Genomic studies controvert the existence of the CUX1 p75 isoform

AbstractCUX1, encoding a homeodomain-containing transcription factor, is recurrently deleted or mutated in multiple tumor types. In myeloid neoplasms, CUX1 deletion or mutation carries a poor prognosis. We have previously established that CUX1 functions as a tumor suppressor in hematopoietic cells across multiple organisms. Others, however, have described oncogenic functions of CUX1 in solid tumors, often attributed to truncated CUX1 isoforms, p75 and p110, generated by an alternative transcriptional start site or post-translational cleavage, respectively. Given the clinical relevance, it is imperative to clarify these discrepant activities. Herein, we sought to determine the CUX1 isoforms expressed in hematopoietic cells and find that they express the full-length p200 isoform. Through the course of this analysis, we found no evidence of the p75 alternative transcript in any cell type examined. Using an array of orthogonal approaches, including biochemistry, proteomics, CRISPR/Cas9 genomic editing, and analysis of functional genomics datasets across a spectrum of normal and malignant tissue types, we found no data to support the existence of the CUX1 p75 isoform as previously described. Based on these results, prior studies of p75 require reevaluation, including the interpretation of oncogenic roles attributed to CUX1.

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Comprehensive genomic profiling in FIGHT-202 reveals the landscape of actionable alterations in advanced cholangiocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4080 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4080-4080 ◽

Cited By ~ 4

Author(s):

Ian M. Silverman ◽

Karthikeyan Murugesan ◽

Christine F. Lihou ◽

Luis Féliz ◽

Garrett M. Frampton ◽

...

Keyword(s):

Point Mutations ◽

Fusion Partner ◽

Genomic Profiling ◽

Cancer Genes ◽

Exact Test ◽

Multiple Tumor ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Genomic Studies ◽

Tumor Types

4080 Background: Genomic studies of cholangiocarcinoma (CCA) have identified actionable alterations in multiple genes including IDH1, IDH2, FGFR2 and BRAF, but no targeted therapies have been approved for this indication. Pemigatinib (formerly INCB054828) is a selective FGFR1-3 inhibitor currently being evaluated in multiple tumor types, including advanced CCA harboring FGFR2 rearrangements. Comprehensive genomic profiling (CGP) was used to identify and enroll advanced CCA patients with FGFR2 rearrangements into FIGHT-202 (NCT02924376). Here we provide an overview of the genomic landscape of advanced CCA and identify actionable alterations. Methods: CGP was performed on tumor samples from 1104 patients with advanced CCA using FoundationOne, a broad-based genomic panel which identifies mutations, rearrangements, and amplifications in 315 cancer genes. Results: The most frequently altered genes in advanced CCA were TP53 (38.1%), CDKN2A/B (28.8%), KRAS (21.9%), ARID1A (15.7%), SMAD4 (11.3%), BAP1 (10.6%), IDH1 (10.5%), PBRM1 (10.0%), FGFR2 (9.4%), ERBB2 (7.6%), PIK3CA (7.0%), MDM2/ FRS2 (5.8%), and BRAF (4.7%). FGFR2: BAP1 was the most significantly co-occurring alteration pair (odds ratio = 8.5; q-value = 1.08 x 10-13, Fisher’s exact test). 42.9% of patients had at least one alteration for which a targeted agent has been either approved or is under investigation. 91 (8.2%) patients had FGFR2 rearrangements, involving 44 unique partner genes, 37 (84.1%) of which were observed only once. The most prevalent FGFR2 rearrangement partner, BICC1, occurred in only 28 (30.7%) FGFR2 rearrangement positive patients. FGFR2 activating point mutations were found in 13 (1.2%) patients. Of 1,091 evaluable patients for microsatellite instability (MSI) or tumor mutational burden (TMB), only 10 (0.9%) were MSI-H and 13 (1.2%) had high TMB (≥ 20 mutations/megabase). None of the MSI-H or TMB-High patients had FGFR2, IDH1 or IDH2 activating alterations. Conclusions: The high frequency (42.9%) of patients with actionable alterations and myriad FGFR2 rearrangement partners strongly support the use of fusion partner-agnostic CGP in advanced CCA.

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Bayesian cell-type deconvolution and gene expression inference reveals tumor-microenvironment interactions

10.1101/2020.01.07.897900 ◽

2020 ◽

Cited By ~ 2

Author(s):

Tinyi Chu ◽

Charles G. Danko

Keyword(s):

Gene Expression ◽

Cell Types ◽

Malignant Cell ◽

Malignant Cells ◽

Cellular Composition ◽

Rna Seq ◽

Cell Type ◽

Primary Glioblastoma ◽

Multiple Tumor ◽

Tumor Types

AbstractUnderstanding the complicated interactions between cells in their environment is a major challenge in genomics. Here we developed BayesPrism, a Bayesian method to jointly predict cellular composition and gene expression in each cell type, including heterogeneous malignant cells, from bulk RNA-seq using scRNA-seq as prior information. We conducted an integrative analysis of 1,412 bulk RNA-seq samples in primary glioblastoma, head and neck squamous cell carcinoma, and melanoma using single-cell datasets of 85 patients. We identified cell types correlated with clinical outcomes and explored spatial heterogeneity in tumor state and stromal composition. We refined subtypes using gene expression in malignant cells, after excluding confounding non-malignant cell types. Finally, we identified genes whose expression in malignant cells correlated with infiltration of macrophages, T cells, fibroblasts, and endothelial cells across multiple tumor types. Our work introduces a new lens that uses scRNA-seq to accurately infer cellular composition and expression in large cohorts of bulk data.

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Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Molecular Cancer ◽

10.1186/s12943-020-01305-3 ◽

2021 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Ruijuan Du ◽

Chuntian Huang ◽

Kangdong Liu ◽

Xiang Li ◽

Zigang Dong

Keyword(s):

Cancer Therapy ◽

Molecular Mechanisms ◽

Aurora Kinase ◽

Interacting Proteins ◽

Multiple Tumor ◽

Oncogenic Pathways ◽

Wide Range ◽

The Family ◽

Tumor Types ◽

Cancer Tissues

AbstractAurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

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Fibroblasts Influence the Efficacy, Resistance, and Future Use of Vaccines and Immunotherapy in Cancer Treatment

Vaccines ◽

10.3390/vaccines9060634 ◽

2021 ◽

Vol 9 (6) ◽

pp. 634

Author(s):

Bailee H. Sliker ◽

Paul M. Campbell

Keyword(s):

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Fibroblast Activation Protein ◽

Cancer Associated Fibroblasts ◽

Cell Type ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

New Research ◽

Tumor Types

Tumors are composed of not only epithelial cells but also many other cell types that contribute to the tumor microenvironment (TME). Within this space, cancer-associated fibroblasts (CAFs) are a prominent cell type, and these cells are connected to an increase in tumor progression as well as alteration of the immune landscape present in and around the tumor. This is accomplished in part by their ability to alter the presence of both innate and adaptive immune cells as well as the release of various chemokines and cytokines, together leading to a more immunosuppressive TME. Furthermore, new research implicates CAFs as players in immunotherapy response in many different tumor types, typically by blunting their efficacy. Fibroblast activation protein (FAP) and transforming growth factor β (TGF-β), two major CAF proteins, are associated with the outcome of different immunotherapies and, additionally, have become new targets themselves for immune-based strategies directed at CAFs. This review will focus on CAFs and how they alter the immune landscape within tumors, how this affects response to current immunotherapy treatments, and how immune-based treatments are currently being harnessed to target the CAF population itself.

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Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Cancers ◽

10.3390/cancers13040678 ◽

2021 ◽

Vol 13 (4) ◽

pp. 678 ◽

Cited By ~ 1

Author(s):

Adrien Procureur ◽

Audrey Simonaggio ◽

Jean-Emmanuel Bibault ◽

Stéphane Oudard ◽

Yann-Alexandre Vano

Keyword(s):

Cell Death ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Mitotic Cell ◽

Immunogenic Cell Death ◽

Dna Damages ◽

Multiple Tumor ◽

Tumor Types

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

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Development and Performance of a CD8 Gene Signature for Characterizing Inflammation in the Tumor Microenvironment Across Multiple Tumor Types

Journal of Molecular Diagnostics ◽

10.1016/j.jmoldx.2021.06.002 ◽

2021 ◽

Author(s):

Peter M. Szabo ◽

Saumya Pant ◽

Scott Ely ◽

Keyur Desai ◽

Esperanza Anguiano ◽

...

Keyword(s):

Tumor Microenvironment ◽

Gene Signature ◽

Multiple Tumor ◽

And Performance ◽

Tumor Types

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Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

International Journal of Molecular Sciences ◽

10.3390/ijms22010190 ◽

2020 ◽

Vol 22 (1) ◽

pp. 190

Author(s):

Fulvio Borella ◽

Mario Preti ◽

Luca Bertero ◽

Giammarco Collemi ◽

Isabella Castellano ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

State Of The Art ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Survival Rates ◽

Younger Women ◽

Multiple Tumor ◽

Tumor Types

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

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Abstract 2778: Comparative multiplex digital phenotyping of the tumor microenvironment across multiple tumor types using a well characterized multi-tumor tissue microarray

10.1158/1538-7445.am2021-2778 ◽

2021 ◽

Author(s):

Marie Cumberbatch ◽

Douglas Wood ◽

Christopher Womack ◽

Milan Bhagat ◽

Mael Manesse ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tissue Microarray ◽

Tumor Tissue ◽

Multiple Tumor ◽

Digital Phenotyping ◽

Tumor Types

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Radioembolization for Rare Metastatic Disease

Digestive Disease Interventions ◽

10.1055/s-0041-1729875 ◽

2021 ◽

Author(s):

Andrew S. Niekamp ◽

Govindarajan Narayanan ◽

Brian J. Schiro ◽

Constantino Pena ◽

Alex Powell ◽

...

Keyword(s):

Colorectal Cancer ◽

Hepatocellular Carcinoma ◽

Metastatic Colorectal Cancer ◽

Treatment Modality ◽

Treatment Options ◽

Efficacy And Safety ◽

Multiple Tumor ◽

Tumor Types ◽

Hepatic Malignancies ◽

Yttrium 90

AbstractRadioembolization has become a widespread treatment modality for both primary and metastatic hepatic malignancies. Although the majority of data and indication for yttrium-90 radioembolization have been for hepatocellular carcinoma and metastatic colorectal cancer, radioembolization with yttrium-90 has rapidly expanded into the treatment options for multiple tumor types with metastases to the liver. This article reviews the clinical data and expanding utilization of radioembolization for rare metastatic diseases with an emphasis on efficacy and safety.

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