Macrophage Flipping from Foe to Friend: A Matter of Interest in Breast Carcinoma Heterogeneity Driving Drug Resistance

2019 ◽  
Vol 19 (3) ◽  
pp. 189-198 ◽  
Author(s):  
Ishita Tandon ◽  
Nilesh Kumar Sharma
Keyword(s):  
Drug Resistance ◽  
Breast Carcinoma ◽  
Tumor Heterogeneity ◽  
Cellular Heterogeneity ◽  
Cancer Type ◽  
Tumor Type ◽  
Cancer Types ◽  
Clinical Drugs ◽  
Molecular Aspects ◽  
Cancer Immunotherapeutic

Tumor heterogeneity within various cancer types including breast carcinoma is pivotal in the manifestations of tumor hallmarks. Tumor heterogeneity is seen as a common landscape where intra-tumoral components including cellular and non-cellular factors create an interface with outside environment that leads to the unique identity of a specific cancer type. Among various contributors to tumor heterogeneity, cellular heterogeneity immensely plays a role in drug resistance and relapse of cancer. Within cellular heterogeneity of tumor, tumor-associated macrophages (TAMs) are the pro-tumor type of immune cells that promote growth, metastasis and drug resistance in breast carcinoma and other cancer types. Revealing the molecular aspects of TAMs can provide a breakthrough to remove therapeutics blockade to existing drugs and this understanding in future will pave the way for a new class of cancer immunotherapeutic. This review addresses current understanding of the role of TAMs in breast carcinoma hallmarks and clarifies the current scenario of pre-clinical drugs directed to tame pro-cancer TAMs.

scholarly journals The transcriptional hallmarks of intra-tumor heterogeneity across a thousand tumors

2021 ◽  
Author(s):  
Avishai Gavish ◽  
Michael Tyler ◽  
Dor Simkin ◽  
Daniel Kovarsky ◽  
L. Nicolas Gonzalez Castro ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Cancer Therapeutics ◽  
Cell Types ◽  
Cancer Type ◽  
Malignant Cells ◽  
Cellular Processes ◽  
Narrow View ◽  
Cancer Types ◽  
Context Specific ◽  
Tumor Types

Each tumor contains malignant cells that differ in genotype, phenotype, and in their interactions with the tumor micro-environment (TME). This results in distinct integrated cellular states that govern intra-tumor heterogeneity (ITH), a central challenge of cancer therapeutics. Dozens of recent studies have begun to describe ITH by single cell RNA-seq, but each study typically profiledonly a small number of tumors and provided a narrow view of transcriptional ITH. Here, we curate, annotate and integrate the data from 77 different studies to reveal the patterns of ITH across 1,163 tumor samples covering 24 tumor types. Focusing on the malignant cells, we find thousands of transcriptional ITH programs that can be described by 41 consensus meta-programs (MPs), each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many different tumors. The MPs cover diverse cellular processes and differ in their cancer-type distribution. General MPs associated with processes such as cell cycle and stress vary within most tumors, while context-specific MPs reflect the unique biology of particular cancer types, often resembling developmental cell types and suggesting the co-existence of variable differentiation states within tumors. Some of the MPs are further associated with overall tumor proliferation or immune state, highlighting their potential clinical significance. Based on functional similarities among MPs, we propose a set of 11 hallmarks that together account for the majority of observed ITH programs. Given the breadth and scope of the investigated cohort, the MPs and hallmarks described here reflect the first comprehensive pan-cancer description of transcriptional ITH.

Costs and outcomes associated with febrile neutropenia-related hospitalizations across patients with varying cancer types: A retrospective analysis

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20560-e20560
Author(s):  
M. B. Schilling ◽  
C. Parks ◽  
R. G. Deeter
Keyword(s):  
Febrile Neutropenia ◽  
Healthcare Cost ◽  
Opportunistic Infections ◽  
Metastatic Breast ◽  
Clinical Impact ◽  
Cancer Type ◽  
Tumor Type ◽  
Healthcare Database ◽  
Hospitalization Costs ◽  
Cancer Types

e20560 Background: Neutropenia, the major dose-limiting toxicity of chemotherapy, is a frequent, often serious, and sometimes fatal complication of myelosuppressive chemotherapy. Its economic and clinical impact is often under-appreciated, and thus this study evaluates the contribution of febrile neutropenia (FN) by tumor type as related to healthcare cost and mortality. Methods: FN patients in this study were identified as having cancer (ICD-9-CM: 140.xx - 208.xx), neutropenia (288.0x) and either opportunistic infections (110 total codes) or fever of unknown origin (780.6) who were hospitalized between 1/05 and 6/08 in a retrospective cohort study from the Aspen US healthcare database (∼11 million pts, >342 inpatient facilities, and >300 million charge-detail records). Unadjusted mean healthcare cost of hospitalization, length of hospital stay (LOS), and mortality rates were calculated, stratifying by cancer type (breast, metastatic breast, and lung cancers, non-Hodgkin lymphoma (NHL), or other hematologic tumors). Results: Among 598 hospitalized patients (mean age 63 years; 53% female) with cancer experiencing FN, the mean cost of hospitalization, LOS and mortality varied significantly by tumor type ( Table ). Conclusions: FN hospitalizations are costly and may be associated with significant mortality. Considerable variations exist across cancer types for hospitalization costs, LOS and mortality. The tumor type is important in assessing the economic and clinical impact of FN hospitalizations. [Table: see text] [Table: see text]

Comprehensive analysis of advanced-stage solid tumors from TCGA reveal widespread variation of genomics evidence levels across cancer types.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13547-e13547
Author(s):  
Dilhan Weeraratne ◽  
Elisa Napolitano Ferreira ◽  
Miguel Mitne Neto ◽  
Hu Huang ◽  
David Brotman ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
The Cancer Genome Atlas ◽  
Braf V600e ◽  
Precision Oncology ◽  
Cancer Type ◽  
Tumor Type ◽  
Advanced Stage ◽  
Level Of Evidence ◽  
Cancer Types ◽  
Level 1

e13547 Background: Improved scalability and affordability of next generation sequencing (NGS) has pivoted cancer care toward genomics-driven treatment decisions. Particularly in advanced-stage or refractory cancer, clinical insights gleaned from NGS have become an integral option as these patients have typically exhausted all lines of available therapy. As precision oncology evolves, NGS is expected to have a differential impact based on the cancer type. In this study, a comprehensive NGS panel was used to determine the strength of clinical evidence in various advanced stage tumor samples from The Cancer Genome Atlas (TCGA). Methods: A hybrid capture panel, Oncofoco, was developed to evaluate SNVs, INDELs, CNVs and TMB in 366 genes. The panel’s utility was validated by interrogating a broader cohort of 2847 TCGA samples (advanced tumors with T3 or T4; or N > = 1; or M > = 1). Watsonä for Genomics, an artificial intelligence offering, was used for variant interpretation and annotation of the 366 genes. A clinical evidence classification system that evaluated the strength of biomarker/drug response associations was used for annotation with level 1/R1 strongest and level 4 weakest from clinical literature, FDA drug labels and guidelines (PMID:28890946). Results: The highest level of evidence for the top nine frequently occurring advanced stage cancers in TCGA is shown in Table. Conclusions: Thyroid cancer and cutaneous melanoma have emerged as the cancer types with the most level 1 evidence (FDA approved drugs) owing to BRAF V600E mutations. Kidney and prostate cancers show no cases with level 1 evidence and also had the largest fraction of unactionable tumors. Over half of colorectal cancer cases had level R1 resistance evidence attributed to KRAS and NRAS mutations. The clinical utility of NGS in late-stage refractory cancer varies widely by tumor type. The presence of level 3 and level 4 evidence in all cancer types bodes well for the development of new targeted drugs. [Table: see text]

scholarly journals Duality of glucocorticoid action in cancer: tumor-suppressor or oncogene?

2021 ◽  
Author(s):  
Isabel Mayayo-Peralta ◽  
Wilbert Zwart ◽  
Stefan Prekovic
Keyword(s):  
Immune Response ◽  
Drug Resistance ◽  
Transcription Factor ◽  
Lung Function ◽  
Human Biology ◽  
Cancer Type ◽  
Disease Development ◽  
Cancer Tumor ◽  
Molecular Aspects ◽  
Glucocorticoid Action

Glucocorticoid receptor (GR) is a key homeostatic regulator involved in governing immune response, neuro-integration, metabolism and lung function. In conjunction with its pivotal role in human biology, GR action is critically linked to pathology of various disease types, including cancer. While pharmacological activation of GR has been used for treatment of various liquid cancers, its role in solid cancers is less clearly defined and seems to be cancer-type dependent. This review focuses on the molecular aspects of GR biology, spanning the structural and functional basis of response to glucocorticoids, as well as how this transcription factor operates in cancer, including the implications in disease development, progression and drug resistance.

scholarly journals RADT-21. NATIONAL PRACTICE PATTERNS AND OUTCOMES OF STEREOTACTIC BODY RADIOTHERAPY VS. CONVENTIONAL EXTERNAL BEAM RADIOTHERAPY FOR SPINAL METASTASES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii186-ii186
Author(s):  
Asad Lak ◽  
Nayan Lamba ◽  
Timothy Smith ◽  
Bryan Iorgulescu
Keyword(s):  
Stereotactic Body Radiotherapy ◽  
Practice Patterns ◽  
External Beam Radiotherapy ◽  
Spinal Metastases ◽  
Cancer Type ◽  
External Beam ◽  
Tumor Type ◽  
Single Fraction ◽  
Cancer Types ◽  
National Practice

Abstract INTRODUCTION Up to 10% of cancer patients experience spinal cord compression from metastatic disease. Palliation and local control were traditionally pursued with conventional external beam radiotherapy (cEBRT), but advancements in image-guidance and intensity-modulation for stereotactic body radiotherapy (SBRT) have dramatically changed the management of these lesions. Herein we evaluate the national practice patterns and outcomes associated with cEBRT vs. SBRT. METHODS U.S. patients newly diagnosed with metastatic cancer necessitating RT to the spine were identified from the National Cancer Database (2004-2016), stratified by RT modality and cancer type, and evaluated using multivariable logistic regression and Cox proportional hazards. RESULTS 34,759 U.S. patients required spinal RT within 3 months of initial stage 4 cancer presentation, primarily for lung adenocarcinoma (25%), lung small cell carcinoma (14%), and prostatic (12%) metastases. Patients overwhelming received cEBRT (30Gy/10; 50%), followed by hypo-fractionated SBRT (15-30Gy/2-6; 11%) and single-fraction SBRT (i.e. stereotactic radiosurgery, SRS; 15-24Gy/1; 0.9%); whereas 38% received another regimen (e.g. 30-37.5Gy/12-15 or 40Gy/20). From 2004→2016, the rates of single-fraction SRS (0.4→1.9%) and hypo-fractionated SBRT (13.1→23.6%) increased, whereas cEBRT (86.5→74.4%) decreased. SBRT was significantly more likely to be utilized at academic hospitals as compared to cEBRT (OR 0.57; 95% CI: 0.49-0.66; p< 0.01). SBRT was more likely utilized for elderly or high comorbidity patients and varied across cancer types. Survival analysis indicated that across all cancer types, single-fraction SRS, was independently associated with improved overall survival compared to cEBRT (HR 1.51; 95%CI: 1.31-1.74; p< 0.01) after adjusting for patient characteristics, care setting, tumor type and systemic treatment. CONCLUSIONS Through analysis of cancer registry data, we found that practice patterns of RT for spinal metastases have been evolving nationally, with an increase in the use of SBRT. Single-fraction SBRT was associated with improved adjusted OS. Notably, we found that utilization of SBRT lags in the community setting.

scholarly journals A Pan-Cancer Study of KMT2 Family as Therapeutic Targets in Cancer

2022 ◽  
Vol 2022 ◽  
pp. 1-10
Author(s):  
Jiamin Zhu ◽  
Zhili Liu ◽  
Xiao Liang ◽  
Lu Wang ◽  
Dan Wu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Microenvironment ◽  
Patient Survival ◽  
Expression Patterns ◽  
Family Members ◽  
Cancer Type ◽  
Tumor Type ◽  
Histone Lysine ◽  
Cancer Types ◽  
Pan Cancer

Objective. Exome sequencing studies have shown that the histone-lysine N-methyltransferase 2 (KMT2) gene is one of the most commonly mutated genes in a range of human malignancies and is linked to some of the most common and deadly solid tumors. However, the connection between this gene family’s function and tumor type, immunological subtype, and molecular subtype dependency is still unknown. Methods. We examine the expression patterns of the histone-lysine N-methyltransferase 2 (KMT2) gene, as well as their relationship to patient survival. We also used a pan-cancer analysis to link their function to immunological subtypes, the tumor microenvironment, and treatment sensitivity. Results. Using the TCGA pan-cancer data, researchers looked at and examined KMT2 expression patterns and their links to patient survival and the tumor microenvironment in 33 cancer types. The expression of the KMT2 family changes significantly across and within cancer types, indicating significant inter- and intracancer heterogeneity. Patients’ overall survival was often linked to the expression of KMT2 family members. However, the direction of the link differed depending on the KMT2 isoform and cancer type studied. Notably, in all cancer types examined, nearly all KMT2 family members were substantially linked with overall survival in patients with renal clear cell carcinoma (KIRC). Furthermore, all KMT2 genes have a strong relationship with immune infiltrate subtypes, as well as varying degrees of stromal cell infiltration and tumor cell stemness. Finally, we discovered that higher expression of KMT2s, particularly KMT2F and KMT2G, was linked to greater chemotherapeutic sensitivity in several cell lines. Conclusions. The necessity to investigate each KMT2 member as a distinct entity inside each particular cancer type is highlighted by our comprehensive investigation of KMT2 gene expression and its relationship with immune infiltrates, tumor microenvironment, and cancer patient outcomes. Our research also confirmed the identification of KMT2 as a potential therapeutic target in cancer, but further laboratory testing is required.

scholarly journals Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

2018 ◽  
Author(s):  
Stefan C. Dentro ◽  
Ignaty Leshchiner ◽  
Kerstin Haase ◽  
Maxime Tarabichi ◽  
Jeff Wintersinger ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Human Cancer ◽  
Driver Mutations ◽  
Whole Genome Sequencing Data ◽  
Tumor Evolution ◽  
Driver Gene ◽  
Cancer Type ◽  
Whole Genome ◽  
Sequencing Data ◽  
Cancer Types

SUMMARYIntra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. To address this question, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples, spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions, with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types, and identify cancer type specific subclonal patterns of driver gene mutations, fusions, structural variants and copy-number alterations, as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution, and provide an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

Recent Advances in the Synthesis and Development of Nitroaromatics as Anti-Infective Drugs

2020 ◽  
Vol 26 (36) ◽  
pp. 4658-4674 ◽  
Author(s):  
Christina Kannigadu ◽  
David. D. N'Da
Keyword(s):  
Infectious Disease ◽  
Drug Resistance ◽  
Chest Pain ◽  
Muscle Pain ◽  
New Drugs ◽  
Lymph Glands ◽  
Recent Advances ◽  
Personality Changes ◽  
Clinical Drugs ◽  
Antiparasitic Agents

: Infectious diseases commonly occur in tropical and sub-tropical countries. The pathogens of such diseases are able to multiply in human hosts, warranting their continual survival. Infections that are commonplace include malaria, chagas, trypanosomiasis, giardiasis, amoebiasis, toxoplasmosis and leishmaniasis. Malaria is known to cause symptoms, such as high fever, chills, nausea and vomiting, whereas chagas disease causes enlarged lymph glands, muscle pain, swelling and chest pain. People suffering from African trypanosomiasis may experience severe headaches, irritability, extreme fatigue and swollen lymph nodes. As an infectious disease progresses, the human host may also experience personality changes and neurologic problems. If left untreated, most of these diseases can lead to death. : Parasites, microbes and bacteria are increasingly adapting and generating strains that are resistant to current clinical drugs. Drug resistance creates an urgency for the development of new drugs to treat these infections. Nitro containing drugs, such as chloramphenicol, metronidazole, tinidazole and secnidazole had been banned for use as antiparasitic agents due to their toxicity. However, recent discoveries of nitrocontaining anti-tuberculosis drugs, i.e. delamanid and pretonamid, and the repurposing of flexinidazole for use in combination with eflornithine for the treatment of human trypanosomiasis, have ignited interest in nitroaromatic scaffolds as viable sources of potential anti-infective agents. : This review highlights the differences between old and new nitration methodologies. It furthermore offers insights into recent advances in the development of nitroaromatics as anti-infective drugs.

scholarly journals Cancer Vaccines: Promising Therapeutics or an Unattainable Dream

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 668
Author(s):  
Howard Donninger ◽  
Chi Li ◽  
John W. Eaton ◽  
Kavitha Yaddanapudi
Keyword(s):  
Stem Cell ◽  
Immune System ◽  
Tumor Immunity ◽  
Cancer Vaccines ◽  
Tumor Antigens ◽  
Host Immune System ◽  
Tumor Type ◽  
Therapeutic Vaccines ◽  
Cancer Types ◽  
Prophylactic Vaccines

The advent of cancer immunotherapy has revolutionized the field of cancer treatment and offers cancer patients new hope. Although this therapy has proved highly successful for some patients, its efficacy is not all encompassing and several cancer types do not respond. Cancer vaccines offer an alternate approach to promote anti-tumor immunity that differ in their mode of action from antibody-based therapies. Cancer vaccines serve to balance the equilibrium of the crosstalk between the tumor cells and the host immune system. Recent advances in understanding the nature of tumor-mediated tolerogenicity and antigen presentation has aided in the identification of tumor antigens that have the potential to enhance anti-tumor immunity. Cancer vaccines can either be prophylactic (preventative) or therapeutic (curative). An exciting option for therapeutic vaccines is the emergence of personalized vaccines, which are tailor-made and specific for tumor type and individual patient. This review summarizes the current standing of the most promising vaccine strategies with respect to their development and clinical efficacy. We also discuss prospects for future development of stem cell-based prophylactic vaccines.

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