tbuckley/cabot-search huggingface dataset:
Abstract 5596: Exploring BRCA1-Y1853ter and potential therapeutic targets in BRCA1-BRCT mutated cancers
Authors: Jingjing Chen
Journal: Cancer Research (2024)

Abstract The breast cancer gene BRCA1 plays a pivotal role as a tumor suppressor gene. Despite the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA1 mutation carriers, the lack of response or the development of acquired drug resistance underscores the pressing need for new therapeutic targets. One intriguing BRCA1 mutation, BRCA1-Y1853ter, characterized by a minimal truncation, has been identified in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. We have developed a Halo Tag and adenovirus-based system where wild-type BRCA1 (WT BRCA1) and mutant BRCA1 protein complexes can be studied in multiple cell types. Here, we used this system to affinity purify BRCA1 wild-type and mutant complexes, followed by label-free quantitative proteomics to investigate the dynamic interactome variations between WT BRCA1 and BRCA1 mutant. Contrary to the assumed loss of function, our preliminary findings suggest a potential gain of function, as a significant number of candidate proteins exhibit enhanced binding affinity with the mutant BRCA1. We are currently exploring whether these distinct binding characteristics are shared among various BRCA1-BRCT mutants, which may hint at a common tumorigenesis mechanism. Our overarching hypothesis is that identifying a specific binding partner, shared among various BRCA-BRCT mutants, could unveil a novel therapeutic target with broader applicability in treating BRCA1-related malignancies. Citation Format: Jingjing Chen. Exploring BRCA1-Y1853ter and potential therapeutic targets in BRCA1-BRCT mutated cancers [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 5596.
Abstract 7584: The solute transported xCT (SLC7A11) modulates lysosome biogenesis and microRNA trafficking in drug resistant renal cell carcinoma
Authors: Abbas Jawadwala, Christopher Rupert, Remi Adelaiye-Ogala, Roberto Pili, Sreenivasulu Chintala, Ashley Orillion, May Elbanna, Nur Damayanti, Ilaria Delle Fontane
Journal: Cancer Research (2024)

Abstract Multi-tyrosine kinase inhibitors (TKIs) like sunitinib bind to over 50 kinases and inhibit several receptors such as VEGFR-1, VEGFR-2, and VEGFR-3 receptors, PDGFRa and PDGFRb, RET, cKIT, and FLT3. TKIs are effective drugs for the treatment of renal cell carcinoma (RCC) but intrinsic/acquired resistance remains a major hurdle. One of the proposed models for TKI resistance is drug sequestration by lysosomes. The solute transporter xCT is a cystine/glutamate antiporter that plays a role in the production of antioxidants in cancer cells. Our lab has found that SLC7A11, the gene that encodes xCT, is overexpressed in sunitinib resistant RCC cells. LAMP1 expression was also increased in sunitinib resistant RCC cells, suggesting an upregulation of lysosome biogenesis. The biochemical knock down of SLC7A11 by shRNA showed a decrease in LAMP1 expression, suggesting a decrease in lysosome biogenesis. SEC24D is a key catalytic component of COPII complex involved in formation of exosomes and secretory pathways. Our preliminary data showed that reduction in xCT expression was associated with a decrease in SEC24D protein levels which was associated with a reduction in the extracellular export and, consequently, an increase in intracytoplasmic levels of miRNA 605, a known tumor suppressor. We are currently testing the hypothesis that xCT may modulate lysosomes biogenesis and micro-RNA trafficking in several clear cell and translation renal cell carcinoma models. In summary, a better understanding of the role of xCT in the regulation of intracytoplasmic organelles may lead to the identification of a novel therapeutic strategy to overcome TKI resistance in RCC. Citation Format: Abbas Jawadwala, Christopher Rupert, Remi Adelaiye-Ogala, Roberto Pili, Sreenivasulu Chintala, Ashley Orillion, May Elbanna, Nur Damayanti, Ilaria Delle Fontane. The solute transported xCT (SLC7A11) modulates lysosome biogenesis and microRNA trafficking in drug resistant 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 7584.
Abstract 4840: Creating a culturally sensitive manual to increase clinical trial participation among African Americans and African Nationals
Authors: Carolina Aristizabal, Eduardo Ibarra, Lourdes A. Baezconde-Garbanati
Journal: Cancer Research (2024)

Abstract Background: Racial and ethnic minorities are immensely underrepresented in clinical trial studies in the United States. Black/African Americans, Latinos/as, Asians, American Indians, and Pacific Islanders make up roughly 30% of all clinical trials (CT) participation across all race groups. Being inclusive of all populations in CT ensures that everyone has access to modern medicines and treatments, but also, that these latest treatments work and react well to all people. Methods: We developed a manual on clinical trials with a target focus to African Americans and African Nationals. We hosted two focus groups with Blacks/African Americans in which we found they are more comfortable getting cancer related information through trusted community services, such as coming from churches. We have connected with over 80 Pastors who agreed to collaborate in clinical trials education. Results: Through outreach and engagement to African American churches in Los Angeles County, we have distributed a copy of this clinical trials educational manual to 90 churches to be disseminated during their services. Our office of Community Outreach and Engagement (COE) regularly attend community health and resource events and provide hard copies of the clinical trials manual at tables/booths designated for our participation. We have attended 50 community events and have disseminated about 1,900 copies of the CT manual so far this year 2023. This manual is also available for free download on our cancer center’s website, in which over 100 toolkits have been downloaded within the last year. Conclusions: By creating a culturally sensitive and adapted educational manual and partnering with trusted services in the community such as faith-based organizations, we can begin to break down barriers to clinical trials participation among all race and ethnic minority groups. Citation Format: Carolina Aristizabal, Eduardo Ibarra, Lourdes A. Baezconde-Garbanati. Creating a culturally sensitive manual to increase clinical trial participation among African Americans and African Nationals [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 4840.
Abstract 2453: Soluble B7H3 has a potential of novel serum biomaker for colorectal cancer
Authors: Akihiro Koizumi, Tomoaki Ito, Kazunori Kato, Takumi Iwasawa, Tomoyuki Kushida, Koichi Sato, Chikako Okamoto
Journal: Cancer Research (2024)

Abstract B7H3 (also known as CD276, an immune checkpoint molecule) is aberrantly over expressed in many types of cancer. Recently, several reports indicate a crucial role for B7H3 in promoting carcinogenesis and metastasis. We investigated whether concentration of the soluble B7H3 could be used as a new prognostic predictor of colorectal cancer by measuring serum level of B7H3. Recently we established a new mAb to B7H3 and developed sandwich ELISA-system detecting human serum B7H3 with high sensitivity and specificity. Measuring the levels of B7H3 in the serum specimens of colorectal cancer donors, we examined the usefulness of B7H3 as a novel biomarker for colorectal cancers. We tested the blood from the 82 donors of colorectal cancers and 9 healthy donors who agreed in writing to this research, just before the operation. The mean value + 2SD in 9 healthy donors was set as the cutoff value. We classified cancer patients into 2 groups with high value of B7H3 and low value of B7H3. We also analyzed the relationships between serum B7H3 levels and disease-free survival (DFS) and overall survival (OS). Serum B7H3 levels were also compared with diagnostic biomarkers such as CEA and CA19-9. B7H3 immunostaining was also performed on tissue samples. The serum levels of B7H3 in patients with colorectal cancer were significantly higher than those of healthy donors. However, there were no correlation between B7H3 and other diagnostic markers CEA and CA19-9. Regarding DFS, the higher value group of serum B7H3 showed a tendency for DFS to decrease in Stage II and III. Regarding OS, there was no significant difference of serum levels of B7H3 in Stage I and IV cases, however, in Stage II and III, OS decreased significantly in the high B7H3 group. In B7H3 immunostaining, the tissue was not sufficiently stained. These data indicate that serum B7-H3 should be useful for novel biomarker for a rationale of disease monitoring and prognosis of colorectal cancer. Citation Format: Akihiro Koizumi, Tomoaki Ito, Kazunori Kato, Takumi Iwasawa, Tomoyuki Kushida, Koichi Sato, Chikako Okamoto. Soluble B7H3 has a potential of novel serum biomaker for 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 2453.
Abstract 6707: IgG based B7-H3xCD3 bispecific antibody for treatment of gynecological tumors
Authors: Sarah Maria Greiner, Jonas Mauermann, Martina Lutz, Ilona Hagelstein, Engler Tobias, André Koch, Hartkopf Andreas, Brucker Sara, Latifa Zekri, Melanie Märklin
Journal: Cancer Research (2024)

Abstract Ovarian cancer is characterized by late stage disease and a poor prognosis. Endometrial cancer is a heterogeneous disease with different prognoses depending on the molecular subtype. Novel treatment strategies are needed to improve patient survival in both entities. T cell-based immunotherapy has significantly improved the treatment options for many malignancies. B7-H3 (CD276) is an interesting target for immunotherapeutic approaches because it is overexpressed on a wide range of tumor entities and has characteristics of immune checkpoint molecules. Its expression not only on tumor cells but also on the tumor vasculature allows improved infiltration of immune effector cells into the tumor to overcome the major limitation of T cell-based therapy of solid tumors, which is the access of immune cells to the tumor site. A novel bispecific antibody in an IgG-based format called CC-3 with B7-H3xCD3 specificity has already been shown to efficiently induce T cell responses against gastrointestinal malignancies. Here we show that B7-H3 is highly expressed on endometrial and ovarian cancer cell lines. Treatment with CC-3 induced T cell activation and degranulation as well as secretion of IL-2, IFNy and perforin. These results demonstrate CC-3 induced T cell reactivity against ovarian and endometrial cancer cells. In addition, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. This resulted in potent target cell lysis. Taken together, our results underscore the potential of CC-3, which is currently in GMP manufacturing, to enable clinical evaluation for the treatment of gynecologic malignancies. Citation Format: Sarah Maria Greiner, Jonas Mauermann, Martina Lutz, Ilona Hagelstein, Engler Tobias, André Koch, Hartkopf Andreas, Brucker Sara, Latifa Zekri, Melanie Märklin. IgG based B7-H3xCD3 bispecific antibody for treatment of gynecological 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 6707.
Abstract 7574: Exploring the therapeutic potential of proteasome inhibitors in targeting SOX2-driven LUSC and SCLC
Authors: Atish Mohanty, Linlin Guo, Sravani Ramisetty, Sharad Singhal, Erminia Massarelli, Prakash Kulkarni, Ravi Salgia
Journal: Cancer Research (2024)

Abstract This study addresses the current lack of small molecules targeting SOX2, a pivotal protein in cancer, through an examination of the effectiveness of FDA-approved drugs and proteasome inhibitors. Building on prior research demonstrating the proteasome inhibitor CFZ's capacity to diminish the expression of ITGB4 and PXN in LUAD effectively, our investigation highlights CFZ and IXA as potent inhibitors at nanomolar concentrations. Notably, CFZ treatment enhances sensitivity to cisplatin by suppressing the expression of ITGB4 and the stemness-associated gene SOX2.At a mechanistic level, CFZ hinders histone acetylation at the SOX2 promoter site, leading to rapid and specific downregulation. RNA-seq analysis of COH2 cells treated with CFZ unveils substantial downregulation of genes related to transcription and DNA binding. Z score analysis further reveals a noteworthy inhibition of key transcription factors (TFs), including SOX2, NANOG, POU5F1, SALL4, and KLF4. This TF inhibition extends to neuroendocrine cell lines, identifying 16 overlapping targets of SOX2 associated with stemness. These findings suggest a potential therapeutic approach for targeting cisplatin-resistant cancer stem cells across various cancer types. Moreover, the study proposes a synergistic effect of cisplatin and CFZ in mitigating the growth of neuroendocrine phenotype, SCLC. Given the limited medical options currently available for this phenotype, this insight holds particular significance. In conclusion, our study unveils CFZ as a potent transcriptional suppressor of SOX2, providing a novel strategy to sensitize cisplatin-resistant cancer stem cells. The results underscore the interplay of genetic and non-genetic mechanisms in drug resistance, emphasizing the significance of repurposing drugs for other indications. Citation Format: Atish Mohanty, Linlin Guo, Sravani Ramisetty, Sharad Singhal, Erminia Massarelli, Prakash Kulkarni, Ravi Salgia. Exploring the therapeutic potential of proteasome inhibitors in targeting SOX2-driven LUSC and SCLC [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 7574.
Abstract 849: Deciphering the link between aging, lobular involution, and breast cancer risk: The role of LIFR/pSTAT3 signaling
Authors: Jaida C. Lue, Derek Radisky, Melody Stallings-Mann, Mark Sherman, Amy Degnim, Bryan McCauley, Tanya Hoskin
Journal: Cancer Research (2024)

Abstract Background: Age-related lobular involution (ARLI), characterized by regression of breast epithelial tissue during the peri-and post-menopausal period, plays a crucial role in breast cancer risk. Delayed or incomplete ARLI is linked with increased postmenopausal breast cancer susceptibility.This study focuses on unraveling the molecular mechanisms of ARLI, drawing parallels with the well-characterized postpartum involution (PPI). Our aim was to discover biomarkers differentiating women who progressed through ARLI from those with stagnant ARLI. Methods: We utilized the Mayo Clinic Benign Breast Disease (BBD) cohort, analyzing 108 perimenopausal women aged 45-55 who had a subsequent benign biopsy between 2-15 years later. We assessed Lobular Involution (Ll) status by comparing the number and size of lobules in initial and subsequent biopsies. RNA profiling of initial biopsies was performed using NanoString 10360 and BC360, identifying differentially expressed genes between ARLI progression and stagnation. Immunohistochemistry (IHC) mapped the expression of these biomarkers in epithelial lobules. Results: We identified 37 genes with significant differential expression, highlighting Leukemia Inhibitory Factor Receptor (LIFR) as upregulated in ARLI stagnant samples. LIFR, part of the IL-6 cytokine signaling pathway, is known for its role in the induction of apoptosis during PPI via pSTAT3 activation. Our IHC analyses of initial biopsies of women who differentially progress through ARLI confirmed differential expression of LIFR that is coordinately regulated with pSTAT3. Conclusion: Our findings reveal significant parallels between ARLI and PPI. Future research will assess how LIFR/pSTAT3 signaling is linked to induction of apoptotic markers in perimenopausal women and will investigate how anomalies in the LIFR/pSTAT3 pathway might contribute to heightened breast cancer risk in women with delayed or incomplete ARLI. This study not only sheds light on the complex biological processes of aging in breast tissue but also opens new avenues for breast cancer risk assessment and prevention strategies. Citation Format: Jaida C. Lue, Derek Radisky, Melody Stallings-Mann, Mark Sherman, Amy Degnim, Bryan McCauley, Tanya Hoskin. Deciphering the link between aging, lobular involution, and breast cancer risk: The role of LIFR/pSTAT3 signaling [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 849.
Abstract 6697: The role of microbiomes in pediatric cancer prevention: A survey of population awareness
Authors: Abeer Abd Elmoneim, Mona Alhassan Alshanqiti, Yara Saad Aljohani, Lubna Hosain Alomari
Journal: Cancer Research (2024)

Abstract Background: Gut microbiome includes the genome of all gut microorganisms; it plays a crucial role in the body’s nutritional, metabolic, physiological, and immunological processes. Persistent imbalance of the gut microbial community is associated with the onset of metabolic and inflammatory disorders, including cancer. The environment has a major role in the great variability of microbiome composition among different people. This high heterogeneity between individuals may be a source of differences in susceptibility to disease. Dietary and lifestyle choices as well as social interactions play a significant role in makeup and function of the gut microbiota, which may affect microbiome-associated diseases. Therefore, strategies that might favorably modulate the gut microbiota to reduce the risk of cancer through diet and lifestyle changes are of great interest. Aim: To detect and increase self-awareness about gut microbiota and its relation to diet and lifestyle habits. Methods: A survey questionnaire is provided asking for microbiome knowledge and lifestyle habits and distributed among the population in Madina city in Saudi Arabia. Study population are the children aged 2-18 years. Data gathered from older children or the parents/guardian of young children. Results: A profile involving each participant’ diet, physical activity, and sociodemographic characteristics through self- reporting questionnaire is obtained. Discussion: Gut microbiota can regulate many functions of the tumor-bearing meta-organism, typically through immunomodulation. Known microbial mechanisms can alter non-hematopoietic and hematopoietic components of the gut epithelial barrier, modulate lymphoid organ activities, and regulate immune tone of the tumor microenvironment (TME). Conclusion: Understanding information about microbiome and its role in causing diseases as well as each participant’ diet, physical activity and other sociodemographic characteristics help to raise participants’ awareness about the importance of taking care of their gut health. Citation Format: Abeer Abd Elmoneim, Mona Alhassan Alshanqiti, Yara Saad Aljohani, Lubna Hosain Alomari. The role of microbiomes in pediatric cancer prevention: A survey of population awareness [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 6697.
Abstract 5692: Posttranscriptional molecular network facilitates KRAS-linked tumorigenesis via XRN1-miR-21 signaling in pancreatic cancers
Authors: Yoona Seo, Seung Eon Oh, Jong Heon Kim
Journal: Cancer Research (2024)

Abstract Aberrant expression of mutant KRAS and miRNA-21 (miR-21) are commonly attribute to malignancy and tumorigenic progression of pancreatic cancers. However, few studies have explored the molecular mechanism linking these two prognostic factors. In this study, we explored the underlying molecular bridge between KRAS and miR-21 regulation in pancreatic cancer. Functional integrative analysis of KRAS, an essential oncogenic driver in pancreatic cancer progression, and together with miR-21 revealed XRN1, a 5′-3′ exoribonuclease, as RNA-linked top-scored molecule with a strong survival correlation and malignancy in pancreatic cancer patients. Depletion of XRN1 led to severe reduction in mature miR-21 expression, while unaltered precursor miR-21 levels; indicating that the XRN1 is critical in miR-21 maturation at post-Drosha step in conjunction with Dicer. Moreover, miR-21 sensor-based experiment also confirmed the critical role of XRN1 on miR-21 biogenesis. Depletion experiments showed that XRN1 positively regulates proliferation and self-renewal capacity of pancreatic cancer cells via its 5′-3′ exoribonuclease activity and concomitantly elevated the expression of PTEN and PDCD4 which are the key miR-21 cellular downstream targets. shRNA-mediated XRN1 depletion also yielded smaller tumor volume and longer survival in pancreatic cancer xenografts and syngeneic model demonstrating the therapeutic potential of targeting XRN1. Subsequent silencing of KRAS reduced XRN1 expression in pancreatic cancer cells, suggesting that KRAS plays a key role in this XRN1-miR-21 axis. Furthermore, drug-resistant pancreatic cells showed elevated expression of both KRAS and XRN1-miR-21 indicating that this axis is also associated with drug sensitivity. In sum, these results suggest that a novel KRAS-XRN1 posttranscriptional regulatory axis plays a pivotal role in tumor progression by mediating miR-21-directed signaling, and thus may suggest a novel targeting strategy for pancreatic cancer therapeutics. Significance: This study identifies molecular regulatory interplay between KRAS and XRN1-miR-21 signaling in pancreatic cancers, elucidates how KRAS-XRN1 modulates tumorigenesis via miR-21, and demonstrates that targeting this signaling can contribute to therapeutic strategies for pancreatic cancers. [Y. Seo and S. E. Oh contributed equally to this work.] Citation Format: Yoona Seo, Seung Eon Oh, Jong Heon Kim. Posttranscriptional molecular network facilitates KRAS-linked tumorigenesis via XRN1-miR-21 signaling in pancreatic cancers [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 5692.