Moving forward with actionable therapeutic targets and opportunities in endometrial cancer: A NCI clinical trials planning meeting report

Abstract Cervical cancer is the fourth most common cancer in women worldwide, and prognosis is poor for those who experience recurrence or develop metastatic disease, in part due to the lack of active therapeutic directions. The National Cancer Institute convened a Cervical Cancer Clinical Trials Planning Meeting in October 2018 to facilitate the design of hypothesis-driven clinical trials focusing on locally advanced, metastatic, and recurrent cervical cancer around the theme of enhancing susceptibility to DNA repair inhibition and DNA damage. Before the meeting, a group of experts in the field summarized available preclinical and clinical data to identify potentially active inducers and inhibitors of DNA. The goals of the Clinical Trials Planning Meeting focused on identification of novel experimental strategies capitalizing on DNA damage and repair (DDR) regulators and cell cycle aberrations, optimization of radiotherapy as a DDR agent, and design of clinical trials incorporating DDR regulation into the primary and recurrent or metastatic therapies for cervical carcinoma. Meeting deliverables were novel clinical trial concepts to move into the National Clinical Trials Network. This report provides an overview for the rationale of this meeting and the state of the science related to DDR regulation in cervical cancer.

Download Full-text

Osteosarcoma Pathogenesis Leads the Way to New Target Treatments

International Journal of Molecular Sciences ◽

10.3390/ijms22020813 ◽

2021 ◽

Vol 22 (2) ◽

pp. 813

Author(s):

Isabel Fernandes ◽

Cecília Melo-Alvim ◽

Raquel Lopes-Brás ◽

Miguel Esperança-Martins ◽

Luís Costa

Keyword(s):

Clinical Trials ◽

Phase I ◽

Poor Prognosis ◽

Therapeutic Targets ◽

Rare Condition ◽

Basic Research ◽

Metastatic Setting ◽

Phase I And Ii ◽

The Way

Osteosarcoma (OS) is a rare condition with very poor prognosis in a metastatic setting. Basic research has enabled a better understanding of OS pathogenesis and the discovery of new potential therapeutic targets. Phase I and II clinical trials are already ongoing, with some promising results for these patients. This article reviews OS pathogenesis and new potential therapeutic targets.

Download Full-text

Early Experiences in Switching between Monoclonal Antibodies in Patients with Nonresponsive Migraine in Spain: A Case Series

European Neurology ◽

10.1159/000518899 ◽

2021 ◽

pp. 1-4

Author(s):

Ignacio Patier Ruiz ◽

Javier Sánchez-Rubio Ferrández ◽

Alba Cárcamo Fonfría ◽

Teresa Molina García

Keyword(s):

Clinical Trials ◽

Monoclonal Antibodies ◽

Therapeutic Targets ◽

Case Series ◽

Similar Efficacy ◽

Migraine Prophylaxis ◽

Therapeutic Failure ◽

Related Peptide ◽

Early Experiences ◽

Calcitonin Gene

Monoclonal antibodies targeting the calcitonin gene-related peptide have been introduced into the therapeutic arsenal of migraine prophylaxis. Clinical trials report similar efficacy between them, and there is no evidence of switching to another one after failure. We aim to describe our experience in switching from erenumab to galcanezumab after therapeutic failure. We retrospectively reviewed 30 migraine patients who received monoclonal antibodies, with 15 of them switched after failure to achieve reduction in migraine days per month ≥30%. A ≥30% reduction in migraine days per month compared to baseline was observed in 8/15 (4/15 ≥ 50%) patients after switch. Some nonresponsive patients may benefit from switching between monoclonal antibodies with different therapeutic targets.

Download Full-text

Inflammatory Cytokines, Immune Cells, and Organ Interactions in Heart Failure

Frontiers in Physiology ◽

10.3389/fphys.2021.695047 ◽

2021 ◽

Vol 12 ◽

Author(s):

Huihui Li ◽

Chen Chen ◽

Dao Wen Wang

Keyword(s):

Heart Failure ◽

Clinical Trials ◽

Inflammatory Cytokines ◽

Immune Cells ◽

Inflammatory Responses ◽

Therapeutic Targets ◽

Pathophysiological Mechanisms

Despite mounting evidence demonstrating the significance of inflammation in the pathophysiological mechanisms of heart failure (HF), most large clinical trials that target the inflammatory responses in HF yielded neutral or even worsening outcomes. Further in-depth understanding about the roles of inflammation in the pathogenesis of HF is eagerly needed. This review summarizes cytokines, cardiac infiltrating immune cells, and extracardiac organs that orchestrate the complex inflammatory responses in HF and highlights emerging therapeutic targets.

Download Full-text

Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

International Journal of Molecular Sciences ◽

10.3390/ijms19082380 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2380 ◽

Cited By ~ 13

Author(s):

Michiel Remmerie ◽

Veerle Janssens

Keyword(s):

Clinical Trials ◽

Endometrial Cancer ◽

Targeted Therapies ◽

Kinase Inhibitors ◽

Therapeutic Potential ◽

Treatment Options ◽

Genetic Alterations ◽

Mitogen Activated Protein Kinase ◽

Type I ◽

Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

Download Full-text