scholarly journals Therapeutic Targeting of Exportin-1 in Childhood Cancer

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6161
Author(s):  
Basia Galinski ◽  
Thomas B. Alexander ◽  
Daniel A. Mitchell ◽  
Hannah V. Chatwin ◽  
Chidiebere Awah ◽  
...  
Keyword(s):  
Childhood Cancer ◽  
Patient Outcomes ◽  
Therapeutic Strategies ◽  
Childhood Cancers ◽  
Therapeutic Targeting ◽  
Current State ◽  
Cytoplasmic Transport ◽  
Fda Approval ◽  
Cargo Proteins ◽  
Outcomes For Children

Overexpression of Exportin-1 (XPO1), a key regulator of nuclear-to-cytoplasmic transport, is associated with inferior patient outcomes across a range of adult malignancies. Targeting XPO1 with selinexor has demonstrated promising results in clinical trials, leading to FDA approval of its use for multiple relapsed/refractory cancers. However, XPO1 biology and selinexor sensitivity in childhood cancer is only recently being explored. In this review, we will focus on the differential biology of childhood and adult cancers as it relates to XPO1 and key cargo proteins. We will further explore the current state of pre-clinical and clinical development of XPO1 inhibitors in childhood cancers. Finally, we will outline potentially promising future therapeutic strategies for, as well as potential challenges to, integrating XPO1 inhibition to improve outcomes for children with cancer.

scholarly journals PSPC1 is a new contextual determinant of aberrant subcellular translocation of oncogenes in tumor progression

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Yaw-Dong Lang ◽  
Yuh-Shan Jou
Keyword(s):  
Nuclear Export ◽  
Synergistic Effects ◽  
Therapeutic Option ◽  
Nucleocytoplasmic Shuttling ◽  
Innovative Strategy ◽  
Fda Approval ◽  
Cargo Proteins ◽  
The Common ◽  
Contextual Determinants ◽  
Nuclear Export Receptor

AbstractDysregulation of nucleocytoplasmic shuttling is commonly observed in cancers and emerging as a cancer hallmark for the development of anticancer therapeutic strategies. Despite its severe adverse effects, selinexor, a selective first-in-class inhibitor of the common nuclear export receptor XPO1, was developed to target nucleocytoplasmic protein shuttling and received accelerated FDA approval in 2019 in combination with dexamethasone as a fifth-line therapeutic option for adults with relapsed refractory multiple myeloma (RRMM). To explore innovative targets in nucleocytoplasmic shuttling, we propose that the aberrant contextual determinants of nucleocytoplasmic shuttling, such as PSPC1 (Paraspeckle component 1), TGIF1 (TGF-β Induced Factor Homeobox 1), NPM1 (Nucleophosmin), Mortalin and EBP50, that modulate shuttling (or cargo) proteins with opposite tumorigenic functions in different subcellular locations could be theranostic targets for developing anticancer strategies. For instance, PSPC1 was recently shown to be the contextual determinant of the TGF-β prometastatic switch and PTK6/β-catenin reciprocal oncogenic nucleocytoplasmic shuttling during hepatocellular carcinoma (HCC) progression. The innovative nucleocytoplasmic shuttling inhibitor PSPC1 C-terminal 131 polypeptide (PSPC1-CT131), which was developed to target both the shuttling determinant PSPC1 and the shuttling protein PTK6, maintained their tumor-suppressive characteristics and exhibited synergistic effects on tumor suppression in HCC cells and mouse models. In summary, targeting the contextual determinants of nucleocytoplasmic shuttling with cargo proteins having opposite tumorigenic functions in different subcellular locations could be an innovative strategy for developing new therapeutic biomarkers and agents to improve cancer therapy.

scholarly journals Outcomes for Children and Adolescents With Cancer: Challenges for the Twenty-First Century

2010 ◽  
Vol 28 (15) ◽  
pp. 2625-2634 ◽  
Author(s):  
Malcolm A. Smith ◽  
Nita L. Seibel ◽  
Sean F. Altekruse ◽  
Lynn A.G. Ries ◽  
Danielle L. Melbert ◽  
...  
Keyword(s):  
United States ◽  
Childhood Cancer ◽  
Cancer Mortality ◽  
Lymphoblastic Leukemia ◽  
The United States ◽  
Mortality Rates ◽  
Mortality Data ◽  
Childhood Cancers ◽  
Essential Information ◽  
The Impact

Purpose This report provides an overview of current childhood cancer statistics to facilitate analysis of the impact of past research discoveries on outcome and provide essential information for prioritizing future research directions. Methods Incidence and survival data for childhood cancers came from the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries, and mortality data were based on deaths in the United States that were reported by states to the Centers for Disease Control and Prevention by underlying cause. Results Childhood cancer incidence rates increased significantly from 1975 through 2006, with increasing rates for acute lymphoblastic leukemia being most notable. Childhood cancer mortality rates declined by more than 50% between 1975 and 2006. For leukemias and lymphomas, significantly decreasing mortality rates were observed throughout the 32-year period, though the rate of decline slowed somewhat after 1998. For remaining childhood cancers, significantly decreasing mortality rates were observed from 1975 to 1996, with stable rates from 1996 through 2006. Increased survival rates were observed for all categories of childhood cancers studied, with the extent and temporal pace of the increases varying by diagnosis. Conclusion When 1975 age-specific death rates for children are used as a baseline, approximately 38,000 childhood malignant cancer deaths were averted in the United States from 1975 through 2006 as a result of more effective treatments identified and applied during this period. Continued success in reducing childhood cancer mortality will require new treatment paradigms building on an increased understanding of the molecular processes that promote growth and survival of specific childhood cancers.

scholarly journals SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families

2021 ◽  
Vol 8 ◽  
Author(s):  
Anthony C. Brandt ◽  
Olivia J. Koehn ◽  
Carol L. Williams
Keyword(s):  
Splice Variants ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Peptide Inhibitors ◽  
Signaling Cascades ◽  
Therapeutic Targeting ◽  
Growing Body ◽  
History Of ◽  
Rho Family ◽  
Mutant Forms

Newly synthesized small GTPases in the Ras and Rho families are prenylated by cytosolic prenyltransferases and then escorted by chaperones to membranes, the nucleus, and other sites where the GTPases participate in a variety of signaling cascades. Understanding how prenylation and trafficking are regulated will help define new therapeutic strategies for cancer and other disorders involving abnormal signaling by these small GTPases. A growing body of evidence indicates that splice variants of SmgGDS (gene name RAP1GDS1) are major regulators of the prenylation, post-prenylation processing, and trafficking of Ras and Rho family members. SmgGDS-607 binds pre-prenylated small GTPases, while SmgGDS-558 binds prenylated small GTPases. This review discusses the history of SmgGDS research and explains our current understanding of how SmgGDS splice variants regulate the prenylation and trafficking of small GTPases. We discuss recent evidence that mutant forms of RabL3 and Rab22a control the release of small GTPases from SmgGDS, and review the inhibitory actions of DiRas1, which competitively blocks the binding of other small GTPases to SmgGDS. We conclude with a discussion of current strategies for therapeutic targeting of SmgGDS in cancer involving splice-switching oligonucleotides and peptide inhibitors.

scholarly journals Variation in end-stage renal disease patient outcomes: what we know, what should we know, and how do we find it out?

1993 ◽  
Vol 3 (11) ◽  
pp. 1738-1747
Author(s):  
P Kurtin ◽  
A R Nissenson
Keyword(s):  
Patient Outcomes ◽  
Outcome Measure ◽  
Disease Patient ◽  
Patient Specific ◽  
Quality Cost ◽  
Current State ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

The size and expense of the ESRD program exceed all predictions made when the program was first initiated. Although the effectiveness of dialytic therapy is unquestioned, its value (quality/cost) is actively debated in this era of constricting resources. To better evaluate the quality of the ESRD program, it is essential to first define and quantitate the outcomes of dialytic care. Although mortality is a convenient outcome measure, it may be affected by many patient-specific as well as other factors that must be considered when evaluating and comparing new and existing technologies or advances. Quality of life is only beginning to be used in depth as an outcome measure, and much work is needed to standardize research methodology and thus move this area forward. The following review describes the current state of knowledge regarding outcomes of ESRD patients and proposes areas for future investigation, which should help increase the understanding of the value of the ESRD program to patients, providers, and payors.

scholarly journals Immunotherapy in gastroesophageal cancers: Current state and future directions

2020 ◽  
pp. 107815522096353
Author(s):  
Hira Shaikh ◽  
Amir Kamran ◽  
Dulabh K Monga
Keyword(s):  
Patient Outcomes ◽  
Molecular Targeted Therapy ◽  
Treatment Options ◽  
Cell Cycle Checkpoints ◽  
Future Directions ◽  
Alternative Strategies ◽  
Current State ◽  
Dismal Prognosis ◽  
The World ◽  
Improve Patient

While gastroesophageal (GE) cancers are one of the most common cancers worldwide, unfortunately, the mortality remains high. Commonly used treatment options include surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy, which improve survival only minimally; thus, affirming the dire need for exploring alternative strategies to improve patient outcomes. Immunotherapy, which has revolutionized the world of oncology, has somewhat lagged behind in GE malignancies. Tumor-associated microenvironment and regulatory T cells, alongside cell cycle checkpoints, have been proposed by various studies as the mediators of carcinogenesis in GE cancers. Thus, inhibition of each of these could serve as a possible target of treatment. While the approval of pembrolizumab has provided some hope, it is not enough to override the dismal prognosis that this disease confers. Herein, we discuss the prospects of immunotherapy in this variety of cancer.

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