tbuckley/cabot-search huggingface dataset:
Abstract 1445: A nuclear localizing peptide that targets glioblastoma
Authors: Calvin D. Lewis, Abhay Singh, Vaishali Kapoor, Dennis E. Hallahan
Journal: Cancer Research (2021)

Abstract Glioblastoma (GBM) is one of the most aggressive and fatal primary brain neoplasms with a median survival of less than 15 months even after current standard of cares including surgical resection, radiotherapy and systemic therapy. Although systemic anticancer agents, such as temozolomide, are used as the standard of care for GBM, therapeutic efficacy is limited due to the off-target systemic toxicity of traditional chemotherapeutics. Targeted systemic therapy is emerging as an important treatment strategy for cancer therapy. Phage display peptide library was used to discover peptides that undergo endocytosis in GBM. We have identified a novel peptide that accumulates intracellularly in multiple GBM cell lines. Intracellular localization was quantified by FACS analysis of the FITC-labeled peptide. As compared to untreated GBM cells, D54, U251 and SF295 human GBM cell lines treated with 5.55 µM of peptide-FITC conjugate showed a significant FITC-positive shift on FACS analysis with 83%, 85% and 71% of cells internalizing the peptide, respectively. Confocal laser scanning microscopy experiments further confirm the intracellular targeting of the FITC-peptide in D54, U251 and SF295 GBM cell lines with associated peptide nuclear localization. Further studies are underway to elucidate the microscopic biodistribution of the nuclear homing peptide (NHP) in GBM mouse models. This work is significant as a novel cell surface, intracellular or nuclear binding partner may be identified for peptide-targeted cancer drug therapy. Furthermore, the NHP has potential to be translated to the clinic as targeted therapy for GBM patients in the form of a peptide-drug conjugate. Citation Format: Calvin D. Lewis, Abhay Singh, Vaishali Kapoor, Dennis E. Hallahan. A nuclear localizing peptide that targets glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1445.
Abstract 2900: PRAMEF2 ubiquitylates and degrades LATS1 leading to enhanced nuclear accumulation of YAP and tumorigenesis
Authors: Madhurima Ghosh, Sanjeev Das
Journal: Cancer Research (2021)

Abstract PRAMEF2 (PRAME Family Member 2) is a Cancer Testis Antigen belonging to the PRAME multi-gene family. All Cancer Testis Antigens are expressed in male testicular germ cells while remaining absent from other adult tissues. Conversely, they show aberrant re-expression in several human malignancies and also elicit immunogenic responses in cancer patients. This makes Cancer Testis Antigens and thereby PRAMEF2, effective and novel targets for cancer vaccine development. However, the physiological function of PRAMEF2 underlying tumorigenesis remains unspecified. Hence, we performed a proteomic screen to explore its unique interactome in the cell. Subsequent size exclusion chromatography and co-immunoprecipitation assays confirmed the role of PRAMEF2 as a BC-box containing substrate recognition subunit of a Cullin 2 based-E3 ubiquitin ligase complex. In the proteomic screen, several proteins were identified, however in-vivo assays revealed LATS1 to be a specific and novel interacting partner of PRAMEF2. LATS1 is a Ser/Thr Kinase of the Hippo Pathway, known to aid tumor suppression. We observed PRAMEF2 mediated ubiquitylation and subsequent proteasomal degradation of LATS1 through ubiquitylation assay. The site for ubiquitylation was mapped to the highly conserved Lysine 860 residue on LATS1. Upon activation of the Hippo Pathway, LATS1 results in phosphorylation of the transcriptional co-activator YAP, leading to its cytosolic translocation. Consequently, PRAMEF2 mediated LATS1 regulation resulted in decreased YAP phosphorylation and its increased accumulation in the nucleus. Furthermore, RTqPCR array and ChIP analysis showed the enhanced expression of YAP target genes implicated in proliferation and metastasis. Moreover, PRAMEF2 depletion also diminished the proliferative capacity, migration potential and invasiveness of tumor cells. Studies in mouse tumor models confirmed that PRAMEF2 abrogates the tumor suppressive function of LATS1 leading to ameliorated tumor growth and metastasis. Taken together, our findings help establish the role of PRAMEF2, an unique Cancer Testis Antigen, as a substrate recognition subunit of a Cullin 2- based E3 ubiquitin ligase complex which ubquitylates and degrades LATS1. Hence, PRAMEF2 realizes its oncogenic potential by increasing YAP nuclear accumulation and promoting tumor cell proliferation and metastasis. Citation Format: Madhurima Ghosh, Sanjeev Das. PRAMEF2 ubiquitylates and degrades LATS1 leading to enhanced nuclear accumulation of YAP and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2900.
Abstract 1845: Enhancing the efficacy of antitumor antibodies with immune checkpoint inhibitors and targeted therapy in melanoma
Authors: Rolando Pérez-Lorenzo, Stephanie O. Erjavec, Raphael Clynes, Angela M. Christiano
Journal: Cancer Research (2021)

Abstract The therapeutic outcomes of current strategies in melanoma treatment have greatly improved within the last decade. However, the persistent relatively low success rate of current standard-of-care strategies underscores the urgent need for improvement of these therapeutic approaches. The use of specific antitumor antibodies recently transformed the cancer therapeutics landscape with successes such as anti-HER2 in breast cancer, and anti-EGFR in HNSCC and colorectal cancer. However, antitumor antibodies have not been developed for the treatment of melanoma. Here, using mouse preclinical models of melanoma (both solid tumor and lung metastasis), we found that the therapeutic efficacy of the specific antitumor antibody TA99 (anti-TYRP1) is significantly enhanced by immune checkpoint blockade. This was associated with a greater CD8+, CD8+/Foxp3+, NK1.1+ and dendritic cell infiltrate, suggestive of an increased anti-tumor immune response. Further, MEK inhibition (MEKi) increased the expression of melanosomal antigens in B16 and YUMM mouse melanoma cell lines in vitro. We next combined TA99 and MEKi to treat B16 melanoma in vivo and observed a synergistic reduction in tumor growth. Treatment of mice bearing YUMM melanoma (BRAF mutant) with TA99/MEKi resulted in the complete elimination of tumors in the majority of animals, and produced durable responses. Moreover, we found a synergistic effect when B16 tumor-bearing mice were treated with TA99 combined with MEKi and immune checkpoint blockade (anti-PD1 and anti-CTLA4). Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which, in combination with antitumor antibodies, generated a robust adaptive antitumor response that was sustained by immune checkpoint inhibition therapy. These improved therapeutic effects of specific antitumor antibodies by current standard-of-care therapeutics have potential near-term translation to the clinic, in light of fully humanized anti-TYRP1 antibodies currently in clinical development. Citation Format: Rolando Pérez-Lorenzo, Stephanie O. Erjavec, Raphael Clynes, Angela M. Christiano. Enhancing the efficacy of antitumor antibodies with immune checkpoint inhibitors and targeted therapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1845.
Abstract 716: Telehealth use among multiple myeloma patients during the COVID-19 pandemic
Authors: Nathan W. Sweeney, Scott R. Goldsmith, Jennifer M. Ahlstrom
Journal: Cancer Research (2021)

Abstract Background:The rapid outbreak of coronavirus disease 2019 (COVID-19) led to delays of non-urgent or routine medical care. Regulatory waivers and policy changes from the Centers of Medicare and Medicaid Services (CMS) for the use of telehealth came as a solution to help fight the outbreak. The aim of this project was to survey the change in the frequency of use of telehealth services among multiple myeloma (MM) patients during the COVID-19 pandemic. Methods:We utilized HealthTree Cure Hub For Multiple Myeloma (healthree.org) and invited patients with active MM cancer or precursor conditions to participate in an online survey. We analyzed patient responses to doctor visits, the use of telehealth before and after the COVID-19 pandemic, and whether they had sufficient access to their doctor. Results:1,301 MM pts participated in the survey between April 15, 2020, and June 8, 2020. During the pandemic, 36% of patients indicated visiting with their physician less often than before, 2% visited more often, and 62% had no change in the frequency of their visits. The percent of patients responding “Sometimes” or “Yes” to the use of telehealth are reported here. Before the pandemic, 10% of patients used telehealth, while 62% of patients indicated using telehealth during the pandemic, a 523% increase. When asked if they had sufficient access to their MM healthcare provider 90% of patients indicated that they did, while 10% indicated they did not. Conclusions:There were significantly fewer in-person visits during the COVID-19 pandemic likely due to the CDC-recommended physical distancing practices. During this time, telehealth use among MM patients dramatically increased compared to telehealth use before the pandemic. It is reasonable to assume that patients indicated having sufficient access to their healthcare provider as a result of patients receiving care through telehealth visits. The authors encourage readers to think more broadly about the benefits of telehealth. Maintaining sufficient access to one healthcare provider addressed in this abstract is only a fraction of the benefits telehealth offers. MM is a rare cancer and as a result, some states have few if any specialists. Maintaining telehealth policy changes made during the pandemic would remove geographical barriers and open access to specialists across the country. Citation Format: Nathan W. Sweeney, Scott R. Goldsmith, Jennifer M. Ahlstrom. Telehealth use among multiple myeloma patients during the COVID-19 pandemic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 716.
Abstract 2178: Spectrum of pathogenic germline mutations in Chinese esophageal squamous cell carcinoma patients through next-generation sequencing
Authors: Ruijun Cai, Yating Zheng, Wenzhuan Xie, Mengli Huang
Journal: Cancer Research (2021)

Abstract Background: Esophageal Squamous Cell Carcinoma (ESCC) is one of the leading cause of cancer death in China, while the nature of genetic factors related to ESCC has not been well-studied. The purpose of this study is to assess the inherited genetic factors regarding pathogenic germline mutations in Chinese ESCC population. Methods: Tumor tissue samples from Chinese patients with ESCC were analyzed using next generation sequencing (NGS) (panel on 381/733-gene). MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). TMB was defined as total number of somatic non-synonymous mutations in coding region. Results: Genomic profiling of DNA of 271 ESCC patients were analyzed using NGS, of which 251 (92.6%) harbored 354 pathogenic or very likely pathogenic germline mutations in 94 genes. In ESCC patients with germline mutations, the most frequently germline mutated genes were CYP2C19 (54.18%), followed by UGT1A1 (41.04%), RAC1 (35.06%), VEGFA (34.66%), DPYD (33.47%), CD74 (31.47%), MGMT (31.08%), CYP2D6 (29.88%), BCL2L11 (12.35%), FANCA (7.97%), ALK (7.57%), APC (7.17%), and BARD1 (5.98%). Of all the 94 germline mutated genes, 26.6% (n=25) lay in the DNA damage repair (DDR) pathways. The most frequently germline mutated DDR genes were FANCA (7.97%), followed by BARD1 (5.98%), FANCG (5.98%), BLM (5.58%), BRCA2 (5.18%), BRCA1 (4.78%), FANCD2 (4.78%), POLD1 (3.98%), ATM (3.59%), and POLE (3.58%). MSI status analysis was performed in 246 of 251 ESCC patients with germline mutated genes, and the results showed that all the patients with germline mutated genes were determined to be MSS. In addition, among 251 ESCC patients with germline mutated genes, 163 of them were tested for PD-L1. The results showed that 45 (27.6%) of the ESCC patients were PD-L1 positive (CPS≥10) and 118 (72.4%) were PD-L1 negative. Of the 247 ESCC patients with germline mutations that could be evaluated for TMB, 60 (24.29%) patients had TMB≥10Muts/Mb. Conclusions: As the first study to explore the pathogenic germline mutation profile of Chinese ESCC patients, our study provides valuable clues for the assessment and clinical management of genetic susceptibility to ESCC patients. Citation Format: Ruijun Cai, Yating Zheng, Wenzhuan Xie, Mengli Huang. Spectrum of pathogenic germline mutations in Chinese esophageal squamous cell carcinoma patients through next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2178.
Abstract 1483: Examining the role of genome editing enzymes in anti tumor immunity
Authors: Faezeh Borzooee
Journal: Cancer Research (2021)

Abstract Background: Tumor antigens (TA) on cancer cells can trigger immune response TA are peptides that are either not present, or are present to a much lesser extent, on normal cells compared to tumor cells. CD8+ Cytotoxic T-cells (CTL) recognize TAs bound to class I major histocompatibility complex (MHC) molecules on the surface of tumor cells. We and others have shown that viruses subvert the mutational activity of the endogenous DNA-editing APOBEC enzymes in human host cells towards immune escape. Viruses do so by adapting their genomic DNA code to position APOBEC's favored mutational “hotspot” DNA sequences such that upon being mutated by the host APOBEC enzymes, the mutated viral protein is less immunogenic for CTL recognition. Like viruses, cancer cells have genomes that are highly plastic and adaptable through mutation; therefore, we hypothesize that the APOBEC DNA-editing enzymes are exploited by cancer cells for modulating TA immunogenicity. Aims of the Study: Aim1: To elucidate the impact of A3-mediated mutations on modulating TA immunogenicity for CTL recognition. Aim 2: To examine whether genomic sequences encoding TAs in the human genome have co-evolved to either attract or avoid APOBEC-driven mutations. Methods: Aim 1: Using the human reference proteome from EMBL/EBI, we located APOBEC-mutable hotspots in genomic DNA encoding the immunopeptidome. We simulated APOBEC-mediated mutations and translated to peptide TAs. We used NetMHCpan 4 to measure the impact of TA mutations on MHC class I binding affinity. In parallel, we are searching for already-identified APOBEC-mediated mutations in sequenced tumor genomes in cancer genome databases such as The Cancer Genome Atlas (TCGA), Catalogue of Observed Somatic Mutations in Cancer (COSMIC) and International Cancer Genome Consortium (ICGC). Aim 2: To investigate the enrichment of APOBEC-hotspots in genomic sequences encoding TAs restricted to each HLA, we are tabulating APOBEC hotspots in genomic DNA sequencing encoding TAs vs. non-TA-encoding sequences. At the sequence level, the ratio of hotspot frequency, in combination with scores of predicted impacts on immunogenicity as obtained in aim 1, will be used to glean whether and how the human genomic sequence has co-evolved with APOBECs from the standpoint of TAs. Results and Significance: Based on the preliminary data we observe that APOBEC-mediated mutations can diminish or enhance immunogenicity. Understanding the balance between these two effects is key in informing how APOBEC expression and activity ought to be regarded in the context of cancer immunotherapy. Citation Format: Faezeh Borzooee. Examining the role of genome editing enzymes in anti tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1483.
Abstract 865: Genomic and evolutionary classification of lung cancer in never smokers from the Sherlock-<i>Lung</i> study
Authors: Tongwu Zhang, Ludmil B. Alexandrov, Wei Zhao, Jian Sang, Jianxin Shi, Bin Zhu, Dmitry A. Gordenin, Montserrat Garcia-Closas, Qing Lan, Nathaniel Rothman, Stephen J. Chanock, David C. Wedge, Maria Teresa Landi
Journal: Cancer Research (2021)

Abstract Lung cancer in never smokers (LCINS) is a common cause of cancer mortality, but is poorly characterized. Here we show, through high coverage whole genome sequencing of 232 tumors/blood pairs, that LCINS can be separated into three subtypes, defined by somatic copy number aberrations. While the dominant subtype (‘piano'), rarely found in lung cancer from smokers, is characterized by quiet copy number profiles, the other subtypes are associated with specific arm-level amplifications and EGFR mutations (‘mezzo-forte'), and whole genome doubling (‘forte'). Piano tumors feature somatic UBA1 mutations, germline AR variants, and stem cell-like properties, including low mutational burden, infrequent TP53 alterations, high intra-tumor heterogeneity, long telomeres, and slow growth as suggested by the occurrence of cancer driver genes decades prior to tumor diagnosis. In contrast, driver mutations in mezzo-forte and forte tumors are generally late clonal events acquired close to tumor diagnosis, thus potentially facilitating target identification with a single biopsy. The mutational signature associated with direct exposure to tobacco smoking (SBS4) was not observed in our study, even in cases with reported exposure to second-hand tobacco smoke. No significant differences of mutational spectra were found between passive and non-passive smokers. While genes within the RTK-RAS pathway have distinct impacts on survival, mutations in TP53, CHEK2, EGFR, or loss of 15q or 22q independently doubled mortality. These genomic alterations in forte and mezzo-forte subtypes, and stem cell-like features in piano tumors create avenues for personalized therapeutic strategies in LCINS. Citation Format: Tongwu Zhang, Ludmil B. Alexandrov, Wei Zhao, Jian Sang, Jianxin Shi, Bin Zhu, Dmitry A. Gordenin, Montserrat Garcia-Closas, Qing Lan, Nathaniel Rothman, Stephen J. Chanock, David C. Wedge, Maria Teresa Landi. Genomic and evolutionary classification of lung cancer in never smokers from the Sherlock-Lung study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 865.
Abstract 215: Developing an integrated prognostic score using germline risk variants and RNA expression from primary breast cancers for prognostication of survival across subtypes
Authors: Padma Sheila Rajagopal, Yanyu Liang, Alvaro Barbeira, Owen Melia, Jiamao Zheng, Yonglan Zheng, Toshio Yoshimatsu, Dezheng Huo, Guimin Gao, Olufunmilayo F. Olopade, Hae K. Im
Journal: Cancer Research (2021)

Abstract Introduction: RNA expression offers prognostication in early-stage, hormone-receptor positive breast cancer. We hypothesized that germline risk variants may influence patients after breast cancer onset, and that integration of common germline risk variants with RNA expression may broaden prognostication across subtypes. Methods: We designed two prognostic scores for women of European ancestry using genome-wide association study (GWAS) summary statistics on cancer risk from the Breast Cancer Association Consortium (133,384 cases and 113,789 controls) and individual-level genotype/clinical information from 694 women in The Cancer Genome Atlas (TCGA). PrediXcan, a transcriptome-wide association tool family, was used to generate gene-level weights of association to breast cancer risk that were then multiplied by gene expression levels. A predicted transcriptomic score (PTRS) used predicted expression levels based on germline genotypes, and an observed transcriptomic score (OTRS) used normalized RNA expression. Cox proportional hazards tested score performance on overall survival (OS) and progression-free survival (PFS). Results: Estimation performance is shown in Table 1. A 1388-gene PTRS with range from -0.5 to 4 offered initial prognostic ability in OS across subtypes (HR: 0.69 per 1-point increase, 95% CI: 0.48-1.00, p-value 0.05). This trend persisted with clinical covariates in a multivariate regression (HR: 0.61, 95% CI: 0.36-1.00, p=0.06). No associations were seen between PTRS/PFS or OTRS/OS. OTRS/PFS trended toward statistical significance with clinical factors included (age, AJCC staging). PTRS for OS did not show subtype-specific performance. Conclusion: Patients with breast cancer do not have broad access to prognostic data across subtypes. Integration of germline and somatic data types offers potential to improve current limitations in prognostic testing for patients. Table 1.Performance of predicted transcriptomic score (PTRS) and observed transcriptomic score (OTRS)Cox regression hazard ratio95% CIp-valuePolygenic score - OS0.960.64-1.400.84PTRS-OS0.690.48-1.000.05OTRS-OS0.990.97-1.000.66Polygenic score - PFS1.100.77-1.600.55PTRS - PFS1.100.80-1.600.49OTRS - PFS0.980.96-1.000.10 Citation Format: Padma Sheila Rajagopal, Yanyu Liang, Alvaro Barbeira, Owen Melia, Jiamao Zheng, Yonglan Zheng, Toshio Yoshimatsu, Dezheng Huo, Guimin Gao, Olufunmilayo F. Olopade, Hae K. Im. Developing an integrated prognostic score using germline risk variants and RNA expression from primary breast cancers for prognostication of survival across subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 215.