tbuckley/cabot-search huggingface dataset:
Abstract 2093: Co-treatment with KRAS G12D inhibitor MRTX1133 plus TTFields against human pancreatic and Colorectal cancer cell lines results in synergistic up-regulation of cleaved PARP in KRAS G12D &amp; unexpectedly in KRAS G12V as well
Authors: Vida Tajiknia, Praveen Srinivasan, Maximilian PInho-Schwermann, William MacDonald, Connor Purcell, Wafik El-Deiry
Journal: Cancer Research (2024)

Abstract Background: Both colorectal and pancreatic cancers are major global health issues and among deadliest cancers with great disease burden. The most commonly mutated oncogenic alteration in human cancers is KRAS, which is prevalent in pancreatic malignancies. The KRAS G12D mutation subtype is present in more than 40% of pancreatic ductal adenocarcinoma (PDAC). To this date there is no available targeted therapy options for patients with KRAS subtype mutations. MRTX1133 has been identified as a non-covalent, potent, and selective inhibitor of KRASG12D. This small molecule inhibitor has been shown to suppress KRASG12D signaling in cells and in vivo. Tumor Treating Fields (TTFields) therapy is a novel approach to treating cancer, the electric fields alter the behavior of cancer cells and prevent them from growing and dividing. We hypothesize that the co-application of MRTX1133 with TTFields will enhance the effects of MRTX1133 in PDAC and colorectal cancer (CRC). Martials and Methods: PDAC cell line CFPAC1 with KRAS G12 V mutation and LS513 CRC cell line with KRAS G12D Mutation were treated with same dose of MRTX1133 (500 nM) and were co-treated with 150kHz TTFields. After 48 hours western blot was used to probe for cleaved PARP, cleaved C3, phosphor-ERK and DUSP6. Results: In both KRAS G12D &amp; KRAS G12V cell lines, synergistic upregulation of cPARP was observed following 48-hour co-treatment. Synergistic inhibition of pERK happened in KRAS G12D cell line but no change in pERK level following TTFields or MRTX1133 treatment was seen. Upregulation of cC3 in KRAS G12D happened in only co-treatment conditions. DUSP6 levels increased following MRTX1133 treatment in KRAS G12V cell line. Conclusions: The surprising synergistic upregulation of cPARP in both KRAS G12V and G12D cells following co-treatment of KRAS G12D inhibitor MRTX1133 and TTFields can bring hope for other KRAS mutation subtypes as well as G12D. the increase in cPARP in KRAS G12V with no effect on pERK is particularly interesting and demonstrates the need of more studies to investigate the mechanisms of this synergy. Citation Format: Vida Tajiknia, Praveen Srinivasan, Maximilian PInho-Schwermann, William MacDonald, Connor Purcell, Wafik El-Deiry. Co-treatment with KRAS G12D inhibitor MRTX1133 plus TTFields against human pancreatic and Colorectal cancer cell lines results in synergistic up-regulation of cleaved PARP in KRAS G12D &amp; unexpectedly in KRAS G12V as well [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 2093.
Abstract 1267: Projected impact of liquid biopsy screening strategies with high sensitivity in focused populations and high specificity in broad populations
Authors: Peter B. Bach, Niti U. Trivedi, Lindsey Cotton
Journal: Cancer Research (2024)

Abstract Purpose: Two 'liquid biopsy' cancer screening approaches exist: Focused and Broad. The Focused approach targets specific cancers and populations lacking adequate screening, emphasizing high sensitivity. The Broad approach aims to detect various cancers in the population, prioritizing high specificity to minimize false-positives but potentially compromising sensitivity. The public health impact and testing burden of these approaches remain unexplored. Methods: Projected cancer mortality reduction and annual test volumes are based on published data for liquid biopsy tests. Focused screening is modeled for patients not undergoing guideline-recommended screening for lung, liver, and colorectal cancers. Broad screening is modeled for individuals aged 50-80, assuming the detection of all cancer types. Averted deaths are calculated by combining published mortality reduction estimates or assumed at 20% if not available. Reductions are adjusted for reported test sensitivities. Liquid biopsy cannot prevent deaths from cancers recommended for screening if the person has already undergone the recommended test. Results: Focused and broad screening strategies annually prevented around 20,000 cancer deaths. Focused screening necessitated testing only one-fifth of the people compared to broad screening (30MM vs. 150MM). The projected reduction in mortality for focused testing relied entirely on randomized studies, while the equivalent statistic for the broad strategy was 53%. Conclusions: Equivalent reductions in cancer deaths can be achieved with focused screening at high sensitivity and broad screening at high specificity, with only one-fifth of the testing burden. The influence of false positives in focused testing and false reassurance in broad testing may impact these findings, which could also be influenced by testing and follow-up costs. Table 1 Annual cancer deaths averted (thousands) Focused cancer testing Broad cancer testing Lung 10-12 4-8 Liver 4-5 1 Colorectal 3-4 1 Other screened cancers* Not modeled 1-2 Unscreened cancers Not modeled 6-10 Total 17-20 14-22 Annual test volume (millions) 30 150 *Other screened cancers includes prostate, breast, cervical. Range reflects the application of reported Stage I or overall sensitivity, respectively. Citation Format: Peter B. Bach, Niti U. Trivedi, Lindsey Cotton. Projected impact of liquid biopsy screening strategies with high sensitivity in focused populations and high specificity in broad populations [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 1267.
Abstract 5029: VAF in ctDNA correlated with advanced breast cancer tumor burden and prognosis
Authors: Jianxin Zhong, Huiping Li, Bin Shao, Hanfang Jiang, Xiaoran Liu, Haoran Tang, Shidong Jia
Journal: Cancer Research (2024)

Abstract Purpose: In patients with first-line advanced breast cancer (ABC), the correlation between ctDNA variant allele frequency (VAF) and tumor disease burden, and its prognostic value remains poorly investigated. Methods: This study included patients with ABC diagnosed at Peking University Cancer Hospital who performed ctDNA test before receiving first-line treatment. Baseline plasma samples were collected for assessing ctDNA alterations and VAF with next-generation sequencing. The sum of tumor target lesion diameters (SLD) was measured with imaging methods according to RECIST 1.1 criteria. Results: The final cohort included 184 patients. The median age of the cohort was 49.4 (IQR: 42.3-56.8) years. The median VAF was 15.6% (IQR: 5.4%-33.7%). VAF showed positive correlation with SLD in patients with relatively large tumor lesions (r = 0.314, p = 0.003), but not in patients with small tumor lesion (p = 0.226). VAF was associated with multiple metastasis sites (p = 0.001). Multivariate Cox regression analysis showed that high VAF was associated with shorter overall survival (OS) (HR: 3.519, 95% confidence interval (CI): 2.149-5.761), and first-line progression-free survival (PFS) (HR: 2.352, 95%CI: 1.462-3.782). Conclusion: ctDNA VAF associated with tumor disease burden, and was a prognostic factor for patients with ABC. A combination of ctDNA test and radiographic imaging might enhance tumor burden evaluation, and improve prognosis stratification in patients with ABC. Citation Format: Jianxin Zhong, Huiping Li, Bin Shao, Hanfang Jiang, Xiaoran Liu, Haoran Tang, Shidong Jia. VAF in ctDNA correlated with advanced breast cancer tumor burden and prognosis [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 5029.
Abstract 3611: A patient-derived organoid platform to assess the effectiveness of γδTCR cell therapy in solid tumors
Authors: Andrea Bisso, Rene Overmeer, Sjoerd Baardman, Chris Coomans, Cesar Oyarce, Sylvia F. Boj
Journal: Cancer Research (2024)

Abstract Recent advances in cancer immunotherapy have positively impacted the life expectancy of patients for an extensive range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, building on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when embedded into the extracellular matrix. Patient-derived organoids are generated from healthy and malignant tissues, and they recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity and morphological and functional traits. Cell therapies have achieved positive results in treating haematological cancers. Recently, the unique tumour-targeting properties of γδ T cell receptors have been leveraged to develop safer and more effective strategies. HUB and Gadeta joined efforts to explore the therapeutic potential of GDT002 - i.e. αβ T cells engineered with a Gadeta proprietary new γδTCR - to target solid cancers. A preclinical basket trial was performed using patient-derived organoids from several tumour types (colorectal, breast, head and neck, ovarian cancers) cocultured with GDT002. The results showed broad reactivity of GDT002 against solid tumor PDOs. Interestingly, GDT002 was particularly efficient at killing ovarian cancer-derived PDOs, allowing Gadeta to move GDT002 to clinical trials for this indication confidently. This study reveals that our tumor organoid co-culture with engineered T cells platform holds significant value for the preclinical development of cellular therapies. Citation Format: Andrea Bisso, Rene Overmeer, Sjoerd Baardman, Chris Coomans, Cesar Oyarce, Sylvia F. Boj. A patient-derived organoid platform to assess the effectiveness of γδTCR cell therapy in solid 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 3611.
Abstract 1217: Defining the anti-tumor activity and immune effects of the RASMULTI(ON) inhibitor RMC-7977 in preclinical models of NRAS-mutant melanoma
Authors: Larissa A. Carvalho, Manali S. Phadke, Keiran S. M. Smalley
Journal: Cancer Research (2024)

Abstract Introduction: Mutations in the small GTPase NRAS are the second most common oncogenic driver in cutaneous melanoma, being found in ~25% of cases. Targeted therapy strategies are currently lacking for NRAS-mutant melanoma. Here, we characterized the anti-tumor activity and immune effects of RMC-7977, a RASMULTI(ON) preclinical tool compound, representative of the investigational agent RMC-6236, in preclinical mouse and human models of NRAS-mutant melanoma. Methods: The in vitro potency of RMC-7977 was determined using mouse and human NRAS-mutant melanoma cell lines. Recovery of signaling was quantified by Western Blot and receptor tyrosine kinase (RTK) arrays. In vivo anti-tumor activity of RMC-7977 was determined in two syngeneic mouse melanoma models (SW1 NRASG13D and NRAS#5 NRASQ61R), and tumor immune infiltrate quantified using multiplexed IHC and flow cytometry. Mechanisms of resistance were defined using RNA-seq. Results: RMC-7977 had good activity in vitro against human cancer cell lines and in mouse models of NRAS-mutant melanoma. Time-course studies demonstrated RMC-7977 rapidly inhibited phospho-ERK signaling, which then began to recover after 8 hr of treatment. There was also evidence of adaptive receptor tyrosine kinase signaling by 48 hr. In syngeneic mouse models of NRAS-mutant melanoma, RMC-7977 led to a rapid inhibition of tumor growth, increased expression of tumor MHC class I and PD-L1 and an increase in CD4+ and CD8+ T cell infiltrate into tumors. Therapeutic escape was associated with decreased CD4+ and CD8+ T cell infiltration and increased numbers of immunosuppressive MDSCs. Cells collected from tumors resistant to RMC-7977 in vivo did not show any shift in sensitivity to the inhibitor when re-challenged in vitro, suggesting that the resistance observed in vivo resulted from mechanisms specific to the tumor microenvironment, for example adaptive RTK signaling or immune escape. RNA-seq and IHC analysis suggested that resistance was associated with decreased MHC expression and antigen presentation, as well as reduced co-stimulation of T cells. Combination studies of RMC-7977 with anti-PD-1 are ongoing to identify potential synergistic interactions in these preclinical models. Conclusion: RMC-7977 has anti-tumor activity in syngeneic mouse models of NRAS-mutant melanoma, associated with a robust immune response. Citation Format: Larissa A. Carvalho, Manali S. Phadke, Keiran S. M. Smalley. Defining the anti-tumor activity and immune effects of the RASMULTI(ON) inhibitor RMC-7977 in preclinical models of NRAS-mutant melanoma [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 1217.
Abstract 5054: Optimization and evaluation of an FFPE dual extraction protocol for next-generation sequencing applications
Authors: Rebecca Hong, Jieying Chu, Steven Hsiao, Daniel Whang, Steven P. Rivera, Heng Xie, Jiannan Guo
Journal: Cancer Research (2024)

Abstract Formalin-fixed paraffin-embedded (FFPE) biopsies are highly valuable and widely used tissue specimens for clinical diagnostics. However, obtaining sufficient and high-quality nucleic acid material from limited FFPE samples presents a challenge for downstream molecular analysis, such as next-generation sequencing (NGS). We present an optimized sequential extraction method that generates high-quality DNA and RNA from a single set of input tissues that is automatable and operation-friendly. This workflow performs well with reduced FFPE tissue input and efficiently supports various high-throughput clinical NGS applications. The DNA/RNA yield, quality, purity, and impacts on NGS assay performances were on par or better than an existing validated comparator extraction method. With comparable FFPE input, the new method demonstrated a superior extraction performance with significantly higher yield, quality, and purity. For DNA, NGS libraries were made with two different library preparation methods: a TA-ligation-based method and a single-strand-based method, followed by hybrid capturing and sequencing. The DNA from the new extraction method demonstrated a superior library conversion rate and improved target enrichment uniformity with both chemistries. This provides the potential of reduced input requirements, allowing very limited tissue, such as fine needle aspirate or core needle biopsy, for clinical NGS testing. The sequencing results were highly concordant between the existing and new extraction methods when the extracted DNA was subjected to a validated comprehensive genomic profiling (CGP) clinical test, demonstrating the quality and robustness of the extraction. For RNA, NGS libraries were made following the validated CGP clinical test with hybrid capturing, and the results were comparable between the two extraction methods. In conclusion, an FFPE extraction method was optimized to allow more clinical biopsy samples to be tested with different NGS workflows, providing a better diagnostic value for patient care. Citation Format: Rebecca Hong, Jieying Chu, Steven Hsiao, Daniel Whang, Steven P. Rivera, Heng Xie, Jiannan Guo. Optimization and evaluation of an FFPE dual extraction protocol for next-generation sequencing applications [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 5054.
Abstract 2101: Patient-derived cells (PDCs) and organoids (PDOs) as critical platforms for developing next therapeutic strategies for NSCLC
Authors: Sewon Park, Yunjoo Joo, Ju-hyeon Lee, Mi Ran Yun, Mi Ra Yu, Seung Yeon Oh, Eun Ji Lee, Dong Kwon Kim, Seul Lee, Kyumin Lim, Min Hee Hong, Sun Min Lim, Jii Bum Lee, Byoung Chul Cho
Journal: Cancer Research (2024)

Abstract Purpose: Patient-derived cells (PDCs) and organoids (PDOs) are constructed from pleural effusions to mimic the biological features of patients. In cancer research, PDC/PDOs could be a critical tool because they can recapitulate tumor mutations. Since commercial cell lines have difficulty mimicking the heterogeneity of tumors, PDC/PDOs are widely used for predicting the preclinical drug efficacy. The aim of this study is to show that the PDC/PDOs can be used as effective tools for developing new therapeutic strategy on non-small cell lung cancer (NSCLC). Experimental design: PDC/PDO models from malignant effusions were established as following. We succeeded the establishment with samples which are positive for malignancy in cytology tests and tumor colony formation. Mutations that cell harbors are confirmed by Sanger sequencing, Whole exome sequencing, or RNA-sequencing. Following the patient treatment history, we confirmed how does established patient derived model response to drugs that patient was treated. Results: A total of 54 PDCs and 171 PDOs were established from NSCLC patients, including models harboring EGFR mutations, KRAS mutations, uncommon EGFR mutations. 8 models of PDC and 7 models of PDO harbor various mutations of resistance mechanisms to EGFR-TKIs (T790M, C797S/C797G, MET amplification). Also, 4 models of PDC and PDO harbor uncommon EGFR mutations (EGFR G719S, L861Q, G719C/S768I, G719S/S768I) and 12 models of PDO harbors KRAS mutation. YUO-139 and YU-1092 are patient derived models that harbors uncommon EGFR mutation G719S and L861Q respectively. The models response to afatinib sensitively. IC50 of YUO-139 and YU-1092 to afatinib were 2.1 nM and 23.8 nM respectively. YUO-143 is a PDO model that harbors EGFR E19del/T790M/C797S which was derived from gefitinib and mavelertinib resistant patient revealed sensitivity to BLU-945 (IC50, 43 nM), a novel fourth-generation EGFR-TKI. Conclusions: Patient derived models could be a critical tool for developing therapeutic strategies for NSCLC. Citation Format: Sewon Park, Yunjoo Joo, Ju-hyeon Lee, Mi Ran Yun, Mi Ra Yu, Seung Yeon Oh, Eun Ji Lee, Dong Kwon Kim, Seul Lee, Kyumin Lim, Min Hee Hong, Sun Min Lim, Jii Bum Lee, Byoung Chul Cho. Patient-derived cells (PDCs) and organoids (PDOs) as critical platforms for developing next therapeutic strategies for NSCLC [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 2101.
Abstract 815: Leveraging clinical workflow for rapid integration of social needs assessment in a urologic oncology clinical practice
Authors: Samuel L. Washington, Kim F. Rhoads, Peter R. Carroll, Salma Shariff-Marco, June M. Chan
Journal: Cancer Research (2024)

Abstract Introduction: Social determinants of health and resulting social needs are known to impact cancer care, yet characterization of social needs within a specific clinic’s population remains in its infancy. We aim to characterize early findings from social needs screening in patients seen in a tertiary urologic oncology clinic. Methods: Screening was conducted using survey questions about specific domains of social needs (e.g., financial strain, unmet transportation needs, and food insecurity) that were integrated into new patient and annual follow-up questionnaires for all patients seen within a urologic oncology faculty clinic, starting in January 2023. Screening items were rapidly implemented into workflow by taking advantage of existing processes. Clinical and demographic data and screening responses were abstracted from the electronic medical record. Summary statistics were calculated. P value&amp;lt;0.05 was deemed statistically significant. Results: A total of 2305 patients were included (4% Non-Hispanic Black, 11% Asian American, 8% Latinx, and 63% Non-Hispanic White). Responses increased from 30 in January to 399 in October. Respondent mean age was 67 years [standard deviation (SD) 12.3] with 87.8% identifying as male. Roughly 13% screened positive for at least one social need (one positive 8.1%, two positive 3.4%, three positive 1.2%) with variations by domain [transportation 3.6%, food insecurity 5.4%, 10.2%] and race and ethnicity (Figure 1, p&amp;lt;0.001 for all). Conclusions: By leveraging the existing clinical workflow, rapid uptake of social needs screening demonstrates variations by social needs domains and race and ethnicity within a urologic oncology patient population. These efforts represent institutional action towards characterizing the burdens faced by our patient population and inform the design of interventions to address social needs within the catchment area, to improve clinical care and clinical trial participation. Citation Format: Samuel L. Washington, Kim F. Rhoads, Peter R. Carroll, Salma Shariff-Marco, June M. Chan. Leveraging clinical workflow for rapid integration of social needs assessment in a urologic oncology clinical practice [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 815.