tbuckley/cabot-search huggingface dataset:
Abstract 910: Clinical inference and biological dissection of tumor ploidy and heterogeneity in cutaneous melanoma for immunotherapy response using deep learning
Authors: Marc Glettig, Giuseppe Tarantino, Tyler Aprati, Haitham Elmarakeby, David Liu
Journal: Cancer Research (2024)

Abstract Background: Tumor ploidy and heterogeneity demonstrated to be pivotal in predicting immunotherapy response in cutaneous melanoma in several independent cohorts (Liu NatMed2019, Tarantino BioRXiv2022). Their estimation can guide more personalized and rational utilization of these immunotherapies. However, 1) the biology underpinning ploidy and heterogeneity is unknown; and 2) these findings were derived in patients using retrospective research tumor-normal paired whole exome sequencing which is not performed for clinical management. Methods: This study addresses this gap by employing deep learning models to predict these crucial markers using routinely available clinical assays, including H&amp;E images. Attention-based computer vision models enable the identification of key morphological features in H&amp;E slides. Segmentation of tumor tissue to perform automated masking, enhances ploidy inference.Moreover, biologically informed neural networks (P-Net, Elmarakeby Nature2021) uncover transcriptional and genomic features linked to ploidy and tumor heterogeneity. Our models are trained on publicly available data (e.g., Liu et al Nature Medicine 2019; TCGA SKCM) from melanoma cohorts and further validated in independent cohorts to ensure robustness. Results: We developed and validated automated tumor tissue masking, enabling the prediction of Whole Genome Doubling (WGD) from H&amp;E Slides with an AUC &amp;gt; 0.75. Attention-based models identify distinct Tumor Microenvironment (TME) structures predictive of high tumor heterogeneity. P-Net application revealed the Calmodulin pathway, previously associated with regulating proliferation in cancer and targeted with chemotherapy, as intricately linked to high tumor heterogeneity, providing valuable insights into underlying mechanisms. Conclusion: In conclusion, our study strategically harnesses and integrates existing datasets to rigorously test, refine, and validate hypotheses concerning the biological and therapeutic implications of genomic heterogeneity and ploidy. Notably, our predictive models with automated tumor masking demonstrate a remarkable AUC &amp;gt;0.75 for biomarkers traditionally challenging to derive from clinical assays. This breakthrough opens avenues for novel therapeutic strategies targeting genomic heterogeneity and ploidy, providing a transformative potential to enhance patient care and outcomes. Citation Format: Marc Glettig, Giuseppe Tarantino, Tyler Aprati, Haitham Elmarakeby, David Liu. Clinical inference and biological dissection of tumor ploidy and heterogeneity in cutaneous melanoma for immunotherapy response using deep learning [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 910.
Abstract 7167: Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung cancer
Authors: Stephanie M. Kong, Mukul Minocha, Po-Wei Chen, Pablo Martinez, Erik S. Anderson, Amanda Parkes, Brett E. Houk, Chih-Wei Lin
Journal: Cancer Research (2024)

Abstract Background: Tarlatamab is a first in class, half-life extended delta-like ligand (DLL3) targeted bispecific T-cell engager (BiTE) immunotherapy that has shown antitumor activity with durable objective responses and promising survival outcomes in the ongoing studies in patients with previously treated small-cell lung cancer (NCT03319940, NCT05060016) (Ahn et al, 2023; Paz-Ares et al, 2023). Here we describe the effects of patient specific factors [age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status, emergence of anti-drug antibodies (ADA)] on tarlatamab exposures. Methods: Tarlatamab serum concentrations were available from 420 subjects (8509 samples) pooled across the ongoing Phase 1 DeLLphi-300 study (dose range 0.003 mg to 100 mg Q2W and 200 mg Q3W) and Phase 2 DeLLphi-301 study (10 mg and 100 mg Q2W). The data were analyzed using a nonlinear-mixed effects modeling approach implemented in NONMEM (v7.5) software. Model selection and evaluation was guided by standard statistical and graphical approaches. Impact of key baseline demographic variables on tarlatamab clearance and volume of distribution were evaluated. Results: Tarlatamab exposures increased in a dose-proportional manner and were not impacted by age, sex, ethnicity, estimates of renal and hepatic function, prior lines of therapy or baseline disease status. Asian race resulted in 14% higher peak serum concentrations relative to Caucasian subjects. Higher body weight (99 kg; 90th percentile) was associated with a 24% decrease in Day 28 pre-dose concentration (Ctrough) relative to median bodyweight (73 kg). Lower body weight (54 kg; 10th percentile) was associated with a 27% increase in Ctrough relative to median bodyweight. Positive ADA status resulted in a 24% decrease in Ctrough. However, at the recommended dose of 10 mg Q2W, neither body weight nor ADA status had a clinically relevant impact on tarlatamab efficacy or safety measures (Ahn et al, 2023). Conclusion: Overall, based on these analyses, no dose adjustment for tarlatamab is required based on age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status or emergence of ADA. Citation Format: Stephanie M. Kong, Mukul Minocha, Po-Wei Chen, Pablo Martinez, Erik S. Anderson, Amanda Parkes, Brett E. Houk, Chih-Wei Lin. Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung 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 7167.
Abstract 6066: An inhibitor of deubiquitinating enzyme UCHL5/USP14, VLX1570, enhances the cytotoxic effects of temsirolimus by suppressing PCNA in uuman renal cell carcinoma
Authors: Kuan-Lin Kuo, Po-Ming Chow, Chen-Hsun Hsu, Shih-Ming Liao, Yen-Ling Chiu, Jun-Ren Dong, Tzu-Yao Ke, Kuo-How Huang
Journal: Cancer Research (2024)

Abstract Renal cell carcinoma (RCC) is a common type of kidney cancer. The overall 5-year survival rate is 74%, but it drops to only 8% for Stage 4 cancers. Several treatments are available for metastatic RCC, including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors. However, these treatments have limited success. VLX1570 is an inhibitor of deubiquitylating enzymes UCHL5/USP14 that is currently in Phase I clinical trials. It has shown promise in various cancer models, but its effects on RCC have not been reported. This study investigated the impact of UCHL5/USP14 expression on tumor progression and patient survival in a clinical cohort. The results showed that VLX1570 induced apoptosis and cell cycle arrest in RCC cells, leading to reduced cell viability. Additionally, VLX1570 synergized with temsirolimus in vitro, likely by inhibiting PCNA. Moreover, the combination treatment suppressed tumor growth in vivo more effectively than either VLX1570 or temsirolimus alone. These findings suggest that UCHL5/USP14 plays a role in RCC progression and prognosis, making it a promising therapeutic target for overcoming drug resistance in this cancer. Citation Format: Kuan-Lin Kuo, Po-Ming Chow, Chen-Hsun Hsu, Shih-Ming Liao, Yen-Ling Chiu, Jun-Ren Dong, Tzu-Yao Ke, Kuo-How Huang. An inhibitor of deubiquitinating enzyme UCHL5/USP14, VLX1570, enhances the cytotoxic effects of temsirolimus by suppressing PCNA in uuman renal cell 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 6066.
Abstract 2045: Novel TFRC humanized mouse model for drug delivery to the brain
Authors: Fabiane Sonego, Angela Pappalardo, Gaëlle Martin, Burak Ozgür, Peter Ravn, Yacine Cherifi, Florence Sotty, Patricia Isnard-Petit, Kader Thiam
Journal: Cancer Research (2024)

Abstract Gliomas are the most common neoplasm in the central nervous system (CNS). Although immunotherapy has shown efficacy in several tumor types, no immunotherapies are approved by the US Food and Drug Administration for treatment of gliomas. One of the biggest challenges in using immunotherapies in the CNS is the existence of the blood-brain barrier (BBB), which limits drug delivery and the subsequent therapeutic drug efficacy. In addition to biodistribution, assessment of PK in preclinical models do not reflect the clinical findings. Conjugation of therapeutic agents with molecules binding to TRFC expressed along the BBB are being used as one of the alternative approaches to deliver drugs into the CNS. Herein, we describe a novel TFRC humanized mouse model (hTFRC), developed to enable assessment of compounds targeting human TFRC and aiming to deliver drug through the BBB. hTFRC model was developed by knock-in at the mouse endogenous locus to enable a physiological expression of TFRC. Splenocytes from hTFRC mice stimulated with labelled pHrodo Red human transferrin show internalization of human transferrin, suggesting that humanization of the transferrin receptor does not change the endocytosis process. In vivo, treatment of hTFRC mice with anti-BACE1/anti-TFRC antibodies enables the transfer of anti-BACE1 to the brain, while anti-BACE1 antibody is not. As a consequence of the drug delivery, mice treated with anti-BACE1/anti-TFRC show a marked reduction in Amyloid-β 1-40 levels in the brain. Altogether, the data suggest that hTFRC is expressed in the BBB and enables the efficient shuttling of therapeutic antibodies to the brain. While assessment of TFRC-targeting antibodies in a glioma model remains to be performed, the hTFRC model is a promising tool to assess delivery and efficacy of immunotherapies in gliomas. Moreover, the hTFRC model is also being intercrossed with the well-established hSA/FcRn humanized mouse model (Viuff et al., 2016), to enable a more translatable PK and biodistribution of compounds targeting TFRC. Citation Format: Fabiane Sonego, Angela Pappalardo, Gaëlle Martin, Burak Ozgür, Peter Ravn, Yacine Cherifi, Florence Sotty, Patricia Isnard-Petit, Kader Thiam. Novel TFRC humanized mouse model for drug delivery to the 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 2045.
Abstract 950: Functional characterization of atypical somatic variants in the Gundersen Precision Oncology Cohort
Authors: Peter Feiszt, Paraic A. Kenny
Journal: Cancer Research (2024)

Abstract The generation and widespread sharing of large somatic mutation datasets has revolutionized our understanding of genetic mechanisms driving cancer initiation and progression. For well-understood mutations, this has created the opportunity for individualized therapeutic intervention in a wide range of malignancies. Beyond these well-characterized mutations, there exists a wide range of alterations that remain poorly understood and which require some kind of functional genomics analysis to determine whether such patients are eligible for the targeted therapy used for more typical mutations in that gene, whether these alterations are passenger mutations that don’t affect throughput on the associated signaling pathway, or reflect another more nuanced phenomenon. Whether using ectopic overexpression in cell lines or generation of genetically modified mice, addressing this problem at scale using functional genomics approaches is challenging. A key limitation is the absence of the original tissue context in which that variant co-evolved with other genetic alterations as well as data on the clinical response of the patient to successive lines of therapy. This can be addressed, in part, by the banking of tissue from patient cohorts who have had comprehensive genomic profiling as part of their routine clinical care. The Gundersen Precision Oncology Cohort is a growing dataset of FFPE specimens and longitudinal clinical data from more than 750 patients who have had comprehensive cancer genome profiling using assays from a wide range of diagnostic companies. We use this resource for biomarker discovery and functional classification of many atypical cancer variants. Current subgroups include atypical point mutations in BRAF, ERBB2 and ERBB3, as well as fusions affecting BRAF, PIK3CA and ROS1. We present examples illustrating the value of this approach for classification of variants detected in a range of tumor types. Citation Format: Peter Feiszt, Paraic A. Kenny. Functional characterization of atypical somatic variants in the Gundersen Precision Oncology Cohort [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 950.
Abstract 6316: Exploring the resistant mechanism of CAR T cell therapy targeting CLDN18.2 by single-cell sequencing
Authors: Mingyang Ma, Changsong Qi, Chang Liu, Lei Jiang, Min Tao, Dan Liu, Panpan Zhang, Zhi Peng, Xiaotian Zhang, Jifang Gong, Yang Chen, Chunhong Zheng, Mi Deng, Lin Shen
Journal: Cancer Research (2024)

Abstract Chimeric antigen receptor T cell (CAR T) therapy has achieved remarkable success in treating hematological malignancies but still faces overwhelming challenges for solid tumors. Our previous clinical trial (NCT03874897) has demonstrated promising results in patients with advanced CLDN18.2-positive gastric after receiving CT041 CAR T cell product. Though the disease control rate (DCR) reached 73% in 37 patients, it was unclear who would benefit from this therapy. Here in this study, we dynamically collected peripheral blood and ascites samples from 5 patients in this clinical trial before and at 3 and 7 days after the infusion of CT041, respectively. Utilizing single-cell sequencing analysis, we found that patients with a high proportion of naive-like T cells were more likely to benefit from CT041. Furthermore, we discovered that the high expression of CLDN18 in the ascites epithelial cells was correlated with a favorable prognosis, while ascites epithelial cells showing high MYC expression and the strong interaction between tumor cells and T cells were identified as adverse prognostic factors for CT041 treatment. These findings may provide theoretical evidence for subsequent screening of CAR T cell therapy benefitable population and improving the efficacy of CAR T cell therapy. Citation Format: Mingyang Ma, Changsong Qi, Chang Liu, Lei Jiang, Min Tao, Dan Liu, Panpan Zhang, Zhi Peng, Xiaotian Zhang, Jifang Gong, Yang Chen, Chunhong Zheng, Mi Deng, Lin Shen. Exploring the resistant mechanism of CAR T cell therapy targeting CLDN18.2 by single-cell sequencing [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 6316.
Abstract 5994: Neutrophils internalized through LC3-associated phagocytosis trigger tumor ferroptotic cell death in glioblastoma
Authors: Tong Y. Lu, Patricia P. Yee, Stephen Y. Chih, Dawit G. Aregawi, Michael J. Glantz, Brad E. Zacharia, Hong-Gang Wang, Wei Li
Journal: Cancer Research (2024)

Abstract Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, however, how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute the necrosis development in glioblastoma (GBM) through transferring myeloperoxidase-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit the neutrophil-induced tumor cell death through blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process is through LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model showed that necrosis formation is reduced, and the tumor-bearing mice can survive longer. Therefore, this study revealed that the neutrophilic granule transfer is through LAP-mediated neutrophil internalization, which then trigger tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM. Citation Format: Tong Y. Lu, Patricia P. Yee, Stephen Y. Chih, Dawit G. Aregawi, Michael J. Glantz, Brad E. Zacharia, Hong-Gang Wang, Wei Li. Neutrophils internalized through LC3-associated phagocytosis trigger tumor ferroptotic cell death in glioblastoma [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 5994.
Abstract 3466: Prognostic implications of lymph node micrometastasis in patients with gastric cancer
Authors: Atsushi Yamamoto, Hirotaka Okamoto
Journal: Cancer Research (2024)

Abstract Purpose: The clinical significance of lymph node micrometastasis (LNMM) remains controversial in gastric cancer (GC). In this study, we investigated the prognostic impact of patients with LNMM GC.Methods: A total of 624 patients with pathologically lymph node metastasis negative (pN0) and N1 status (pN1) who underwent gastrectomy between 2004 and 2018 were enrolled in this retrospective study. The diameter of tumor cell clusters in metastatic lymph nodes was measured in 120 patients with pN1 GC. Results: Patients with lymph node tumors of diameter &amp;lt; 1500 μm (LNMM) had significantly better prognosis than those with tumors of diameter ≥ 1500 μm (p = 0.012; log-rank test). Cox’s proportional hazards model revealed that LNMM (p = 0.016), several dissected lymph nodes (p = 0.049), and the provision of adjuvant chemotherapy (p = 0.002) were independent prognostic factors for overall survival of patients with pN1 GC. There was no significant difference in overall survival between patients with LNMM who received chemotherapy and those who did not (p = 0.332). Conclusions: LNMM is associated with favorable prognosis and could be an independent prognostic marker in patients with pN1 GC. LNMM in GC may be considered as one of the factors preventing adjuvant chemotherapy. Citation Format: Atsushi Yamamoto, Hirotaka Okamoto. Prognostic implications of lymph node micrometastasis in patients with gastric 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 3466.
Abstract 7328: Relationship between PIN3 16bp duplication of TP53 and HPV in HIV women in Mali
Authors: Mamoudou Maiga, Brehima Diakite, Yaya Kassogue, Ban Traore, Oumar Kassogue, Bakarou Kamate, Cheick B. Traore, Jane L. Holl, Lifang Hou
Journal: Cancer Research (2024)

Abstract Background: TP53 polymorphisms can influence the immune response to HPV, affecting TP53's role in cell cycle regulation and apoptosis, crucial for controlling HPV infection and preventing cancer. Objective: Explore the link between TP53 PIN3 16-bp duplication and HPV infection in HIV-positive Malian women. Methods: This study explored the link between PIN3 16-bp duplication polymorphism of TP53 and HPV infection in 50 HIV-positive women in Mali. Data included surveys, self-sampled vaginal swabs, and blood collection. HPV typing used GeneXpert, and PIN3 genotyping utilized AS-PCR. Results: Participants, primarily &amp;gt;30 years (92%), had a mean age of 43.30 ± 10.332 years. HPV prevalence was 36%, with P3 being the most common subtype (30.8%). PIN3 genotypic frequencies were A1A1 (50%), A1A2 (34%), and A2A2 (10%). History of sexually transmitted infections correlated with higher mutation rates (37.8% A1A2, 10.8% A2A2). A2A2 genotype prevalence was higher in HIV-positive women with specific HPV subtypes (P5, P4, HPV16, P3, P18/45). A1A2 genotype was observed in 60% of HPV subtype P3 cases and 20% of P4 and P18/45 cases. Conclusion: These results suggest a link between TP53 gene polymorphisms and susceptibility to different HPV subtypes in HIV-positive women, warranting further research into their functional implications and impact on HPV-related diseases in this population. Keywords: TP53 polymorphism, HPV, HIV, Malian population Citation Format: Mamoudou Maiga, Brehima Diakite, Yaya Kassogue, Ban Traore, Oumar Kassogue, Bakarou Kamate, Cheick B. Traore, Jane L. Holl, Lifang Hou. Relationship between PIN3 16bp duplication of TP53 and HPV in HIV women in Mali [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 7328.
Abstract 192: Orchestrating CDC42 turnover to regulate membrane protrusion and tumor metastasis
Authors: Sen-Yung Hsieh
Journal: Cancer Research (2024)

Abstract F-actin cytoskeleton remodeling is essential for cell migration, organ development, and immune responses. CDC42, a factor orchestrating F-actin remodeling for membrane dynamics, switches between its inactive GDP- and active GTP-bound forms. However, the biological and clinical significance of the mechanisms regulating CDC42 protein turnover remains unclear. Here we show that KLHL23-mediated CDC42·GTP polyubiquitylation for degradation and RhoGDI-mediated CDC42·GDP sequestration away from the plasma membrane co-inactivate CDC42 in a spatiotemporal context, influencing membrane dynamics and homeostasis during migration. Via a functional genomic screen, we identified KLHL23 as a suppressor of tumor invasion. Decreased KLHL23 level was associated with tumor metastasis and poor clinical outcomes in patients with liver and pancreas cancers. KLHL23 functions as the E3 ligase responsible for CDC42 polyubiquitylation and degradation. KLHL23 shares with RhoGDI the switch II region of CDC42 for binding, enhancing selective targeting of CDC42·GTP and CDC42·GDP, respectively. KLHL23 depletion in cells leads to F-actin and membrane over-protrusion, as well as epithelial-mesenchymal transition and tumor metastasis. Fluorescence resonance energy transfer assays reveal that the KLHL23—CDC42·GTP interaction plays a primary role in quenching CDC42 activity during membrane protrusion-retraction, while the RhoGDI—CDC42·GDP interaction occurs lately. Our results demonstrate the spatiotemporal interplay between RhoGDI and KLHL23 in regulating CDC42 turnover for membrane dynamics. As KLHL23/RhoGDI—CDC42 axis dysregulation causes tumor metastasis, our findings open avenues for exploring novel therapeutics. Citation Format: Sen-Yung Hsieh. Orchestrating CDC42 turnover to regulate membrane protrusion and tumor metastasis [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 192.