tbuckley/cabot-search huggingface dataset:
Abstract 4621: Dual targeting as an effective therapeutic strategy for malignant brain tumors
Authors: Elle Y. Magnan, Karthik Gourishetti, Sydney Thomas, Deepak Bhere
Journal: Cancer Research (2024)

Abstract Glioblastoma, a type of brain cancer known for its aggressive nature and resistance to traditional treatments, remains a significant challenge for the medical community. Despite advances in surgical, radiation, and chemotherapy strategies, patients with glioblastoma typically have a poor prognosis, with a median survival time of only 15 months. While temporary symptom relief may be possible for some patients, complete tumor remission is often not achieved. Given the complexity of this disease, effective treatment options for glioblastoma are highly sought after. In this study, we have evaluated the effectiveness of a combinatorial approach using stem cell-derived exosomes enriched with miR-124 cargo paired with viral oncolysis for treating glioblastoma. Human Umbilical Cord Stem cells (hUCs) are genetically modified with specific miR plasmids, and then cultivated in a specialized medium that has been depleted of exosomes. The exosomes (exo) that contain the target miR are subsequently extracted, purified, quantified, and characterized. These exosomes are then utilized for all subsequent investigations. Using a combination of cell viability assays and microscopy, the overall effect of the exo-miR-124 and oncolytic virus on both established and patient-derived primary GBM cells is analyzed. Additionally, a time course western blot analysis is conducted to comprehend the molecular mechanisms underlying the effects of the miR modification and viral oncolysis on cell proliferation and death pathways. Orthotopic animal models of GBM will be utilized to assess the effects of miR modulation and viral oncolysis in vivo. Our research has shown that stem cell-derived exosomes are an effective way to deliver microRNA to specific cells, including tumor cells. This is because they can evade the immune system and target cells directly. Our experiments have shown that combining miR modulation paired with viral oncolysis as a promising approach for treating glioblastoma. Specifically, we have found that miR modulation and viral oncolysis can halt tumor cell proliferation in vitro by targeting multiple pathways involved in GBM growth and progression. Citation Format: Elle Y. Magnan, Karthik Gourishetti, Sydney Thomas, Deepak Bhere. Dual targeting as an effective therapeutic strategy for malignant brain tumors [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 4621.
Abstract 2106: Creating a living public oncology drug resource using PRISM cell line viability screening
Authors: Matthew G. Rees, Mustafa Kocak, Claudine Mapa, Dennie Frederick, Ellen Nguyen, Alvin Kalathungal, Anthony Fazio, John F. Davis, Emily Reeves, Ariah Tucci, Rachael Barry, Colleen Harrington, Jillian Eskra, Melissa M. Ronan, William R. Sellers, Jennifer A. Roth
Journal: Cancer Research (2024)

Abstract Cancer treatment options are rapidly expanding, with many new targeted agents and therapeutic modalities under development. However, systematic characterization of the cellular effects of emerging drug candidates is limited. Screening such agents against the approximately 900 diverse cancer cell lines in the PRISM assay can provide insights into drug specificity and cancer subtype selectivity and, leveraging the rich genomic and functional characterization of PRISM cell lines, support for annotated mechanisms of action. Our goal was to generate a large, high-quality, oncology-focused dataset that can benefit the cancer research community by characterizing new test agents of high clinical relevance. In the past year, this effort has been utilized to screen a total of 180 test agents with plans to extend testing to an additional 140 over the next year. The collection includes biologics (e.g., cytokines, antibodies, antibody-drug conjugates), targeted protein degraders, and small molecules. Supporting the quality of the screening collection and the robustness of the PRISM assay, the majority of inhibitors (including mutant-selective KRAS inhibitors, and inhibitors targeting the WRN helicase, a preferential vulnerability in cancers with microsatellite instability) tested to date closely mimic the effects of genetic knockout and/or knockdown of their annotated target, as measured by CRISPR and shRNA data available through the Dependency Map Portal (depmap.org). Further, while we observe strong modality-independent co-clustering of test agents annotated to act on the same target(s) (e.g., tucatinib with the antibody-drug conjugates T-DM1 and T-DXd for HER2), intriguing differences in efficacy and selectivity emerge in individual cell line models. All PRISM reference screening data and analyses will be made publicly available through depmap.org to serve as a benchmark for new drug development candidates and to further the efforts of researchers worldwide to match emerging cancer therapies to the patients most likely to benefit. Citation Format: Matthew G. Rees, Mustafa Kocak, Claudine Mapa, Dennie Frederick, Ellen Nguyen, Alvin Kalathungal, Anthony Fazio, John F. Davis, Emily Reeves, Ariah Tucci, Rachael Barry, Colleen Harrington, Jillian Eskra, Melissa M. Ronan, William R. Sellers, Jennifer A. Roth. Creating a living public oncology drug resource using PRISM cell line viability 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 2106.
Abstract 6463: Highly frequent gene mutations and co-occurring genes analysis in colorectal cancer
Authors: Qinqin Zha, Frank Scarpa, Madhu Rengaraj, Anna Juncker-Jensen
Journal: Cancer Research (2024)

Abstract Background: Colorectal cancer (CRC) is the second most leading cause of cancer-related deaths worldwide. Understanding the molecular alterations that drive CRC is critical for improving patient outcomes. Next-generation sequencing (NGS) has revolutionized CRC molecular profiling by simultaneous analysis of multiple genes with high accuracy and sensitivity. In this study, we analyzed a cohort of CRC formalin-fixed paraffin-embedded (FFPE) samples to identify highly frequent gene mutations and co-occurring genes in CRC. Methods: FFPE samples from CRC patients tested from January 2020 to May 2023 were analyzed using NeoTYPE® Colorectal Tumor Profile. This profile analyzes 44 biomarkers through a combination of NGS focusing on a panel of 36 genes known to be frequently mutated in CRC, as well as 3 FISH and 3 IHC biomarkers. Gene mutation frequency, co-occurring mutation genes and clinical significance were explored and analyzed. In addition, immunotherapy markers, Microsatellite Instability (MSI) and Tumor Mutation Burden (TMB) were assessed. Results: A total of 2,920 patients (1,577 men and 1,343 women) with CRC were included in this study. Average sequence coverage was 2386X with mean minor allelic frequency of 30%. A higher average number of variant allele frequency were observed in metastatic versus primary colorectal cancer (P &amp;lt; .001). We found that APC, TP53, KRAS, PIK3CA and ARID1A were the most frequently mutated genes. APC truncated mutation p. R1450* were the most common mutations. KRAS, PIK3CA and TP53 missense mutations are the prevalent consequence. Notably, a subset of patients exhibited high microsatellite instability (MSI-H) or TMB high, indicating potential eligibility for immune checkpoint inhibitor therapy. In addition, we found APC mutations co-occurring with TP53 or KRAS mutations (p &amp;lt;.001) in our cohort. Conclusion: Our results provide insight into the genetic landscape of CRC and highlight the importance of understanding co-occurring mutations in this disease. Specifically, APC mutations frequently coincide with TP53 mutations, jointly contributing to the onset of CRC. TP53 often play a role in promoting genomic instability and evading mechanisms that regulate cell growth. The identification of highly frequent mutations and co-occurring genes may have important implications for the development of targeted therapies and personalized treatment approaches for CRC patients. Citation Format: Qinqin Zha, Frank Scarpa, Madhu Rengaraj, Anna Juncker-Jensen. Highly frequent gene mutations and co-occurring genes analysis in colorectal 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 6463.
Abstract 2971: A cytosolic growth factor receptor serves as a convergent core of condensates for anabolic activity in cancer and senescence
Authors: Taegyun Kim, Haebeen Choi, Taeyoung Yoon, Chanhee Kang
Journal: Cancer Research (2024)

Abstract Anabolic activity, driven by growth factor signaling, is essential for cellular activities, including cell growth, proliferation, and protein synthesis. Dysregulation of growth factor signaling has been implicated in numerous human pathological conditions, including cancer and aging. Interestingly, cancer cells and senescent cells - two completely different cell fates - are reported to have an increased anabolic activity. Here, we show endosomal condensation of a growth factor receptor as a molecular switch for such anabolic enhancement. Endosomal condensates of a growth factor receptor (ecGFR) exhibit liquid-liquid phase separation (LLPS), acting as a signaling hub locked in the ‘ON’ state by preventing their lysosomal degradation. Furthermore, we identify a regulatory circuit that operates in both cancer and senescence to facilitate the formation of ecGFR and its physicochemical properties. Pharmacological and genetic resolution of ecGFR corrects aberrant anabolism in cancer and senescence, thereby suppressing cancer growth and senescence-associated hyperinflammation in vitro as well as in vivo. Thus, our study provides a convergent anabolic core between cancer and senescence that could be exploited as a therapeutic vulnerability for human pathological conditions associated with aberrant anabolism. Citation Format: Taegyun Kim, Haebeen Choi, Taeyoung Yoon, Chanhee Kang. A cytosolic growth factor receptor serves as a convergent core of condensates for anabolic activity in cancer and senescence [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 2971.
Abstract 4973: Impact of technology on quality of thoracic multidisciplinary cancer conferences
Authors: Opuruiche Ibekwe, Carmelo Gaudioso, Kristopher M. Attwood, Saraswati Pokharel, Charles L. Roche, Chukwumere E. Nwogu
Journal: Cancer Research (2024)

Abstract Background: Complex cancer cases require discussion at Multidisciplinary Cancer Conferences (MCCs) to determine the best management. The study aim was to assess the impact of navify® tumor board solution (NTBS) technology on the quality of information presented, case discussions, and care plans at thoracic MCCs. Methods: Between September 2020 and February 2022, using a before-after study design, we prospectively collected data through direct observation of thoracic MCCs at an academic cancer center. The NTBS technology was introduced in March of 2021. Additionally, we reviewed medical records to assess several factors including the rate of change in care plans as decided by the MCC, compliance of all care plans with national guidelines, and concordance of treatment received with MCC recommendations. Observational data was collected via a validated tool “Metric for the Observation of Decision-Making". We used SAS v9.4 (Cary, NC) for statistical analyses. Results: We identified 151 and 166 thoracic cancer cases before and after implementation of NTBS, respectively. The overall quality of case presentation and discussion, represented by a mean composite score (the summation of individual variables scored on a 1-5 scale, poor to excellent), increased from 56.8 to 82.0 (p&amp;lt;.001). This improvement was also observed across multiple sub-components of the composite score including case history (3.4 vs 4.6), reason for presentation (3.2 vs 4.6), comorbidities/performance status/psychosocial information (2.8 vs 4.2), patient views (1.2 vs 3.3), radiology and pathology presentations (3.5 vs 4.8 and 3.2 vs 4.4, respectively), and contribution from surgical, medical, and radiation oncologists (3.9 vs 4.3, 3.3 vs 3.8, and 3.5 vs 3.8, respectively), as well as the moderation by the MCC chair (4.9 vs 5.0). All these results were statistically significant with p&amp;lt;.001. There was no statistically significant difference between the two cohorts in rate of change in care plans by the MCC, care plan compliance with national guidelines, and concordance of treatment received with MCC recommendations. Conclusion: Technology improves the quality of information and discussion at tumor boards. However, this study did not demonstrate an impact on compliance with practice guidelines. Practitioners should explore the available tumor board technology platforms to optimize the conduct of MCCs in their respective institutions. Citation Format: Opuruiche Ibekwe, Carmelo Gaudioso, Kristopher M. Attwood, Saraswati Pokharel, Charles L. Roche, Chukwumere E. Nwogu. Impact of technology on quality of thoracic multidisciplinary cancer conferences [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 4973.
Abstract 6045: Development and characterization of ATC-324: An AUTOTAC-based androgen receptor degrader for prostate cancer treatment
Authors: Tri Pham, Tae Hyun Bae, Ki Woon Sung, Abdo Najy, Alaleh Zamiri, Hyejeong Jang, Su Ran Mun, Seongho Kim, Dongping Shi, Steven Kregel, Elizabeth Heath, Michael Cher, Yong Tae Kwon, Hyeong-Reh Kim
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) progression is largely driven by the androgen receptor (AR), making it a prime target for therapy. However, therapy resistance often arises due to AR mutations and splice variants, such as AR-v7. AUTOTAC (AUTOphagy-TArgeting Chimera) is a novel protein degradation platform that utilizes the autophagy-lysosomal pathway to selectively degrade disease-causing proteins. In this study, we characterize ATC-324, an AUTOTAC-based AR degrader designed for the treatment of PCa. ATC-324 comprises enzalutamide linked to YT 6-2, a small molecule activator of the autophagy receptor p62/SQSTM1. ATC-324 induces the formation of the AR/p62 complex while activating autophagic flux, leading to the autophagy-lysosomal degradation of AR. To characterize ATC-324, we employed various AR-dependent, AR-null, and enzalutamide-resistant PCa cell lines. Given that bone metastasis is a major clinical complication of castrate-resistant PCa associated with greater morbidity and mortality, we utilized the bone-in-culture array (BICA) assay, an ex vivo bones culture model, to investigate the impact of ATC-324 on PCa cell survival and growth in the bone microenvironment. We demonstrated that ATC-324 effectively degrades wild-type, mutant, and splice variants of AR. In addition, ATC-324 induces AR-dependent apoptosis and cytotoxicity. Importantly, ATC-324 maintains its potency in enzalutamide-resistant PCa cells. Utilizing the BICA assay, we showed that ATC-324 exhibits cytotoxicity against 22Rv1 bone micrometastases at even lower concentrations than in 2D cell culture. In conclusion, our study demonstrates the successful development and characterization of ATC-324 as a potent and selective degrader of various forms of AR. Furthermore, its effectiveness against enzalutamide-resistant cells indicates its capability to overcome therapy resistance. The observed cytotoxicity against bone micrometastases suggests a therapeutic potential for combating bone metastasis, a major complication of castration-resistant PCa. Our study underscores the potential of the AUTOTAC platform to selectively degrade disease-causing proteins Citation Format: Tri Pham, Tae Hyun Bae, Ki Woon Sung, Abdo Najy, Alaleh Zamiri, Hyejeong Jang, Su Ran Mun, Seongho Kim, Dongping Shi, Steven Kregel, Elizabeth Heath, Michael Cher, Yong Tae Kwon, Hyeong-Reh Kim. Development and characterization of ATC-324: An AUTOTAC-based androgen receptor degrader for prostate cancer treatment [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 6045.
Abstract 4321: The oncogenic DMTF1β splice variant promotes autophagy-dependent cancer cell motility
Authors: Mario P. Tschan, Jun Xu, Anna M. Bill
Journal: Cancer Research (2024)

Abstract The oncogenic isoform DMTF1β, which is generated by alternative splicing of the DMTF1 tumor suppressor gene is associated with increased cell proliferation and tumorigenesis. Despite these correlative findings little is known about the DMTF1β mechanism of action. In order to decipher the oncogenic DMTF1β signaling pathway, we performed RNA sequencing of DMTF1β depleted prostate cancer cells and analyzed the DMTF1β-specific protein interactome in these cells. Interestingly, autophagy-related pathways belonged to the most downregulated networks in DMTF1β knockdown cells. Moreover, we found that predominantly DMTF1β, but not a protein lacking the β-specific domain interacts with the key autophagy ULK1-ATG13 protein complex. These interactions were confirmed by co-immunoprecipitation and proximity ligation assays. Importantly, DMTF1β binding to ULK1 stabilized this key autophagy protein. Accordingly, knocking down DMTF1β significantly lowered autophagic flux in breast and prostate cancer cells as assessed by LC3-dependent and independent autophagy assays. Since published data show an important role for autophagy in migration and invasion of cancer cells, we next investigated whether DMTF1β is regulating these cellular processes. Indeed, DMTF1β depleted breast and prostate cancer cells displayed significantly decreased wound closure, trans-well invasion and metastatic foci formation in a zebra fish xenograft model. Importantly, pharmacological inhibition of ULK1 kinase activity or knocking down ULK1 reversed DMTF1β-mediated cancer cell migration. In agreement, decreased cell motility in DMTF1β knockdown cancer cells could be rescued by ectopic expression of the VPS34 complex member Beclin-1. In summary, we identified a novel DMTF1β-ULK1 signaling pathway that activates aberrant cancer cell migration most probably by increasing basal cell autophagy. Targeting autophagy using ULK1 inhibitors may represent a promising strategy to lower metastatic activity of tumor cells. Citation Format: Mario P. Tschan, Jun Xu, Anna M. Bill. The oncogenic DMTF1β splice variant promotes autophagy-dependent cancer cell motility [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 4321.
Abstract 1216: Pan-RAS inhibition by a tumor-targeted biotherapeutic
Authors: Greg L. Beilhartz, Huazhu Liang, Molly Udaskin, Christine Ng, Nikolina Radulovich, Roman A. Melnyk
Journal: Cancer Research (2024)

Abstract Oncogenic RAS signaling drives tumor growth in about 30% of human malignancies. In recent years the first mutant-specific inhibitors of KRAS G12C (sotorasib and adagrasib) entered the clinic. While some durable responses were noted in KRAS-mutant non-small cell lung cancer, the clinical experience of KRAS G12C inhibitors is marked by rapid drug resistance, either intrinsic or acquired, causing re-activation of the MAPK pathway. Common resistance mechanisms include compensatory signaling through the related RAS isoforms NRAS and HRAS, as well as the selection of non-G12C KRAS mutations, among others. The bacterial peptidase RRSP potently cleaves all RAS mutants and isoforms in the conserved Switch I region. We have shown that receptor-mediated intracellular delivery of RRSP using an engineered protein delivery system (RASx) can inactivate all RAS signaling in a cell, causing apoptosis in RAS-addicted tumor cells in vitro and in vivo. Since systemic pan-RAS inhibition is not likely to be tolerated therapeutically, precise tumor targeting is a necessary feature of a true pan-RAS inhibitor. Here, we describe the unique ability of the RASx system to specify the cell surface receptor used by RRSP to enter cells, allowing exquisite targeting and killing of KRAS, NRAS and HRAS-driven tumor cells while sparing healthy tissues. We screened a panel of patient-derived tumor organoids (PDOs), to demonstrate broad tumor cell killing across pancreatic and colorectal cancer-derived PDOs. 97% of KRAS mutant organoids were sensitive to RASx, independent of the specific mutation. Intriguingly, 46% of wildtype RAS PDOs were sensitive to RASx, including organoids with activating mutations in EGFR. In contrast, PDOs with mutations downstream of RAS such as BRAF V600E were resistant to RASx. Indeed, RASx is effective not only against RAS-addicted tumors, but also wildtype RAS tumors driven by upstream receptor tyrosine kinases, potentially expanding the clinical utility of this platform. RASx is a first-in-class, tumor-targeted pan-RAS inhibitor that represents a unique entry into the growing armamentarium against oncogenic RAS. Citation Format: Greg L. Beilhartz, Huazhu Liang, Molly Udaskin, Christine Ng, Nikolina Radulovich, Roman A. Melnyk. Pan-RAS inhibition by a tumor-targeted biotherapeutic [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 1216.