tbuckley/cabot-search huggingface dataset:
Abstract 923: Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in Kras mutant lung cancer
Authors: Hyejin Choi, Jiehui Deng, Shuai Li, Tarik Silk, Lauren Dong, Elliott J. Brea, Sean Houghton, David Redmond, Hong Zhong, Jonathan Boiarsky, Esra A. Akbay, Paul D. Smith, Taha Merghoub, Kwok-Kin Wong, Jedd D. Wolchok
Journal: Cancer Research (2020)

Abstract KRAS is one of the most commonly identified driver oncogenes in non-small cell lung cancer (NSCLC) and is frequently associated with disease refractory to currently available modalities of treatment. Targeted therapy to inhibit MEK signaling has shown promising tumor growth control in preclinical models, but is followed by quick rebound in tumor growth. Recently, immune checkpoint blockade has demonstrated clinical activity by dis-inhibiting T cells suppressed in the tumor microenvironment. Thus, we sought to identify the most effective therapy for the treatment of KRAS mutant NSCLC patients by targeting cancer cells and activating immune infiltrating cell populations concurrently. To achieve this, we focused on studying the impact of pulsatile MEK inhibition on the immune microenvironment utilizing Kras mutant lung cancer cell lines and Kras mutant transgenic lung cancer mouse models. We found that pulsatile MEK inhibition maintained T cell activation better than continuous treatment ex vivo and in vivo. Treatment with two different MEK inhibitors (selumetinib and trametinib) each resulted in higher CTLA-4 and PD-1 expression in T cells using pulsatile treatment, compared to continuous treatment ex vivo. In addition, the pulsatile schedule showed superior anti-tumor effects and delayed drug resistance compared to continuous administration in vivo. Further, a combination of pulsatile MEK inhibitor treatment and CTLA-4 blockade resulted in the most prolonged survival of Kras tumor-bearing mice. Similar experiments in immune-deficient mice confirmed that this prolonged survival is conferred by adaptive immunity. Our findings set the foundation for a combinatorial therapeutic strategy using pulsatile targeted therapy together with immune checkpoint blockade in patients to optimally enhance tumor apoptosis and promote long-term immune response simultaneously. We are now continuing our studies using a KRAS G12C inhibitor to define its immune modulating properties and will then rationally combine with immune based therapy. Citation Format: Hyejin Choi, Jiehui Deng, Shuai Li, Tarik Silk, Lauren Dong, Elliott J. Brea, Sean Houghton, David Redmond, Hong Zhong, Jonathan Boiarsky, Esra A. Akbay, Paul D. Smith, Taha Merghoub, Kwok-Kin Wong, Jedd D. Wolchok. Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in Kras mutant lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 923.
Abstract 286: Regulation of APOBEC3B gene expression through the Rb/E2F pathway
Authors: Pieter A. Roelofs, William L. Brown, Paul N. Span, John W. Martens, Chai Y. Goh, Boon H. Chua, Dennis Kappei, Reuben S. Harris
Journal: Cancer Research (2020)

Abstract The propensity of tumors to increase genomic diversity allows for a bottleneck-type adaptation to anti-cancer treatments. The genomic alterations fueling these adaptations in many different tumor types are, in part, brought about by ongoing endogenous activity of the DNA cytosine deaminase APOBEC3B (A3B). The ability of A3B to convert DNA cytosine bases into uracils has been shown to facilitate C-to-T transitions, C-to-G transversions, and DNA breakage. While low in healthy tissues, A3B expression and activity is elevated in tumors and may increase further throughout metastatic disease. However, molecular mechanisms responsible for transcriptional upregulation of A3B in tumor cells are poorly understood. Here, we investigate the possibility that the Rb/E2F pathway, which is often dysregulated in breast cancer, contributes to A3B gene expression. First, we cloned the A3B promoter upstream of a luciferase reporter and used a combination of deletion and site-directed mutagenesis to demonstrate that only one out of five in silico predicted E2F binding sites is functionally relevant, as disrupting this site caused constitutive reporter activation. Moreover, expression of the BK polyomavirus T-antigen, which inactivates Rb, induced the reporter and additional activation was not observed by mutating the functional E2F binding site. Second, SILAC-labelled nuclear protein extracts were subjected to affinity purification coupled to quantitative mass spectrometry to compare transcriptional complexes that bound wild-type promoter sequences, but not sequences with mutant E2F binding site promoter elements. These proteomics experiments showed that proteins belonging to the DREAM and PRC1.6-complexes strongly bind the wild-type but not the mutant E2F binding sites. Third, RNAi-mediated knock-down of candidate E2F family members implicated E2F6, and to a lesser extend E2F4, which are components of the PRC1.6 and DREAM complexes, respectively, in A3B gene repression. Taken together, these studies indicate that A3B expression may be suppressed by the concerted effort of two different E2F binding complexes and that Rb inactivation, by viral T-antigen here and genetic mutation as often seen in breast cancer, is able to upregulate A3B gene expression, promote genomic DNA mutagenesis, and fuel tumor evolution. Citation Format: Pieter A. Roelofs, William L. Brown, Paul N. Span, John W. Martens, Chai Y. Goh, Boon H. Chua, Dennis Kappei, Reuben S. Harris. Regulation of APOBEC3B gene expression through the Rb/E2F pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 286.
Abstract 3813: Activation of EGFR induces loss of primary cilia in oral mucosa carcinogenesis
Authors: Fengg yin, Zihao Wei, Jing Li, Liang Xie, Qianming Chen
Journal: Cancer Research (2020)

Abstract Objective: Primary cilia are evolutionally conserved cell structures involving multiple cell functions by sensing extracellular signals. Loss of primary cilia is frequently observed in various cancer types, suggesting that the absence of this organelle may promote tumorigenesis. However, little is known about the role of primary cilia in oral premalignant lesions and oral squamous cell carcinoma (OSCC). Materials and Methods: Immunofluosense staining was carried out to detect the incidence of primary cilia in every stages of oral carcinogenesis from normal to OSCC. Immunohistochemical analysis was used for validating the correlation between the ciliary incidence and the expression level of EGFR in the oral carcinogenesis. Furthermore, the change of primary cilia was detected by activating and inhibiting the EGFR pathway activity in vitro. Results: A significant decrease in the percentage of ciliated cells was found on both oral leukoplakia (OLK), as well as OSCC tissues, compared to normal oral mucosa epithelium, and this loss of cilia was independent of the increased proliferative index. A parallel increase of EGFR activity was observed in OLK and OSCC tissues. In addition, EGF stimulation induced obvious primary cilia absorption, whereas inhibition of EGFR by gefitinib significantly restored cilia formation in vitro. We further found that the activation of EGFR resulted in the phosphorylation of AURKA, a pivotal kinase promoting disassembly of primary cilia. Conclusion: EGFR-AURKA pathway might be a critical regulator of ciliary loss in the carcinogenesis of oral mucosa. This may provide insight into the development of new therapeutic strategies to prevent oral premalignant lesions from becoming malignant. Citation Format: Fengg yin, Zihao Wei, Jing Li, Liang Xie, Qianming Chen. Activation of EGFR induces loss of primary cilia in oral mucosa carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3813.
Abstract 6213: Extracellular vesicles <i>MDM2</i>-DNA derived from dedifferentiated liposarcoma induces MMP2 production from preadipocytes
Authors: Lucia Casadei, Federica Calore, Ameya Deshmukh, Abeba Zewdu, Paolo Fadda, Danielle Braggio, Martin Wabitsch, Carlo M. Croce, Dina Lev, Raphael Pollock
Journal: Cancer Research (2020)

Abstract Dedifferentiated liposarcoma (DDLPS) is molecularly characterized by wt p53 and MDM2 gene amplification causing MDM2 protein over-production, the key oncogenic process in DDLPS. Commonly located in fat-bearing retroperitoneal areas, almost 60% of DDLPS patients undergo multifocal recurrence, typically amenable to palliative treatment only, and occasionally develop distant metastasis. These factors lead to an abysmal 10% 10 year overall survival rate. Tumor cell-derived extracellular vesicles (EVs) can facilitate loco-regional malignancy dissemination by depositing molecular factors that participate in the development of pre-metastatic niches for tumor cell implantation and growth. High number of MDM2 DNA molecules was identified within EVs from DDLPS patient serum (ROC vs normal; 0.95) as well as from DDLPS cell lines. This MDM2 DNA could be transferred to preadipocytes (P-a), a major and ubiquitous cellular component of the DDLPS tumor microenvironment (TME), with subsequent P-a production of matrix metalloproteinase 2 (MMP2), a critical component in the metastatic cascade. Since multifocal loco-regional DDLPS spreading is the main cause of the remarkably high lethality of this disease, a better understanding of the underlying oncogenic processes and their regulatory mechanisms is essential to improve the outcome of this devastating disease. Citation Format: Lucia Casadei, Federica Calore, Ameya Deshmukh, Abeba Zewdu, Paolo Fadda, Danielle Braggio, Martin Wabitsch, Carlo M. Croce, Dina Lev, Raphael Pollock. Extracellular vesicles MDM2-DNA derived from dedifferentiated liposarcoma induces MMP2 production from preadipocytes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6213.
Abstract 3466: Can grape powder supplemented diet prevent prostate cancer progression
Authors: Tanvi Joshi, Ishani Patel, Avinash Kumar, Virginia Donovan, Anait S. Levenson
Journal: Cancer Research (2020)

Abstract Epidemiological and experimental studies suggest a correlation between diet, particularly fat consumption and the risk of developing prostate cancer (PCa). In previous studies, we reported that stilbenes, namely resveratrol and pterostilbene, restrained prostatic intraepithelial neoplasia (PIN) formation and reduced tumor development and progression in mice models of PCa with high expression of metastasis-associated protein 1 (MTA1), an epigenetic modifier involved in the regulation of prostate cancer progression and metastasis. In this report, we evaluated three major aspects: 1) whether altering diet [low fat diet (LFD) versus high fat diet (HFD)] affects PCa progression; 2) whether grape powder (GP) supplementation to the diets protects against PCa progression, and 3) whether MTA1 targeting is the main mechanism of action. We addressed these questions by utilizing the prostate-specific (PB-Cre4) Pten heterozygous transgenic mice (Pten+/f), which mimic slow-growing PCa progression in humans. Upon accumulating 56 mice of desired genotype, we randomized mice in two major groups and fed them ad libitum with either LFD or HFD. Each of these diets contained either 0% GP or 10% GP supplementation. The same groups were assigned for control wild-type (WT) mice (Pten+/f; Cre-). After 33 weeks on corresponding diets, mice were sacrificed and urogenital system was collected for histological and immunochemical analysis. In addition, protein and RNA was isolated from the prostate tissues for molecular analysis. Blood was also collected for cytokines evaluation and pharmacokinetic analysis. The results demonstrated the following beneficial effects of GP supplementation: LFD and HFD - fed Pten+/f mice showed added favorable histopathology (H&amp;E), intact basal layer (SMA) and luminal cells (CK-8); significant reduction of the proliferative rate of prostate epithelial cells (Ki67); non-significant trend for reducing HFD-induced MTA1 expression in Pten+/f and WT mice; protective effects against “bad” genotype and HFD-induced activation of Akt pathway; attenuation of HFD-associated increase in AR levels in both Pten+/f and WT mice; reduction of HFD-provoked increased inflammation marker IL-1β levels; non-significant trend for reducing angiogenesis (CD31; VEGF-C) in Pten+/f mice; and trend towards decreasing inflammatory TGFβ1 expression in Pten+/f mice. Curious results were obtained concerning the effect of GP on apoptosis. There were no significant changes in body weight, food intake or fat intake in GP supplemented diets groups. Citation Format: Tanvi Joshi, Ishani Patel, Avinash Kumar, Virginia Donovan, Anait S. Levenson. Can grape powder supplemented diet prevent prostate cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3466.
COVID-19 and Cancer: Unintended Consequences
Authors: Margaret Tempero
Journal: Journal of the National Comprehensive Cancer Network (2020)

Unintended Consequences I had hoped that I could stop dwelling on the pandemic by now.Unfortunately, we are still in this battle, and I can't stop talking about it.For those who care for patients, it has been doubly hard.We worry about our own safety and, more importantly, about the safety of our patients.COVID-19 and cancer is a very bad combination.But the fight to protect patients with cancer from COVID-19 is only part of the story; more trouble is coming.Many have wondered why clinic volumes are down and why emergency departments aren't busy.Initially I thought it was a temporary lull and that as people became accustomed to new precautions we would return to "business as usual."Perhaps things have picked up a little, but we are not functioning on all cylinders yet.In late July, JCO Clinical Cancer Informatics published a fascinating and, I think, rather terrifying article about clinical encounters for patients with cancer and about cancer screening encounters since the pandemic began.The journal compared monthly data from this year versus 2019. 1 This was a large informatics exercise involving 20 US institutions and 28 million patients.For patients with cancer, the largest decline in encounters appeared in April and the greatest decreases were in patients with breast cancer (47.7%), prostate cancer (49.1%), and melanoma (51.8%).Presumably, some of these decreases might reflect delayed surveillance visits or second opinion consultations that might, arguably, have little impact on outcomes.Instead, the really scary data showed decreases in cancer screening encounters.Breast and colorectal cancer screenings dropped by 89.2% and 84.5%, respectively.Yikes!If this trend continues, we are likely to see many patients diagnosed at later stages, requiring more complex care and more resources.And as the pandemic wanes, the pent up demand for cancer screening studies could put a major strain on our capacity to provide services, creating further delays in diagnosis.I fear COVID-19 will have dark effects on cancer care and clinical outcomes for a very long time.I'm not sure how much we can change this, but I believe that as long as we have the capacity to provide screening procedures, we should urge the public not to neglect this important aspect of healthcare maintenance.Frankly, I think my hospital and clinic are pretty safe places to be.We've thought a lot about how to secure COVID-19 care sites and providers to prevent contamination.We disinfect between encounters, and we approach every patient as someone who might be an asymptomatic carrier.I'm reminded of a quote from Robert Frost: "In 3 words I can sum up everything I've learned about life: it goes on."People will continue to get cancer and require care.Our job is to ensure that every step, from diagnosis to treatment, is safe.
Treating toxic epidermal necrolysis with systemic immunomodulating therapies: A systematic review and network meta-analysis
Authors: Tsung-Yu Tsai, I-Hsin Huang, Yuan-Chen Chao, Hua Li, Tyng-Shiuan Hsieh, Hsiao-Han Wang, Yu-Ting Huang, Chun-Yuan Chen, Ying-Chih Cheng, Po-Hsiu Kuo, Yu-Chen Huang, Yu-Kang Tu
Journal: Journal of the American Academy of Dermatology (2020)
Abstract 1699: IMMUcan: Broad cellular and molecular profiling of the human tumor microenvironment
Authors: Henoch S. Hong, Robin Liechti, Christoph Reinhard, Marie M. Morfouace
Journal: Cancer Research (2020)

Abstract The development of next generation therapeutics for cancer patients requires an improved understanding of the underlying mechanisms of resistance to existing therapies as well as novel biomarkers that can help identify patients most likely to benefit from the treatments. Most studies addressing these questions have predominantly relied on a limited set of tumor profiling techniques or have been hampered by relatively small patient numbers. In response to this need, the IMMUcan consortium has been formed. Co-led by the EORTC (Brussels, Belgium), SIB (Lausanne, Switzerland), Eli Lilly (Indianapolis, IN, USA) and Merck KGaA (Darmstadt, Germany), IMMUcan is an EU-funded, public-private partnership of expert immunologists, cell biologists, technology developers and clinical key opinion leaders. The mission of IMMUcan is to generate broad molecular and cellular profiling data of the tumor microenvironment from up to 3,000 patients derived from five indications: non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer and breast cancer. Most of these patients will be treated under standard of care and recruited via the EORTC-SPECTA infrastructure. All acquired tumor samples will undergo detailed and standardized analyses applying diverse profiling modalities including whole exome sequencing to determine the mutational landscape, total RNA sequencing for transcriptome analysis, multiplex immunofluorescence (IF) and imaging mass cytometry (IMC) facilitating the assessment of approx. 80 proteins at single cell resolution. To avoid inter-lab variations, each profiling method (sequencing, IF or IMC) will be performed by a single expert laboratory, which will process all IMMUcan samples. These data will be integrated with clinical information and centralized in a Knowledge Management System. Once published, the entire IMMUcan dataset will be made available to the scientific community for further study and interrogation. IMMUcan also acquires blood samples, including PBMCs, saliva as well as fresh-frozen stool samples. In addition, we have established workflows to generate reports documenting clinically actionable molecular alterations, which are returned to the treating physicians within 6-8 weeks. Thus far, 31 patients have been recruited and first tumor profiling data from these patients will be presented. Funding: IMI2 JU grant agreement 821558, supported by EU's Horizon 2020 and EFPIA. Citation Format: Henoch S. Hong, Robin Liechti, Christoph Reinhard, Marie M. Morfouace, IMMUcan consortium. IMMUcan: Broad cellular and molecular profiling of the human tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1699.
Abstract 3641: Successful classification of hematological neoplasm by array profile
Authors: Colin Grace, Temenuzhka Boneva, Elisabeth P. Nacheva
Journal: Cancer Research (2020)

Abstract In addition to structural chromosome aberrations resulting in fusion genes, the genome profile of haematological malignancies is characterized by copy number changes (gains and losses) relative to the ploidy level. Array comparative genome hybridization (aCGH)1 Combined with FISH and/or multiplex PCR array screening offers a reliable tool for assessment of genome complexity in haematological malignancies in diagnostic settings. The aCGH assay in our diagnostic algorithm uses 8 × 60K SurePrint G3 (Agilent, USA). The slides are scanned to measure the fluorescence ratio (FR), software evaluates imbalances. We recognize that the raw data in the form of log ratios, some 64,000 data points, contain sufficient information to identify the disease category without resorting to converting the log ratios to gains and losses and mapping them to individual chromosomes, a process open to operator interpretation. As an alternative and bearing in mind the current interest in machine learning, we attempted to auto-classify the data for the modest collection of 2,300 patient samples in our archive, according to their WHO classification. We were able to collect 175 samples for each group classified as myelodisplasia (MDS), acute myeloid leukemia (AML), myeloma (MM) and chronic lymphocytic leukemia (CLL), We used a Logistic Regression Classifier implemented in Mathematica 12. The classifier took only 2 minutes on average to complete the training. We took a total of 700 array sample files, each of 59,032 data points, of which 100 were randomly selected as a validation set. The balance of 600 files, distributed evenly and randomly over the 4 test diseases were used as a training set. We used a Confusion Matrix to evaluate and display the results as shown in the table. Confusion MatrixAMLCLLMDSMMTotalAML1609025CLL0150116MDS0116017MM1021417Predicted17162715 In spite of the small training set we correctly classified the MDS (16/17), CLL (15/16) and MM (14/17), 9 AML were reported as MDS a due to sharing genome imbalances. There was also confusion between the B cell disorders, MM and CLL known to carry overlapping genome aberrations. The auto classification offered by this method is a promising attempt to support a speedy and reliable assessment of genome complexity. There is no doubt that a better classifier would have been created with a larger training set. 1 Kallioniemi A et al., Kallioniemi OP, Sudar DA, Rutovitz D, Gray JW, Waldman F, Pinkel D (1992). “Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors”. Science. 258 (5083): 818-821). Citation Format: Colin Grace, Temenuzhka Boneva, Elisabeth P. Nacheva. Successful classification of hematological neoplasm by array profile [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3641.
Classification of 2 distinct wound types in recessive dystrophic epidermolysis bullosa: A retrospective and cohort natural history study
Authors: Daniel C. Solis, Claudia Teng, Emily S. Gorell, Melissa Barriga, Jaron Nazaroff, Shufeng Li, Ying Lu, Anna Bruckner, M. Peter Marinkovich, Jean Y. Tang
Journal: Journal of the American Academy of Dermatology (2020)