: 69 nM) and K562 (IC50: 38 nM) cell lines. In the xenograft model of MDA-MB-436 cells with BRCA mutations, LAE120 demonstrated robust single-agent tumor inhibitory activity (TGI: 88%, 10 mg/kg BID) and a favorable dose-dependent response (TGI: 106%, 25 mg/kg BID). We also observed strong tumor-inhibition efficacy of LAE120 as a single agent in the K562 xenograft model with Bcr-Abl expression (TGI: 86%, 10 mg/kg BID). Current research indicates that USP1 inhibitors exhibit synergistic activity in combination with PARP inhibitors and re-sensitizes PARP refractory tumors. Similar results have been confirmed in the xenograft model of BRCA-mutated MDA-MB-436 cells. The combination of LAE120 and Olaparib (PARP inhibitor) yielded a more robust and durable anti-tumor efficacy at low dose (TGI: 110%, LAE120, 5 mg/kg BID + Olaparib, 50 mg/kg QD). LAE120 also displayed favorable ADME properties and PK profiles. Preclinical-tox studies indicated the molecule was well tolerated without significant toxicities and hematological observations. Both in vitro and in vivo data strongly support further investigation of LAE120, whether as a single agent or in combination therapy. Citation Format: Jintao Wang, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Chaojun Cai, Minhua Zhang, Ming Li, Justin Gu. Preclinical candidate LAE120, a novel selective USP1 inhibitor shows effective anticancer and combination activity with PARP inhibitor [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 670.
Abstract 6918: Ba/F3-BCR-ABL engineering cell line panel, a useful platform for novel drug discovery
Authors: Guoqian Wang, Yao Peng, Yu Wang, Yao Tang, Jingxiao Xu, Jinying Ning, Feng Hao
Journal: Cancer Research (2024)

Abstract In the past few years, with the great success of Imatinib, the first kinase inhibitor, Imatinib rapidly became the first-line treatment for CML (Chronic myelogenous leukemia) carrying the BCR-ABL mutation. It opened a new chapter in targeted cancer treatment. Despite the increase in overall survival allowed by imatinib, the onset of drug resistance led scientists to investigate imatinib's fine structural mechanism of action to develop new and more effective compounds against mutated forms of Bcr-Abl. 7 BCR-ABL inhibitors have been approved, they are Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib, Olverembatinib, and Asciminib. However, acquired resistance has been a major challenge in the treatment of CML, and some patients still experience disease progression or even death due to drug resistance. BCR-ABL kinase domain mutations are one of the important mechanisms of acquired resistance, with the T315I mutation being the most common type of drug resistance mutation, accounting for approximately 25% of drug-resistant CML cases. Patients with T315I mutations in CML are resistant to all current first- and second-generation BCR-ABL inhibitors. Asciminib is designed as an allosteric inhibitor combined with an ATP-competitive TKI agent, which may hinder the development of mutation-driven acquired resistance or restore efficacy against highly resistant BCR-ABL mutants. Our group has generated 38 Ba/F3-BCR-ABL engineering cell lines as useful models for novel drug discovery in vitro and in vivo, including wild-type BCR-ABL and inhibitors leading drug resistance mutations, such as T315I, E255, Y253, F317, F359. V299, G250, A337T, V468F, and double mutations. Each cell was validated by cell sequencing and cell efficacy verification using approved BCR-ABL inhibitors. The Ba/F3-BCR-ABL engineering cell line panel can be useful for developing and evaluating next-generation BCR-ABL inhibitors and exploring newly acquired resistance mutations in BCR-ABL. Citation Format: Guoqian Wang, Yao Peng, Yu Wang, Yao Tang, Jingxiao Xu, Jinying Ning, Feng Hao. Ba/F3-BCR-ABL engineering cell line panel, a useful platform for novel drug discovery [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 6918.