scholarly journals Neoadjuvant checkpoint blockade for cancer immunotherapy

Science ◽  
2020 ◽  
Vol 367 (6477) ◽  
pp. eaax0182 ◽  
Author(s):  
Suzanne L. Topalian ◽  
Janis M. Taube ◽  
Drew M. Pardoll
Keyword(s):  
De Novo ◽  
Clinical Trial Design ◽  
Treatment Resistance ◽  
Common Denominator ◽  
Ongoing Research ◽  
Checkpoint Pathway ◽  
Neoadjuvant Immunotherapy ◽  
Activity Spectrum ◽  
New Treatment ◽  
Cancer Immunotherapies

Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti–PD-1 or anti–PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti–PD-1 and anti–PD-L1 efficacy.

Methodological issues in clinical trial design for TMS

2012 ◽  
Author(s):  
Mark A. Demitrack ◽  
Sarah H. Lisanby
Keyword(s):  
Major Depression ◽  
Trial Design ◽  
Magnetic Stimulation ◽  
Clinical Trial Design ◽  
Treatment Resistance ◽  
Methodological Issues ◽  
Multicenter Trials ◽  
Number Of Patients ◽  
New Treatment ◽  
Methodological Considerations

This article explores the emergence of transcranial magnetic stimulation (TMS) as a new therapeutic approach and the implications of this technology for the study and treatment of neuropsychiatric disorders, with a focus on major depression. Relapse, chronicity, and varying degrees of treatment resistance characterize major depression. A substantial number of patients are not effectively treated with pharmacology or medications alone. It is proposed that TMS, along with other device-based therapies emerging in psychiatry, may define a potential new treatment platform, with existing therapeutics for major depression. Through the example of a study, this article describes the methodological considerations in the development of TMS for the treatment of major depression. Device-based approaches to therapeutic neuromodulation hold the promise of significant clinical advantages compared to existing treatments for major depression, but evidence in well designed and properly blinded multicenter trials is still lacking, hence, research in this area is ongoing.

scholarly journals Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs

2021 ◽  
Vol 7 (4) ◽  
pp. 75
Author(s):  
Eva Slabáková ◽  
Zuzana Kahounová ◽  
Jiřina Procházková ◽  
Karel Souček
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Treatment Resistance ◽  
Response To Treatment ◽  
Neuroendocrine Prostate Cancer ◽  
Non Coding Rnas ◽  
New Treatment

Neuroendocrine prostate cancer (NEPC) represents a variant of prostate cancer that occurs in response to treatment resistance or, to a much lesser extent, de novo. Unravelling the molecular mechanisms behind transdifferentiation of cancer cells to neuroendocrine-like cancer cells is essential for development of new treatment opportunities. This review focuses on summarizing the role of small molecules, predominantly microRNAs, in this phenomenon. A published literature search was performed to identify microRNAs, which are reported and experimentally validated to modulate neuroendocrine markers and/or regulators and to affect the complex neuroendocrine phenotype. Next, available patients’ expression datasets were surveyed to identify deregulated microRNAs, and their effect on NEPC and prostate cancer progression is summarized. Finally, possibilities of miRNA detection and quantification in body fluids of prostate cancer patients and their possible use as liquid biopsy in prostate cancer monitoring are discussed. All the addressed clinical and experimental contexts point to an association of NEPC with upregulation of miR-375 and downregulation of miR-34a and miR-19b-3p. Together, this review provides an overview of different roles of non-coding RNAs in the emergence of neuroendocrine prostate cancer.

scholarly journals Endosomal Cholesterol in Viral Infections – A Common Denominator?

2021 ◽  
Vol 12 ◽  
Author(s):  
Mirco Glitscher ◽  
Eberhard Hildt
Keyword(s):  
Viral Infections ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Antiviral Treatment ◽  
Life Cycles ◽  
Cholesterol Homeostasis ◽  
Common Denominator ◽  
Lipid Uptake ◽  
Ongoing Research ◽  
Cellular Cholesterol

Cholesterol has gained tremendous attention as an essential lipid in the life cycle of virtually all viruses. These seem to have developed manifold strategies to modulate the cholesterol metabolism to the side of lipid uptake and de novo synthesis. In turn, affecting the cholesterol homeostasis has emerged as novel broad-spectrum antiviral strategy. On the other hand, the innate immune system is similarly regulated by the lipid and stimulated by its derivatives. This certainly requires attention in the design of antiviral strategies aiming to decrease cellular cholesterol, as evidence accumulates that withdrawal of cholesterol hampers innate immunity. Secondly, there are exceptions to the rule of the abovementioned virus-induced metabolic shift toward cholesterol anabolism. It therefore is of interest to dissect underlying regulatory mechanisms, which we aimed for in this minireview. We further collected evidence for intracellular cholesterol concentrations being less important in viral life cycles as compared to the spatial distribution of the lipid. Various routes of cholesterol trafficking were found to be hijacked in viral infections with respect to organelle-endosome contact sites mediating cholesterol shuttling. Thus, re-distribution of cellular cholesterol in the context of viral infections requires more attention in ongoing research. As a final aim, a pan-antiviral treatment could be found just within the transport and re-adjustment of local cholesterol concentrations. Thus, we aimed to emphasize the importance of the regulatory roles the endosomal system fulfils herein and hope to stimulate research in this field.

scholarly journals Minimal Effects, Maximum Panic: Social Media and Democracy in Latin America

2020 ◽  
Vol 6 (4) ◽  
pp. 205630512098445
Author(s):  
Eugenia Mitchelstein ◽  
Mora Matassi ◽  
Pablo J. Boczkowski
Keyword(s):  
Social Media ◽  
Latin America ◽  
Social Engagement ◽  
Hate Speech ◽  
De Novo ◽  
Electronic Government ◽  
Qualitative Assessment ◽  
Common Denominator ◽  
Negative Effects ◽  
Positive Effects

In face of public discourses about the negative effects that social media might have on democracy in Latin America, this article provides a qualitative assessment of existing scholarship about the uses, actors, and effects of platforms for democratic life. Our findings suggest that, first, campaigning, collective action, and electronic government are the main political uses of platforms. Second, politicians and office holders, social movements, news producers, and citizens are the main actors who utilize them for political purposes. Third, there are two main positive effects of these platforms for the democratic process—enabling social engagement and information diffusion—and two main negative ones—the presence of disinformation, and the spread of extremism and hate speech. A common denominator across positive and negative effects is that platforms appear to have minimal effects that amplify pre-existing patterns rather than create them de novo.

scholarly journals Circulating tumor cell heterogeneity in neuroendocrine prostate cancer by single cell copy number analysis

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Vincenza Conteduca ◽  
Sheng-Yu Ku ◽  
Luisa Fernandez ◽  
Angel Dago-Rodriquez ◽  
Jerry Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Cell ◽  
De Novo ◽  
Genomic Analysis ◽  
Treatment Resistance ◽  
Circulating Tumor Cell ◽  
Prostate Adenocarcinoma ◽  
Neuroendocrine Prostate Cancer ◽  
Patient Heterogeneity ◽  
Tumor Cell Heterogeneity

AbstractNeuroendocrine prostate cancer is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. The combined loss of tumor suppressors RB1, TP53, and PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with a phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer.

scholarly journals Natural Compounds in Sex Hormone-Dependent Cancers: The Role of Triterpenes as Therapeutic Agents

2021 ◽  
Vol 11 ◽  
Author(s):  
Codruţa Şoica ◽  
Mirela Voicu ◽  
Roxana Ghiulai ◽  
Cristina Dehelean ◽  
Roxana Racoviceanu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Active Role ◽  
Structural Features ◽  
Sex Hormone ◽  
Ongoing Research ◽  
New Treatment ◽  
Highly Correlated

Sex hormone-dependent cancers currently contribute to the high number of cancer-related deaths worldwide. The study and elucidation of the molecular mechanisms underlying the progression of these tumors was a double-edged sword, leading to the expansion and development of new treatment options, with the cost of triggering more aggressive, therapy resistant relapses. The interaction of androgen, estrogen and progesterone hormones with specific receptors (AR, ER, PR) has emerged as a key player in the development and progression of breast, ovarian, prostate and endometrium cancers. Sex hormone-dependent cancers share a common and rather unique carcinogenesis mechanism involving the active role of endogenous and exogenous sex hormones to maintain high mitotic rates and increased cell proliferation thus increasing the probability of aberrant gene occurrence and accumulation highly correlated with abnormal cell division and the occurrence of malignant phenotypes. Cancer related hormone therapy has evolved, currently being associated with the blockade of other signaling pathways often associated with carcinogenesis and tumor progression in cancers, with promising results. However, despite the established developments, there are still several shortcomings to be addressed. Triterpenes are natural occurring secondary metabolites biosynthesized by various pathways starting from squalene cyclization. Due to their versatile therapeutic potential, including the extensively researched antiproliferative effect, these compounds are most definitely a cornerstone in the research and development of new natural/semisynthetic anticancer therapies. The present work thoroughly describes the ongoing research related to the antitumor activity of triterpenes in sex hormone-dependent cancers. Also, the current review highlights both the biological activity of various triterpenoid compounds and their featured mechanisms of action correlated with important chemical structural features.

scholarly journals Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 1058
Author(s):  
Zheng Yao Low ◽  
Isra Ahmad Farouk ◽  
Sunil Kumar Lal
Keyword(s):  
Drug Development ◽  
De Novo ◽  
Drug Repositioning ◽  
Personalised Medicine ◽  
Technological Advancement ◽  
The Novel ◽  
Ongoing Research ◽  
Alternative Approach ◽  
Good Potential ◽  
Novel Drug

Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for drug developers. Recently, drug repositioning has gained recognition as an alternative approach that explores new avenues for pre-existing commercially approved or rejected drugs to treat diseases aside from the intended ones. Drug repositioning results in lower overall developmental expenses and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities. The greatest advantage of drug repositioning is that it breathes new life into the novel, rare, orphan, and resistant diseases, such as Cushing’s syndrome, HIV infection, and pandemic outbreaks such as COVID-19. Repositioning existing drugs such as Hydroxychloroquine, Remdesivir, Ivermectin and Baricitinib shows good potential for COVID-19 treatment. This can crucially aid in resolving outbreaks in urgent times of need. This review discusses the past success in drug repositioning, the current technological advancement in the field, drug repositioning for personalised medicine and the ongoing research on newly emerging drugs under consideration for the COVID-19 treatment.

scholarly journals Bias, benefit, or both: evaluating new glioma therapies

1998 ◽  
Vol 4 (6) ◽  
pp. E11 ◽  
Author(s):  
James R. Perry
Keyword(s):  
Malignant Glioma ◽  
Selection Bias ◽  
Phase Ii ◽  
Clinical Trial Design ◽  
Treatment Resistance ◽  
Phase Iii ◽  
Outcome Analysis ◽  
Tumor Control ◽  
Phase Ii Trials ◽  
Therapeutic Trials

Despite the development of many new promising therapies for malignant glioma, virtually all randomized controlled trials testing them have proven negative. These disappointing results are largely due to complex mechanisms of treatment resistance, but increasingly there is evidence that experimental bias rather than benefit accounts for both the promising early phase I/II trial results and later phase III failures. This paper highlights the aspects of clinical trial design and outcome analysis that specifically affect interpretation of results from therapeutic trials for malignant glioma. Phase II trials of both tumor response and tumor control are subject to selection bias; the early promising results seen with interstitial brachytherapy and intraarterial chemotherapy and yet negative phase III results are examples of this. Methods for detecting selection bias include modeling techniques in which databases of patients with known outcomes are used to emulate phase III outcomes. Modeling may assist in the determination of whether a given phase II result appears to exceed that expected by selection bias alone. Such an experiment on paper is quite unlikely to replace a well-designed randomized trial; however, in this time of increasing numbers of novel therapies but shrinking resources, these techniques should find utility in selecting those therapies most suitable for testing in cooperative group randomized trials.

scholarly journals Neuroendocrine and Aggressive-Variant Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3792
Author(s):  
Nicholas Spetsieris ◽  
Myrto Boukovala ◽  
Georgios Patsakis ◽  
Ioannis Alafis ◽  
Eleni Efstathiou
Keyword(s):  
Prostate Cancer ◽  
De Novo ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Molecular Characteristics ◽  
Castration Resistant Prostate Cancer ◽  
Ongoing Research ◽  
Platinum Based Chemotherapy ◽  
Hormonal Therapies ◽  
Aggressive Variant

In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies.

STEM-05. FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND UNRECOGNIZED PATHWAY DEPENDENCIES IN RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi22-vi22
Author(s):  
Chirayu R Chokshi ◽  
David Tieu ◽  
Kevin R Brown ◽  
Chitra Venugopal ◽  
Lina Liu ◽  
...  
Keyword(s):  
Tumor Recurrence ◽  
De Novo ◽  
Tyrosine Phosphatase ◽  
Treatment Resistance ◽  
Recurrent Glioblastoma ◽  
De Novo Mutations ◽  
Genome Wide ◽  
Molecule Inhibitor ◽  
Signaling Axis ◽  
Single Domain Antibodies

Abstract Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses support parallel tumor-intrinsic mechanisms of treatment resistance which rely on acquisition of immunosuppressive capacity, including a defective mismatch repair pathway, ablation of PTEN activity, and a novel combination of de novo mutations in SWI/SNF components. We map a multilayered genetic and functional response to resist chemoradiotherapy and drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel driver of self-renewal, proliferation and tumorigenicity at GBM recurrence. Mechanistically, genetic perturbation and a small molecule inhibitor of PTP4A2 repress axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and exploit a genetic dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies also mimic the effects of PTP4A2 inhibition. We conclude that functional reprogramming drives tumorigenicity and present a dependence on a PTP4A2-ROBO1 signaling axis at GBM recurrence.

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