tbuckley/cabot-search huggingface dataset:
Abstract 3083: Unveiling the role of chemotherapy-resistant, slow-cycling cancer cells in driving cancer cachexia
Authors: Jaebeom Cho, Ho-Young Lee
Journal: Cancer Research (2024)

Abstract Cancer cachexia, a systemic disease marked by substantial, involuntary weight loss, predominantly affecting muscle and adipose tissue, manifests in patients with advanced-stage cancer. The emergence of cancer cachexia poses significant challenges to cancer treatment, diminishing the efficacy of anticancer medications, and the resultant muscle loss adversely impacts the daily lives of patients, diminishing the overall quality of life. Notably, cancer cachexia is implicated in 30-40% of cancer-related deaths, underscoring the pivotal need to comprehend its underlying principles and propose apt interventions to enhance both survival rates and the well-being of cancer patients. Based on our previous findings, cancer cells exhibiting a slow cell cycle, resistant to widely employed clinical chemotherapy agents, exhibit the formation of proinflammatory tumor microenvironment. The escalation of systemic inflammatory cytokines has long been suggested as a potential mechanism contributing to cancer cachexia. Building upon these insights, we hypothesized that slow-cycling cancer cells (SCCs) featuring resistance to chemotherapy are pivotal contributors to cancer cachexia. We investigated the impact of drug-resistant SCCs on the loss of differentiated myotubes and lipid droplets in vitro and muscle and fat loss in in vivo conditions. Interestingly, these cells induced more severe muscle and fat losses. Upon scrutinizing this cell population, we found the overexpression of a particular membrane protein, Protein A. The increase of this Protein A enhanced the release of exosomes from the cell through a novel mechanism distinct from its classical functions, consequently amplifying the release of inflammatory substances originating from cancer cells. In summary, our study elucidates that chemotherapy-resistant cancer cells, characterized by a slow cell cycle, intensify the secretion of inflammatory substances in a manner contingent upon the overexpression of a membrane protein A, which leads to the depletion of muscle and fat located in the distal peripheral regions. Citation Format: Jaebeom Cho, Ho-Young Lee. Unveiling the role of chemotherapy-resistant, slow-cycling cancer cells in driving cancer cachexia [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 3083.
Abstract 5081: Immune sensitization of melanoma to checkpoint inhibitor therapy using acoustically active nanoparticles
Authors: Michael Ian Henderson, Li Xiang, Samuel Drennan, Xin Yi, Jared Fischer, Adem Yildirim
Journal: Cancer Research (2024)

Abstract Advanced melanoma remains the most fatal form of skin cancer with novel therapeutic approaches required to treat inoperable metastatic lesions. While immunotherapies have shown promise in improving long-term melanoma survival, its treatment efficacy is limited, with only 50% of patients responding. Focused ultrasound (FUS) offers as a non-invasive strategy for targeted tumor ablation, thereby strengthening immunotherapy efficacy by release of tumor associated materials. However, control over tumor material release through FUS, without causing excessive thermal damage to surrounding healthy tissue remains challenging. To address this challenge, our group has previously developed acoustically active nanoparticles (AANPs) responsive to low intensity ultrasound for mechanical tumor ablation by generating strong and durable acoustic cavitation in the tumor tissue. Building upon previous success with AANPs, our current work focuses on sensitizing melanoma tumors to checkpoint inhibitor therapy by releasing tumor antigens into circulation using AANPs and FUS. Our findings revealed sensitization of an immunologically cold B16-F10 metastatic melanoma tumors following treatment, which resulted in a notable 12-day stall in tumor growth. When combined with immune checkpoint inhibitors α-PD-L1 and α-CTLA-4, this approach showed a complete response in B16-F10 bearing mice with impressive memory immune response upon a tumor rechallenge. Herein, these novel AANPs represent a promising advancement to enable accurate immune surveillance by boosting the release of tumor antigens and offers new strategies for improved immunotherapy of melanoma and other solid tumors. Citation Format: Michael Ian Henderson, Li Xiang, Samuel Drennan, Xin Yi, Jared Fischer, Adem Yildirim. Immune sensitization of melanoma to checkpoint inhibitor therapy using acoustically active nanoparticles [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 5081.
Abstract 3096: CETSA Navigate HT: A new paradigm for high-throughput screening
Authors: Helena Almqvist, Victoria Brehmer, Laurence Arnold, Tomas Friman, Stina Lundgren, Daniel Martinez Molina
Journal: Cancer Research (2024)

Abstract The CEllular Thermal Shift Assay (CETSA) technology is a powerful way to assess target engagement across various matrixes. By the introduction of the high-throughput format (CETSA Navigate HT), this technology offers a reliable high-throughput screening method in natural cellular environments that can successfully be applied in compound screening for hit identification and confirmation already during lead generation. Due to its broad applicability to native, full length protein targets in the live cellular environment, without the need for expensive and time-consuming protein and/or compound labelling efforts, CETSA Navigate HT may be regarded as a new paradigm for high-throughput screening and actives generation. As a case study to demonstrate the applicability of CETSA Navigate HT in hit identification, we have applied the technology for primary screening of a 12000 compound library for CDK4, a protein targeted in several cancers. Hits identified from this screen are privileged from the onset by binding to the target in a physiologically relevant cellular matrix and in a binding-mode agnostic way. This is in contrast to traditional screening methods targeting activity or in vitro interactions where cellular activity is addressed in later stages. Data from follow up studies using functional assays will be presented as well as mass spectrometry based CETSA selectivity profiling and comparison to commercially available de novo CDK4/6 inhibitors. Citation Format: Helena Almqvist, Victoria Brehmer, Laurence Arnold, Tomas Friman, Stina Lundgren, Daniel Martinez Molina. CETSA Navigate HT: A new paradigm for high-throughput screening [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 3096.
Abstract 4167: Selective imaging of cancer-associated fibroblasts in the breast cancer microenvironment with near-infrared fluorescent probes
Authors: Megan S. Michie, Junwei Du, Jiayu (Jennifer) Ye, Kathleen Duncan, Mikhail Y. Berezin, Samuel Achilefu
Journal: Cancer Research (2024)

Abstract Tumors consist of a complex mixture of resident and infiltrating cells that can support their survival and evasion of treatment. Selective detection of genetically stable cells in the tumor microenvironment (TME) offers insight into tumor biology beyond the malignant cells, which are the focus of most molecular imaging approaches to cancer detection. Motivated by the goal of non-invasively understanding the primary breast TME, we have developed fluorescent molecular probes that target cancer-associated fibroblasts (CAFs), a major component of the stromal compartment of many tumors, and emit light in the near-infrared (NIR) spectral window, providing access to deeper tissues than visible probes. We synthesized and characterized a series of CAF-targeted antibody- and small molecule-based fluorescent imaging agents utilizing a highly hydrophilic NIR dye and ligands that target Fibroblast Activation Protein (FAP). FAP is a key cell-surface marker of breast cancer CAFs with an S1 phenotype, which are modulators of immunosuppression, metastatic spread, and are associated with worse outcomes, especially in HER2+ and triple-negative breast cancer. Modifications to the chemical structure of the linker and targeting ligands allowed us to alter the specificity and brightness of the CAF-probes in cellulo. Imaging of a co-implanted tumor model of SKBR3 human breast cancer cells and FAP expressing fibroblasts after administering our lead small-molecule CAF imaging agent revealed selective tumor targeting of CAF-rich tumors compared to cancer cell predominant tumors with favorable pharmacokinetics and tumor-to-background ratio (TBR) greater than 2. Similar imaging studies with MMTV-PyMT transgenic mice, an established murine model of breast cancer, showed analogous enhanced uptake in mammary tumors (TBR &amp;gt; 2) and clearance over 24 hours. NIR fluorescence also correlated with CAFs isolated from PyMT tumor tissue via flow cytometry, consistent with our hypothesis that this agent can specifically detect endogenous CAFs. This study identified a novel, bright, and water-soluble FAP-specific NIR agent for in vivo imaging, setting the stage for simultaneous optical imaging of malignant cells and activated fibroblasts in the TME to elucidate cancer-host interactions. Citation Format: Megan S. Michie, Junwei Du, Jiayu (Jennifer) Ye, Kathleen Duncan, Mikhail Y. Berezin, Samuel Achilefu. Selective imaging of cancer-associated fibroblasts in the breast cancer microenvironment with near-infrared fluorescent probes [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 4167.
Abstract 4767: Changes in the NSE and S100B levels following treatment with peripheral neuropathy-inducing drugs
Authors: Priya R. Vontikommu, Shriya Selvakumar, Umamaheshwari Natarajan, Appu Rathinavelu
Journal: Cancer Research (2024)

Abstract Neo-adjuvant chemotherapy is considered the standard of care for patients with multiple myeloma (MM). Peripheral neuropathy (PN) is one of the most common chemotherapy-induced side effects that impact 50% of all patients who receive chemotherapy and can lead to discontinuation of drug treatment. Treatment with Bortezomib (BTZ), Cisplatin (CIS), and Vincristine (VIN) has been established as the most common trigger of Chemotherapylnduced Peripheral Neuropathy (CIPN) among cancer patients. Since CIPN can lead to disabling long-term adverse effects, many cancer patients discontinue or limit their treatment regimen once they see signs or symptoms of CIPN. Therefore, it was hypothesized that developing diagnostic/prognostic biomarkers that can accurately predict the onset or progression of CIPN would help to determine the chemotherapy eligibility with the above-mentioned drugs and proactively prepare for protective care. Hence, our initial goal was to elucidate the molecular mechanisms underlying the onset and progression of CIPN that would allow for the identification of suitable biomarkers that can be used for monitoring before or during chemotherapy with BTZ, CIS, and VIN. Initially, we conducted in vitro studies to identify the underlying molecular mechanisms activating CIPN related pathways. We used neuronal Schwann cells (RT4), for testing the neurotoxic effects of BTZ, CIS, and VIN that might precede or coincide with the onset of CIPN in an in vivo condition. Interestingly, the BTZ treatment was able to significantly reduce the intracellular level of NSE and S100B in RT4 cells compared to the untreated controls, when they were measured using an immunofluorescence assay and Western blot. Furthermore, we conducted an in vivo study to determine the CIPN using rats. We used the sciatic nerve (SN) from drug-treated animals to check the S100B level using the ELISA method. Our preliminary results showed that levels of S100B in the SN of Rats were reduced following 8 weeks of treatment with the PN-inducing chemo drugs. We anticipate that this study will enrich our understanding of how chemotherapy medications induce PN in cancer patients and guide us to identify reliable biomarkers (This project was supported by the PFRDG grant of the Nova Southeastern University, Ft. Lauderdale Florida, and the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida). Citation Format: Priya R. Vontikommu, Shriya Selvakumar, Umamaheshwari Natarajan, Appu Rathinavelu. Changes in the NSE and S100B levels following treatment with peripheral neuropathy-inducing drugs [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 4767.
Abstract 4134: The abscopal effect of combination IRE with αPD-1 treatment against PDACs
Authors: Qizhen Cao, Nicholas A. Egan, Weiyi Peng, Chun Li
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with a high capacity of metastatic dissemination, which results in a dismal 5-year relative survival rate. Irreversible electroporation (IRE) represents an innovative intervention utilizing short high-voltage electric pulses to induce cell death through either permanent membrane lysis or disruption of cellular homeostasis. Previous studies from our lab have demonstrated that the combination of IRE and immune checkpoint blockade using anti-PD-1 antibody (αPD-1) enhances the infiltration of CD8+ cytotoxic T cells, significantly prolonging survival in an orthotopic murine PDAC model. However, the impact of IRE/αPD-1 on metastatic PDAC tumors, known as the abscopal effect, remains unclear. In this investigation, we bilaterally implanted C57BL/6J mice with subcutaneous KRAS* PDAC tumors, treating the right flank tumors with or without IRE, in conjunction with or without αPD-1 administered intraperitoneally. Tumor growth in both the treated (with or without IRE) and untreated (abscopal) left flank tumors was closely monitored until humane euthanasia or long-term survival. In a separate study, mice serum and tumor tissues were collection on the 5th day post-IRE/αPD-1 treatment. Luminex cytokine assays were conducted on the collected serum, and immunostaining was performed on tumor tissue. Results demonstrated significantly enhanced antitumor activity in both IRE-treated and untreated tumors on mice treated with combined IRE and αPD-1, leading to a marked extension of overall survival. Luminex cytokine assays revealed a substantial increase in crucial cytokines, including IL-2, IFN-gamma, IL-18, IL-19, and IL-3, known for their pivotal roles in fostering cytotoxic T lymphocyte development, promoting T cell differentiation into effector T cells, and facilitating the recruitment of effector CD8+ T cells to the tumor microenvironment. Moreover, immunofluorescence staining of tumor tissue illustrated a notable accumulation of CD169+ macrophages in IRE-treated tumors compared to untreated tumors. Tumors from the combined IRE with αPD-1 group exhibited increased CD8+ T cell accumulation compared to other groups. These data suggest IRE combined with PD-1 blockade promotes robust antitumor immune, leading to systemic antitumor activity and robust abscopal effect. Citation Format: Qizhen Cao, Nicholas A. Egan, Weiyi Peng, Chun Li. The abscopal effect of combination IRE with αPD-1 treatment against PDACs [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 4134.
Abstract 4148: Extracellular matrix biophysical properties change during nevus to melanoma progression
Authors: Aditya Kavuturu, Maira A. Constantino, Antonella Sassano, Glenn Merlino
Journal: Cancer Research (2024)

Abstract Cutaneous malignant melanoma is one of the most aggressive forms of skin cancer and its major etiological risk factor is ultraviolet (UV) solar radiation. The extracellular matrix (ECM) has been shown to influence many of the hallmark characteristics of tumor development, survival, and progression across several types of cancer, including melanoma. Interactions between the tumor and the ECM often results in rearrangement, cross-linking, and deposit of specific ECM proteins, which can contribute to stiffening of the tissue and tumorigenesis. To simulate tumorigenesis, we have previously used a hepatocyte growth factor (HGF) transgenic mouse model, which develops melanoma nevii when exposed to UVB radiation. This model is highly representative of human melanoma lesions in terms of biological, genetic, and etiologic criteria. In general, microrheology involves injecting beads into a medium, tracking movement of the beads using two-photon microscopy, and using the movement to calculate the viscosity and elasticity of the medium. The physical properties of the ECM during tumorigenesis have not been well studied at the cellular level, and microrheology has rarely been used in vivo. In our in vivo microrheology study, we injected fluorescent beads into the skin of these transgenic mice. Then, we used intra-vital microscopy with particle tracking to image the beads and measure changes in ECM elasticity as nevii grow into melanoma tumors. These results, combined with transcriptomic analysis of ECM regulation and proteomic analysis of ECM signaling, could provide unique insights into components of the extracellular matrix that are involved in melanoma tumor development and offer opportunities for therapeutics to target oncogenesis. &amp;lt;!–EndFragment–&amp;gt; Citation Format: Aditya Kavuturu, Maira A. Constantino, Antonella Sassano, Glenn Merlino. Extracellular matrix biophysical properties change during nevus to melanoma progression [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 4148.
Abstract 418: BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response
Authors: Aravind M. Krishnan, Haoyang Jiang, Tianpeng Zhang, Hardeep Kaur, Tao Shi, Youngho Kwon, Patrick Sung, Roger A. Greenberg
Journal: Cancer Research (2024)

Abstract The Bloom Syndrome helicase (BLM) is critical for Alternative Lengthening of Telomeres (ALT), a homology directed repair mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT positive cells to assemble a replication stress associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2 commensurate with the appearance of telomere C-strand specific single-stranded DNA. Moreover, DNA2 nuclease deficiency increased 5’-lagging strand flap formation and ALT in a BLM dependent manner, and BLM promoted ALT in response to telomere C-strand, but not G-strand, single-stranded nicks. These findings define the seminal events in the ALT DNA damage response, linking aberrant lagging strand DNA replication with a BLM directed HDR mechanism that sustains telomere length in a subset of human cancers. Citation Format: Aravind M. Krishnan, Haoyang Jiang, Tianpeng Zhang, Hardeep Kaur, Tao Shi, Youngho Kwon, Patrick Sung, Roger A. Greenberg. BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage 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 418.
Abstract 415: Keratin-fusion mutation promotes tumor aggressiveness via genomic instability induction
Authors: Hsiang-Hao Chuang, Brian Yu-Ting Kuo, Kalpana Sriramadasu, Yi-Che Chen, Jim Jinn-Chyuan Sheu
Journal: Cancer Research (2024)

Abstract Keratin intermediate filament is one critical component of cellular architectures, which provides necessary mechanical support to vanquish environmental stresses. Our previous study shows that keratin fusion mutation promotes tumor aggressiveness via enhancing cancer stemness in oral squamous cell carcinoma. It implies proper functions of keratins play a critical role in maintain cell integrity and fate determination. In the present study, keratin fusion mutation functions as a driver to promote genomic instability via centrosome overduplication and trigger the formation of polyaneuploid cancer cell (PACC). Interestingly, genes involved in DNA damage repair were found upregulated in keratin fusion expressing cells, an important feature for mitotic slippage during cancer progression. In addition, PACCs caused by keratin fusion render cancer cells insensitive to cisplatin treatment, which coupled with lower levels of γH2AX induction and higher survival rates. Transcriptome analyses revealed enhanced activity for Regulation_of_Actin_Cytoskeleton in the PACCs, leading to increased actin filament network and higher invasiveness. In summary, keratin fusion mutation promote cancer aggressiveness through genomic instability-mediated PACC formation and cytoskeleton remodeling, which lead to enhanced drug resistance and metastasis. Citation Format: Hsiang-Hao Chuang, Brian Yu-Ting Kuo, Kalpana Sriramadasu, Yi-Che Chen, Jim Jinn-Chyuan Sheu. Keratin-fusion mutation promotes tumor aggressiveness via genomic instability induction [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 415.