Researchers published a research perspective about a recent study that uncovered FSP1 as a novel target gene that mediates ferroptosis resistance and radioresistance in lung cancer cells.
Figure 1: KEAP1-NRF2 axis and its molecular effectors in the regulation of ferroptosis.
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Ferroptosis is a type of cell death caused by the accumulation of iron and lipid peroxides in cells. Cancer cells are often resistant to ferroptosis, which allows them to survive and proliferate. Radioresistance is another common feature of cancer cells that allows them to resist the effects of radiation therapy.
A new research paper (published on April 22, 2022) identified ferroptosis suppressor protein 1 (FSP1) as a novel KEAP1/NRF2 target gene and demonstrated that FSP1 plays an essential role in NRF2-mediated ferroptosis resistance and radioresistance in KEAP1-deficient lung cancer cells.
“In a recent study by Pranavi Koppula et al. from The University of Texas MD Anderson Cancer Center, FSP1 was demonstrated as a novel target of NRF2 and to play a vital role in KEAP1/NRF2-mediated ferroptosis regulation [13], which reveals the important role of genetic regulation of FSP1 in cancer development.”
The KEAP1-NRF2 regulatory pathway is crucial for protecting cells against oxidative damage. In lung cancer cells, KEAP1 mutations lead to NRF2 deregulation and contribute to tumorigenesis. Researchers have been searching for an effective way of targeting this pathway in cancer cells to sensitize them to ferroptosis/radiation-inducing agents. They found that FSP1 is upregulated in KEAP1-mutant lung cancer cells, and its expression is associated with resistance to ferroptosis and radiotherapy. Coenzyme Q10- (CoQ) FSP1 signaling represents a potential target for overcoming resistance to ferroptosis and radiotherapy in KEAP1-mutant lung cancer cells.
“Currently, there are four major ferroptosis-defending systems, while NRF2 could directly control two of them, SLC7A11/GSH/GPX4 axis and CoQ/FSP1 axis.”
This study provides new insights into the role of target genes in the KEAP1-NRF2 pathway and how they contribute to cancer cells’ resistance to ferroptosis and radiotherapy. However, the mechanism by which KEAP1-NRF2 target genes mediate resistance to ferroptosis is not yet fully understood. Fortunately, the identification of FSP1 as a key target gene involved in this process opens up new therapeutic avenues for the treatment of lung cancer.
“Here, Pranavi Koppula and her colleagues’ study indicates that pharmacological targeting of CoQ-FSP1 signaling to overcome KEAP1 deficiency-induced radioresistance could be a potentially effective therapeutic strategy in treating KEAP1 mutant lung cancers.”
Click here to read the full research perspective published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
Researchers investigated the efficacy of HDAC inhibitors in combination with PARP inhibitors and chemotherapeutic drugs in multiple blood cancer cell lines.
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Chromatin constitutes chromosomes in eukaryotic cells and comprises DNA and proteins. Chromosomes produce proteins and enzymes that are essential for cellular function and maintenance, including DNA repair. A critical process for DNA repair is poly(ADP-ribosyl)ation, or PARylation.
PARylation is triggered by poly(ADP ribose) polymerase (PARP) enzymes. When DNA becomes damaged, PARP enzymes bind to the damaged location in the cell. In cancer cells, however, this natural process can be counterproductive in respect to cancer treatment. PARylation can produce DNA repair mechanisms in cancer cells that can lead to cell death evasion and even drug resistance. Inhibiting PARylation may be a viable therapeutic strategy for cancer treatment.
HDAC Inhibitors
Histones, the main proteins that constitute chromatin, undergo post-translational modifications that regulate gene expression. Histone acetylation is an important epigenetic process that affects gene expression by relaxing the chromatin structure, making chromatin remodeling more feasible. Histone deacetylases (HDACs) are enzymes that can have the opposite effect. Histone deacetylation makes the chromatin more compact and difficult to remodel. The overexpression of HDAC has also been associated with tumorigenesis. Histone deacetylase inhibitors (HDACi) are a class of therapeutics that have shown promise in the treatment of hematologic malignancies (blood cancer) and solid tumors.
“Overexpression of HDACs has been associated with tumorigenesis by down-regulation of tumor suppressor genes [3, 4]; hence, HDAC inhibitors (HDACi) including vorinostat (SAHA), romidepsin (Rom), panobinostat (Pano) and belinostat have been approved by the United States Food and Drug Administration for the treatment of hematologic and other malignancies [5]. These inhibitors restore appropriate gene expression, resulting in induction of cell differentiation, cell cycle arrest and apoptosis [6].”
“Despite their preclinical efficacy, HDACi do not seem to be clinically highly effective as monotherapy, and potentially more effective anti-tumor activity is observed when they are combined with other anti-cancer drugs [7–9].”
Studies on the interactions of HDACi with PARPi in cancers of the blood are limited, especially when combined with chemotherapeutic agents. The researchers used a panel of hematologic cancer cell lines (acute myeloid leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, and multiple myeloma) and patient-derived cell samples to study the effect of HDACi (including SAHA (Vorinostat), panobinostat (Pano), romidepsin (Rom) and trichostatin A (TSA)) on PARylation. In addition, the team looked at the efficacy of HDACi combined with PARPi, including Olaparib (Ola) and niraparib (Npb), and with chemotherapeutic agents gemcitabine (Gem), busulfan (Bu) and melphalan (Mel).
Results
The researchers found that hematologic cancer cell lines and patient-derived cell samples exposed to various HDACi resulted in a significant caspase-independent inhibition of protein PARylation. HDACi-mediated inhibition of protein PARylation was mainly catalyzed by PARP1. These findings suggest that HDACi could potentially be used in combination with PARP inhibitors and chemotherapeutic drugs to treat blood cancers.
“Our results indicate that the anti-tumor efficacy of HDACi is partly due to down-regulation of PARylation, which negatively affects the status of DNA repair proteins. This repair inhibition, combined with the high levels of oxidative and DNA replication stress characteristic of cancer cells, could have conferred these hematologic cancer cells not only with a high sensitivity to HDACi but also with a heightened dependence on PARP and therefore with extreme sensitivity to combined HDACi/PARPi treatment and, by extension, to their combination with conventional DNA-damaging chemotherapeutic agents. The observed synergism of these drugs could have a major significance in improving treatment of these cancers.”
Conclusion
HDACi drugs can inhibit PARylation. The combination of HDACi-mediated inhibition of PARylation was complemented by PARPi and chemotherapeutic agents in multiple blood cancer cell lines. The efficacy of this combined treatment was superior to that of any single agent, supporting the further clinical development of HDACi in cancer therapy. These findings could potentially be used to improve the treatment of hematologic cancers.
“In conclusion, our results provide a molecular explanation for the HDACi-mediated inhibition of DNA repair in hematologic cancer cells and support the combinatorial application of HDACi, PARPi and chemotherapeutic agents for the treatment of hematologic malignancies.”
Click here to read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
In this trending new study, researchers used CRISPR-based genome-wide screens to identify genetic determinants of PARP10-mediated cellular survival.
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Genetic interactions involved in the survival of cancer cells are potential therapeutic targets in personalized cancer therapy. “Synthetic lethal” is a type of genetic interaction where the knockout of one gene can cause cell death but only in the presence of another dependent gene. Cancer researchers view synthetic lethality screening as a powerful tool in precision medicine.
“Identifying genetic susceptibilities based on PARP10 expression levels is thus potentially relevant for finding new targets for precision oncology.”
“Here, we employed complementary CRISPR loss-of-function genome-wide screening to identify genes required for proliferation of PARP10-overexpressing and PARP10-knockout cells.”
The Study
To identify potential synthetic lethal targets, the researchers conducted a CRISPR-based, genome-wide genetic screen of both PARP10-overexpressing and PARP10-knockout tumorigenic and non-tumorigenic breast cells. The screen looked for genes that were required for cell proliferation in the presence of PARP10 overexpression or PARP10 knockout.
“Here, we performed a series of CRISPR genome-wide loss-of-function screens in isogenic control and PARP10-overexpressing or PARP10-knockout cell lines, to identify genetic determinants of PARP10-mediated cellular survival.”
In the PARP10 overexpressing cells, the top results from their CRISPR screen were validated with biological pathway enrichment analyses, using both KEGG and Gene Ontology databases. A functional interaction between ATM and PARP10 expression was found. ATM promoted cell proliferation in PARP10-overexpressing cells.
In the genome-wide CRISPR knockout screens, genes required for the viability of PARP10-knockout cells were identified. In the PARP10 knockout cells, the top results from their CRISPR screen were validated with biological pathway enrichment analyses, using both KEGG and Gene Ontology databases. They identified the CDK2-Cyclin E1 complex as a genetic determinant for the proliferation of PARP10-knockout cells.
“Our work identifies a network of functionally relevant PARP10 synthetic interactions, and reveals a set of factors which can potentially be targeted in personalized cancer therapy.”
Conclusion
The researchers identified several genes that were differentially required for cell proliferation in the presence of PARP10 overexpression or knockout. Some of these genes have been previously implicated in cancer, while others were novel candidate cancer targets. The identification of these potential synthetic lethal interactions provides new insights into the role of PARP10 in cancer and may be useful for precision oncology. This study highlights the importance of using complementary CRISPR-based screens to identify potential cancer targets.
“We found that DNA repair factors, including ATM, a master regulator of the DNA damage checkpoint response, are specifically promoting the proliferation of PARP10-overexpressing cells. Moreover, we identified a role for PARP10 in regulating ATM recruitment to stressed replication forks. Finally, we found that the CDK2-cyclin E1 complex is specifically required for the proliferation of PARP10-deficient cells. Our work reveals novel PARP10 genetic interactions of functional relevance and identifies a set of factors which can potentially be targeted in personalized cancer therapy.”
Click here to read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
In a new study, researchers evaluated the high altitude in Ecuador and how it may influence HIF-1 expression and the survival of Ecuadorian patients with gastric cancer.
El Panecillo hill in Quito, Ecuador
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Altitude is considered any elevation above sea level. Higher altitude environments are known to influence various physiological processes in the human body, including those related to hypoxia-inducing factors (HIF), vitamin D, ultraviolet radiation, oxygen toxicity, and changes in pH. Researchers have suggested that altitude may even affect the development and progression of some diseases, including stomach/gastric cancer.
“Gastric cancer is the third leading cause of death in the world and is estimated to cause almost 15 million deaths by 2035 [2].”
Gastric Cancer & Altitude
The primary subtype of gastric cancer is gastric adenocarcinoma (GA). GA develops in the mucus-secreting cells that line the stomach (gastric epithelium). Higher incidence rates of GA have been found among populations living at high altitudes. High altitudes are notorious for low air pressure and decreased oxygen saturation levels. Decreases in oxygen (hypoxia) can activate the transcriptional regulator hypoxia-inducing factor-1 (HIF-1). HIF-1 is known to be upregulated in a variety of human cancers, including GA. The role of HIF-1 in GA pathogenesis and prognosis has not yet been fully understood.
“Gastric adenocarcinoma (GA) has a high incidence in Ecuador, in men it ranks third and in women it ranks fifth.”
There is a higher incidence of GA among people living in Ecuador. This is a country that straddles the equator yet, the altitude in Ecuador varies significantly across the country. For example, the altitude is 2,850 meters in the capital city of Quito (the second-highest capital city in the world). In Guayaquil (a coastal city in Ecuador) the altitude is only nine meters. These facts make Ecuador an optimal location for studying the effects of altitude on gastric adenocarcinoma.
“Ecuador has a varied altitude diversity and there is a differential incidence of cancer between populations living in the Andean or mountainous region when compared to coastal populations or living at low altitude.”
A total of 229 Ecuadorians were assessed in this study. The researchers included 155 cases of GA; 99 of the individuals with GA lived in the mountainous regions of Quito and Ambato, and 56 individuals lived in the coastal region of Guayaquil. (Controls accounted for 74 people; 25 from the coast and 49 from the mountains.) The team followed-up with all individuals in this study from 2005 to 2018 and collected blood and tissue samples. They performed immunohistochemistry and other analyses to evaluate HER2 and HIF-1 expression.
“Analyses were performed using Fisher’s exact and Breslow-Day tests for homogeneity and Kaplan-Meier curves and restricted median survival time ΔRMST.”
Results & Conclusion
After 10 years, median survival was significantly higher among GA patients living along the coast. In the GA samples, HIF-1 was observed in 66.1% of the coastal patients and in 43.4% of the mountainous patients. Positive HIF-1 expression was associated with improved survival among GA patients living in the mountains. Interestingly, in the control group (without GA), HIF-1 expression was observed in 95.9% of the mountainous samples and only 32% of the coastal samples. Their results showed that 89% of the control population exhibited gastritis.
The researchers were forthcoming about the limitations of this study. Differences in quantities and the male-to-female ratios within the GA and control coastal and mountainous groups may have influenced data. Despite these limitations, the researchers observed that coastal GA patients and individuals who expressed HIF-1 had a better prognosis. However, HIF-1 expression was only associated with better survival in the mountain region. These findings suggest that HIF-1 expression may be a protective factor against GA progression in people living at high altitudes.
“Concluding, this study suggests that HIF-1 has a differential expression pattern in gastric samples according to geographical features, being highly expressed even in non-carcinomatous cells (gastritis and normal mucosa) from individuals living in regions of high altitude, indicating that the gastric HIF-1 expression may be an adaptation of the individual to high altitudes.”
Click here to read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
Researchers developed a multi-protein expression-based risk model to predict recurrence-free survival for ESCC patients.
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Esophageal cancer is the sixth most common cause of death from cancer worldwide. The two main types of esophageal cancer are adenocarcinoma and esophageal squamous cell carcinoma (ESCC). ESCC arises from the cells lining the esophagus, and it is most common in areas of the world where tobacco use and alcohol consumption are high.
“Biomarkers to predict the risk of disease recurrence in Esophageal squamous cell carcinoma (ESCC) patients are urgently needed to improve treatment.”
“Our study is important because: (i) it is based on changes in expression levels of the biomarker proteins in different subcellular compartments and is not limited to alterations in the overall protein expression levels; (ii) investigates the comprehensive clinical relevance of subcellular alterations in expression of multiple key components of Wnt pathway in the same ESCC patients’ cohort; (iii) correlates these findings with disease outcome and (iv) develops a Biomarker risk score for defining the risk of recurrence of ESCCs.”
Figure 1: Immunohistochemical analysis of Wnt protein in esophageal tissues.
The researchers aimed to develop and validate a panel of biomarkers with the potential to predict tumor recurrence in patients with ESCC, as well as to generate a risk model for clinical decision-making. This study enrolled 80 ESCC cases, 61 esophageal dysplastic tissues and 47 normal tissues. A multi-protein signature was generated from microarray data using the Cox proportional hazard model which was then internally validated on an independent set of samples by immunohistochemistry. The researchers demonstrated that a panel of four biomarkers (cytoplasmic β-catenin, nuclear c-Myc, nuclear DVL and membrane α-catenin) constituted the prognostic molecular signature for ESCC patients. They found that this protein signature could predict disease recurrence in patients with ESCC.
“Our panel of biomarkers predicted disease recurrence more effectively as compared to individual biomarkers analyzed in this study and demonstrated the strong predictive power of this panel of biomarkers for ESCC patients.”
Conclusion
The research team found that a panel of four biomarkers could predict disease recurrence in patients with ESCC. Furthermore, they showed that this protein signature could be used to stratify patients into high- and low-risk groups. This study provides valuable insights into the role of these proteins in the development and progression of esophageal cancer. The development of this risk model may help to tailor treatment and follow-up strategies for patients with ESCC.
“In conclusion, integrated analysis of expression of the panel of 4 proteins in ESCC patients has allowed us to validate the robustness of our biomarker panel in stratification of patients at high or low risk of disease recurrence. This risk classifier has the potential to identify the high risk patients for more rigorous personalized treatment and the low risk patients may be spared from the harmful side effects of toxic therapy as well reduce the burden on health care providers. The findings of our study set the foundations for external validation of the prognostic signature as a step forward in translation of this panel of protein markers for ESCC patients and establish their clinical relevance for larger worldwide application in future studies.”
Click here to read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
Researchers investigated common gut microbiome features of response among immunotherapy patients with different advanced-stage cancers.
Illustration of a gut microbiome
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Immunotherapy has become a powerful breakthrough in cancer treatment, however, 50% of patients do not respond to immunotherapy. What internal or external features inhibit or confer patient or tumor response to immune system-harnessing therapeutics? These patient/tumor features that impact responsiveness to immunotherapy have yet to be fully elucidated.
“Increasing evidence has emerged that gut microbial communities help shape the host immune system [9–11].”
The Gut Microbiome
The gut microbiome is the collection of all microbes living in the gastrointestinal tract. A growing body of evidence indicates that the gut microbiome is an important component of the human immune system. This evidence has prompted researchers to hypothesize that the gut microbiome may play a role in immunotherapy response. It has since become a focal point in immunotherapy research and also has the potential to serve as a biomarker for immunotherapy response.
Researchers previously found evidence that specific gut bacteria can influence immunotherapy outcomes by modulating immune responses in patients with melanoma, non–small cell lung cancer and renal cell cancer. (“Treatment responders generally exhibit increased gut microbial community diversity and are enriched in certain bacterial taxa including Akkermansia and Bifidobacterium [16, 19].”) While this is important, it is unclear whether these response signals are generalizable across different tumor types, geographical variations in the microbiome or sequencing platforms and analysis methodologies. Identifying microbiome features associated with immunotherapy response regardless of the type of cancer or where it started in the body may be the next step toward improving immunotherapy outcomes in cancer patients.
To find common gut microbiome features of response to immunotherapy, a tumor-agnostic and geographically limited (U.S. patients only) approach was used in this study. The researchers’ discovery cohort included 16 patients with nine different advanced-stage cancers who were enrolled in NCI immunotherapy trials (the NCI cohort). Patient samples and 16S rRNA gene sequencing data were collected. Patients who positively responded to immunotherapies (responders) and those who did not (non-responders) were categorized. The researchers used uni- and multivariate analyses to identify common microbiome features and complex microbial community interactions.
Common microbiome features and immunotherapy response signals in the discovery cohort were further validated with larger datasets. Three previously published 16S rRNA gene sequencing datasets from melanoma patients were added to a combined dataset. This combined dataset was used to validate the NCI cohort results in a meta-analysis. Data from all four studies were used in statistical analyses and machine learning models aimed to predict immunotherapy response.
“Using the combined dataset, we trained and validated models with machine learning algorithms to predict patients’ clinical responses, followed by cross-sequencing-platform validation using shotgun metagenomic sequencing data.”
The Results
“Results suggest baseline gut microbiome features may be predictive of clinical outcomes in oncology patients on immunotherapies, and some of these features may be generalizable across different tumor types, patient cohorts, and sequencing platforms.”
The researchers found that the gut microbiome composition of responders to immunotherapy was different from that of non-responders. Several species of bacteria were differentially abundant between responders and non-responders in the NCI cohort, and some were also consistent with results from the meta-analysis. Hierarchical clustering showed a higher immunotherapy response rate among patients with enriched bacteria in the Firmicutes phylum and a lower response rate among patients enriched in the Bacteroidetes phylum at baseline. Machine learning models using microbiome features and immunotherapy response signals found in this study demonstrated a favorable prediction accuracy with the highest AUC (area under the curve) value of around 0.75.
Conclusion
“In conclusion, analyses of our cohort and the combined microbiome dataset have provided a robust assessment of immunotherapy patients’ gut microbiomes.”
Researchers used a tumor-agnostic approach to find common gut microbiome features of response to immunotherapy in cancer patients. The machine learning models developed in this study were able to demonstrate a favorable prediction accuracy of 75% at best. These results suggest that the gut microbiome may be predictive of immunotherapy response in cancer patients and that some of these features may be generalizable across different tumor types, patient cohorts, and sequencing platforms. These findings suggest that the gut microbiome is a promising biomarker for immunotherapy response. However, more research is needed to validate these findings in larger and more diverse patient populations.
“Results suggest baseline gut microbiome features may be predictive of clinical outcomes in oncology patients on immunotherapies, and some of these features may be generalizable across different tumor types, patient cohorts, and sequencing platforms. Findings demonstrate how machine learning models can reveal microbiome-immunotherapy interactions that may ultimately improve cancer patient outcomes.”
Click here to read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
In a new Oncotarget study, researchers assessed an epigenetic and immunotherapy treatment regimen among patients with blastic mantle cell lymphoma (bMCL).
Mantle cell lymphoma
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Mantle cell lymphoma (MCL) is a type of non-Hodgkin’s lymphoma (NHL) that is aggressive, difficult to treat and typically affects older adults. Recurrence and mortality rates among patients with MCL have remained high, despite recent therapeutic advances. Blastic mantle cell lymphoma (bMCL) is a rare subtype of MCL associated with a worse disease trajectory.
“Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes.”
Epigenetic therapy includes a range of drugs that can target epigenetic mechanisms, including DNA methylation and posttranslational modifications of histones. For example, vorinostat (SAHA; a histone deacetylase inhibitor) and cladribine (chemotherapy that also inhibits DNA methylation) are epigenetic agents. Rituximab, a maintenance immunotherapeutic agent, is a CD20-directed monoclonal antibody. These three treatments combined encompass a novel potential epigenetic and immunotherapy treatment regimen (SCR) for mantle cell lymphoma (MCL).
“Relapsed and [treatment] naïve MCL patients were treated with vorinostat (SAHA), cladribine and rituximab (SCR) regimen and followed for OS [overall survival], progression free survival (PFS) and with correlative basic science studies to investigate potential mechanisms of action of this epigenetic/immunotherapy combination.”
The Study
Since blastic MCL patients are rare, only 13 bMCL (four relapsed, nine previously untreated) patients treated with the SCR regimen were assessed in the prospective part of this study. All patients were male and Caucasian, and the median age at diagnosis was 62 years old. The patients were treated until they achieved remission, met the criteria for removal from the study, withdrew from the study, or passed away. Four patients were changed from rituximab to ofatumumab (a potent fully-human anti-CD20 antibody) due to rituximab intolerance (allergies, reactions) or lack of efficacy.
“Of 13 bMCL patients, all patients responded to therapy, with 12 patients meeting criteria for remission (CR, n = 6; PR, n = 6). Of those achieving CR, 5 remain in CR more than 5 years after diagnosis.”
Results
After a median of 4.8 cycles of therapy, 12 patients achieved a complete response (CR), and one patient maintained stable disease (SD). The patients reported an increased overall survival greater than 40 months, and several patients maintained durable remissions without relapse for longer than five years. These results are remarkably superior to current treatment regimens with conventional chemotherapy, which range from 14.5-24 months among bMCL patients.
“The median OS of 43.4 months and PFS of 17.3 months for MCL patients with blastic disease treated with SCR therapy is one of the most important outcomes in this study.”
Another important finding was that the G/A870 CCND1 polymorphism was a strong predictor of blastic MCL, nuclear localization of cyclinD1 and response to SCR therapy. The team identified two distinct mechanisms of resistance to SCR therapy. The researchers reported that the loss of CD20 expression and evading treatment by seeking sanctuary in the central nervous system were two major resistance mechanisms to SCR therapy.
“These data indicate that administration of epigenetic agents improves efficacy of anti-CD20 immunotherapies.”
Conclusion
Although the study sample was relatively small, the researchers’ results are promising. The SCR regimen was demonstrated to be an effective epigenetic and immunotherapy treatment for mantle cell lymphoma, with long-term remissions and improved overall survival in bMCL patients. Researchers revealed important insights into the mechanisms of action of SCR and potential resistance mechanisms. This study also highlights the potential for future research exploring the efficacy of SCR in other cancers, along with other predictive biomarkers of response.
“This approach is promising in the treatment of MCL and potentially other previously treatment refractory cancers.”
Click here to read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
Researchers found that diverse geroprotectors differently affect a mechanism linking cellular aging to cellular quiescence in budding yeast.
Saccharomyces cerevisiae yeast budding cell under the microscope.
The Trending With Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.
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The mechanisms of cellular aging and cellular quiescence have been preserved throughout evolution. Cellular quiescence is a temporary state of cell cycle arrest and low metabolic activity. Importantly, quiescent (Q) cells maintain the ability to quickly activate and re-enter the cell cycle (in response to the appropriate stimuli). Recent research has shown that cellular quiescence may play a role in cellular aging.
In a 2020 study, research findings indicated that the rate at which yeast cells age is determined by a complicated program that affects 1) when a state of quiescence is entered, 2) how long quiescence is maintained and 3) when the cell exits quiescence. Researchers found that caloric restriction (CR) (a geroprotective intervention) appears to remodel this program, and this remodeling could be responsible for the CR-dependent delay of yeast chronological aging. Thus, the researchers considered the question: Does a single mechanism exist which links cellular aging to cellular quiescence?
“We have introduced a new yeast model for studying mechanisms linking cellular aging to cellular quiescence [109, 110].”
In a new study, researchers (Anna Leonov, Rachel Feldman, Amanda Piano, Anthony Arlia-Ciommo, Jennifer Anne Baratang Junio, Emmanuel Orfanos, Tala Tafakori, Vicky Lutchman, Karamat Mohammad, Sarah Elsaser, Sandra Orfali, Harshvardhan Rajen, and Vladimir I. Titorenko) from Concordia University, Montreal, used a new yeast model to test their hypothesis that a mechanism exists linking cellular aging to cellular quiescence. On July 28, 2022, their research paper was published in Oncotarget and entitled, “Diverse geroprotectors differently affect a mechanism linking cellular aging to cellular quiescence in budding yeast.”
Caloric Restriction Delays Cellular Aging by Quiescence Program Changes
“Our hypothesis posits that this mechanism integrates four different processes, all of which are initiated after yeast cells cultured in a medium initially containing glucose consume it.”
In a 2017 study, researchers cultured yeast in a medium initially containing 0.2% glucose (CR). After consuming the glucose, the cells began to differentiate into quiescent and non-quiescent cell populations. Quiescent cells that developed in these cultures had different buoyant densities and could be separated into high- and low-density sub-populations.
CR delayed yeast chronological aging by causing specific changes in four processes of a cellular quiescence program. Process one consists of a cell-cycle arrest and leads to the formation of high-density Q cells. Process two is the conversion of high-density Q cells into low-density Q cells. Processes three and four are the fast or slow decline of quiescence in low- or high-density Q cells, respectively. The researchers believe that these processes could converge into a mechanism that links cellular aging to cellular quiescence in chronologically aging budding yeast.
Figure 1: A hypothetical model for the four processes linking cellular aging to cellular quiescence.
How do Other Geroprotectors Change the Quiescence Program?
“Here, we tested our hypothesis by assessing how four different geroprotectors influence the four processes that could link cellular aging to cellular quiescence.”
In the current study, the team’s first objective was to compare the effects of four different geroprotectors on the four quiescence processes. CR, lithocholic acid (LCA) and the single-gene deletion mutations tor1Δ and ras2Δ all delay chronological aging and extend the longevity of S. cerevisiae. Geroprotectors other than CR were examined in each of the four processes. They found that these geroprotectors differently affected processes one and two and decelerated processes three and four. Two ways of slowing down yeast chronological aging were determined by testing the four geroprotectors. One way was specific to CR and the ras2Δ mutation, and the other way was characteristic for LCA and the tor1Δ mutation.
“We selected CR and LCA to investigate the two ways different geroprotectors postpone yeast chronological aging by differently targeting the mechanism potentially linking cellular aging to cellular quiescence.”
They hypothesized that the abilities of CR and LCA to regulate the four processes of a cellular quiescence program are the same used to slow yeast chronological aging. Their next objective was to test the hypothesis that specific metabolic Q cell traits can contribute to the different effects of CR and LCA on processes one and two and their similar effects on processes three and four. Two CR-specific changes in metabolic traits of Q cells were assessed: increased intracellular concentrations of glycogen and trehalose within Q cells.
“Therefore, we assessed the contributions of the increased intracellular concentrations of glycogen and trehalose within Q cells to the CR- and LCA-driven changes in cellular quiescence and to the CR- and LCA-promoted slowdowns of yeast chronological aging.”
Cellular Aging Delayed in Two Different Ways
In summary, study results showed that both CR and the ras2Δ mutation stimulated the development of high-density Q cells (process 1) and decelerated yeast chronological aging by arresting the cell cycle in early G1, whereas LCA and the tor1Δ mutation did so by arresting the cell cycle in late G1. Both CR and the ras2Δ mutation promoted an age-related conversion of high-density Q cells into low-density Q cells (process 2), whereas LCA and the tor1Δ mutation postponed this conversion. All four geroprotective interventions delayed a fast aging-associated deterioration in the quiescence of low-density Q cells (process 3) and postponed a slow aging-associated decline in the quiescence of high-density Q cells (process 4).
It is possible that the different ways these geroprotectors regulate the first two processes do not contribute to the aging-delaying capabilities of these geroprotectors. However, the researchers in this study believe there are two different ways of employing geroprotector-dependent changes in the first two processes that decelerate yeast chronological aging. They also found that a rise in trehalose within quiescent yeast contributes to chronological aging and quiescence maintenance.
“The second line of evidence for the existence of a mechanism linking cellular aging to cellular quiescence comes from our observation that an increase in intracellular trehalose within Q cells is an essential contributor to both chronological aging and quiescence maintenance in S. cerevisiae.”
Figure 6: A model for the two different ways of delaying yeast chronological aging by geroprotectors that differently affect the mechanism potentially linking cellular aging to cellular quiescence.
Conclusion
“This study and our previously published data [109] provide conclusive evidence for the existence of a mechanism that links cellular aging to cellular quiescence in chronologically aging S. cerevisiae. The mechanism integrates processes 1, 2, 3 and 4 discussed above in the text and schematically depicted in Figures 1 and 6.”
Collectively, these data provide conclusive evidence for a mechanistic link between cellular aging and cellular quiescence. In the future, the researchers aim to better understand how to target the cellular quiescence program in order to delay cell aging and the onset of aging-related diseases.
“In conclusion, because the mechanisms of cellular aging and cellular quiescence are evolutionarily conserved [1, 3, 62, 66], this study makes an important next step toward the understanding of how the knowledge-based targeting of cellular quiescence can be used for slowing down cellular and organismal aging and for delaying the onset of aging-associated diseases.”
Click hereto read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
In a recent Oncotarget paper, researchers investigated telomere shortening in patients with Barrett’s esophagus as a potential biomarker of high risk for esophageal cancer.
The Trending With Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.
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Smokers are significantly more likely than nonsmokers to have acid reflux. In many Western countries, a popular diet—known for its convenience, availability and, frankly, its lack of nutritional value—is also known to cause acid reflux. Some of the affordable foods and beverages easily accessible to Western consumers include fried food, fast foods, pizza, potato chips (and other processed snacks), high-fat meats (bacon, sausage), cheese, alcohol, soda, energy drinks, and etcetera. Unfortunately, this indulgent type of diet is accompanied by consequences beyond oily skin and an expanding waistband.
Barrett’s Esophagus
Chronic acid reflux can lead to gastroesophageal reflux disease. Gastroesophageal reflux disease can lead to Barrett’s esophagus (BE). BE is a premalignant condition in which the lining of the esophagus becomes damaged by acid reflux. BE can lead to the onset of a type of cancer called esophageal adenocarcinoma (EAC). Over the past few decades, statistics have reported that the incidence of EAC in Western populations is increasing.
“Esophageal adenocarcinoma (EAC) is on the rise in western countries with increased incidence and high mortality [1, 2].”
“Here we aimed to provide functional evidence for the hypothesis that telomere shortening can directly contribute to tumor initiation, and thus serve as a potential biomarker for BE cancer risk stratification [22, 24].”
Telomere Shortening and Tumor Initiation
“Shortened telomeres is a common sight in epithelial cancers and has also been described in EAC and its precancerous lesions.”
In this study, researchers investigated the impact of shortened telomeres in a mouse model for Barrett’s esophagus (L2-IL1B). The L2-IL1B mouse model is characterized by inflammation that leads to a Barrett-like metaplasia. The team knocked out the mTERC gene (mTERC−/−), which is the catalytic subunit of telomerase in the L2-IL1B mice.
After mTERC knockout, the researchers found that the telomeres shortened and the mice displayed signs of DNA damage. The tumor area along the squamocolumnar junction (SCJ) was increased in the second generation of these mice, and histopathological dysplasia (abnormal changes) was also increased. In vitro studies indicated that organoid formation capacity increased in BE tissue from the L2-IL1B mTERC−/− G2 mice.
“In summary, we here demonstrated a functional role of telomere shortening, a well observed property of BE, in promoting early onset esophageal tumor initiation in the L2-IL1B mouse model.”
Additional results of the study found that the telomeres in human BE epithelial cells lining the stomach with or without dysplasia were shorter than in gastric cardia tissue (the junction between the lower esophagus and the stomach). The study also found that differentiated cells that make mucus (goblet cells, which help protect the stomach lining) had longer telomeres than cells actively dividing (and more likely to become cancerous) in the columnar lined BE epithelium.
“Moreover, besides the importance during early carcinogenesis in the mouse model, shortening of telomeres was specifically decreased in dysplastic columnar-type tissue rather than in differentiated goblet cells in human BE- and LGD tissue samples.”
Conclusion
“Here, we demonstrate that telomere dysfunction aggravates the histological phenotype, extends the tumor area in the inflammation-based L2-IL1B mouse model for BE and acts as a driver for early dysplasia development.”
In summary, these findings suggest that shortened telomeres may play a role in tumor development in a mouse model of BE and are associated with proliferating columnar epithelium in human BE. The study suggests that shortened telomeres should be evaluated further as a possible biomarker for predicting EAC cancer risk in people with BE.
“It is plausible that with our measurements we could emulate this with shortened telomeres being at higher risk of genome instability and lowered cell-to-cell variability marking clonal expansion. However, larger studies are needed to test these hypotheses.”
Click hereto read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
Researchers developed a new tool aimed at better classifying HPV+ HNSCC patients with good or poor prognosis in an effort to personalize treatment and improve patient outcomes.
New Tool Uses NF-κB Activity to Classify HPV+ Head and Neck Cancer
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Over the last 10 years in the United States, the human papillomavirus (HPV) has caused more head and neck squamous cell carcinomas (HNSCC) than uterine cervical cancers. Primarily caused either by exposure to HPV or to ethanol or tobacco, HNSCC is a disease that impairs fundamental tissues involved in respiration, speech and digestion. HPV-positive and -negative HNSCC have contrasting clinical, epidemiological and histological features.
“A major discovery in the recent past is that HPV associated HNSCC have improved survival compared to tobacco associated tumors.”
Therefore, treating HNSCC in accordance with HPV status is crucial for avoiding unnecessarily harsh therapeutic side effects in HPV+ HNSCC patients. However, while oncologic outcomes among patients with HPV+ HNSCC are generally favorable, approximately 30% experience a more aggressive disease course and recurrence. Coupled with increasing incidence worldwide, this highlights a growing need for the development of effective clinical stratification tools to accurately identify HPV+ HNSCC patients who have a good or poor prognosis.
“To improve on genomic classification, we designed this study to provide a foundation for development of NF-κB related, RNA based classification strategies to better identify HPV+ HNSCC patients with good or poor prognosis that could potentially aid in future efforts towards treatment personalization.”
The Study
The researchers from this study previously found that TRAF3 and CYLD genes are negative regulators of a family of inducible transcription factors involved in inflammation, called nuclear factor kappa B or NF-κB. The team found that somatic mutations or deletions in either TRAF3 or CYLD (not commonly found in uterine cervical cancer or HPV-negative HNSCC) lead to increased NF-κB pathway activation in HPV+ HNSCC. NF-κB overactivity may lead to cancer cell growth and survival. Alterations in these NF-κB related genes may be potential therapeutic targets in HPV+ HNSCC, and their expression may be capable of predicting treatment outcomes.
“[…] we hypothesized that tumor groups based on NF-κB related gene expression may correlate with treatment outcome, considering that tumors lacking defects in TRAF3 and CYLD may have unrecognized mechanisms driving constitutive NF-κB activation.”
In the current study, the researchers developed an RNA-based NF-κB classification tool called the NF-κB Activity Classifier, or NAC. They used bioinformatics and machine learning techniques, expression-based classification, principal component (PC) analysis, gene set enrichment analysis, and weighted gene correlation network analysis (WGCNA) to verify that the NAC is indeed capable of identifying tumors with high or low NF-κB activity and tumors with good and poor survival.
“This report validates and expands on our findings that significant expression changes related to NF-κB activity occur in the subset of HPV+ HNSCC tumors marked by TRAF3 or CYLD mutations. We are planning future studies investigating the importance of ‘long-tail’ mutations in the NF-κB pathway which might further illuminate the origins of NF-κB dysregulation in HPV+ HNSCC.”
Conclusion
“Here we present data that these subclasses may also be identified by direct assessment of NF-κB activity; as demonstrated by gene expression differences highlighted by the NF-κB Activity Classifier.”
In summary, the researchers identified genomic differences within subclasses of HPV+ HNSCC. They found that defects in TRAF3 and CYLD genes and NF-κB activity were correlated with survival. Therefore, the NF-κB Activity Classifier could be a useful guide for clinicians who make therapeutic decisions for patients with HPV+ HNSCC.
“Future applications of the NF-κB Activity Classifier may be to identify HPV+ HNSCC patients with better or worse survival with implications for treatment strategies.”
Click hereto read the full research paper published by Oncotarget.
Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
