Tagged: Oncotarget

Epigenetics and Immunotherapy Combined Fights Rare Lymphoma

In a new Oncotarget study, researchers assessed an epigenetic and immunotherapy treatment regimen among patients with blastic mantle cell lymphoma (bMCL).

Mantle cell lymphoma
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.”

In previous studies, researchers reported that a combination of epigenetic and immunotherapy treatments may have synergistic activity and offer better outcomes in patients with MCL. In the current study, Francis R. LeBlanc, Zainul S. Hasanali, August Stuart, Sara Shimko, Kamal Sharma, Violetta V. Leshchenko, Samir Parekh, Haiqing Fu, Ya Zhang, Melvenia M. Martin, Mark Kester, Todd Fox, Jiangang Liao, Thomas P. Loughran, Juanita Evans, Jeffrey J. Pu, Stephen E. Spurgeon, Mirit I. Aladjem, and Elliot M. Epner from Pennsylvania State University College of MedicinePenn State Hershey Cancer InstituteWinter Haven Hospital Cassidy Cancer CenterIcahn School of Medicine at Mount SinaiNational Cancer InstituteUniversity of VirginiaUVA Cancer CenterUniversity of Arizona College of MedicineOregon Health and Science University, and Beverly Hills Cancer Center used samples from a previous trial to perform correlative studies focused on clinical results in patients with blastic MCL. On August 16, 2022, their research paper was published in Volume 13 of Oncotarget, entitled, “Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma.”

Epigenetic and Immunotherapy

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

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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.

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How Heartburn Can Turn Into Esophageal Cancer, and a Possible Biomarker

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.

Acid reflux / heartburn

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 [12].”

Since the popularity of smoking and a heartburn-inducing diet is likely to continue in the West, the early detection of EAC is critical for improving patient outcomes. If a biomarker could indicate a BE patient’s present risk of EAC, early EAC treatment could curb incidence and mortality rates. However, such a biomarker has yet to be confirmed. On February 14, 2022, researchers from Technische Universität MünchenColumbia University Irving Medical Center and Universitätsklinikum Freiburg published the research paper, “Telomere shortening accelerates tumor initiation in the L2-IL1B mouse model of Barrett esophagus and emerges as a possible biomarker,” in Oncotarget.

“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 [2224].”

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 here to read the full research paper published by Oncotarget.

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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.

For media inquiries, please contact media@impactjournals.com.

Trending With Impact: Dual Requirement in Stem Cell Leukemia/Lymphoma

For the first time, researchers revealed the protein interactome, phospho-proteome and total proteome for the oncogenic fusion protein BCR-FGFR1.

Figure 6: Signaling pathways activated by BCR-FGFR1.
Figure 6: Signaling pathways activated by BCR-FGFR1.

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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Chromosomes are found in the nucleus of cells and consist of proteins and tightly coiled strands of DNA. During cell division, chromosomal translocations can occur while the chromosomes are being copied. This type of mutation can mean that an entire chromosome has moved to another location, or that a chromosome has broken, usually into two pieces, and moved to another site. Some translocations are harmless, but others can lead to aberrant cell proliferation and cancer.

“Over the last half century, chromosomal translocations encoding functional oncogenic proteins have been identified as drivers of multiple cancers, and account for 20% of all malignant neoplasms [1, 2].”

For example, the t(8;22)(p11;q11) chromosomal translocation leads to the initiation of an oncogenic fusion protein called the Breakpoint Cluster Region Fibroblast Growth Factor Receptor 1 (BCR-FGFR1). BCR-FGFR1 is a single driver of 8p11 myeloproliferative syndrome, which is also known as stem cell leukemia/lymphoma (SCLL).

“Stem cell leukemia/lymphoma (SCLL) exhibits distinct clinical and pathological features characterized by chromosomal translocations involving the FGFR1 gene at chromosome 8p11.”

In a trending new study, researchers from the University of California San Diego and Sanford Burnham Prebys Medical Discovery Institute examined mutations in PLCγ1 and Grb2 binding sites individually and when combined together in a double mutant within BCR-FGFR1. On May 11, 2022, the research paper was published in Oncotarget and entitled, “Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation.”

The Study

In this study, the researchers used quantitative proteomic analyses to identify the crucial protein-to-protein interactions that may be necessary to activate BCR-FGFR1. The team used NIH3T3, HEK293T and 32D cells to assay five types of mutations: wild type BCR-FGFR1, a kinase-dead variant of BCR-FGFR1, a derivative of BCR-FGFR1 that contained a single mutation abolishing the Grb2 interaction site, a derivative of BCR-FGFR1 that contained a single mutation abolishing the PLCγ1 interaction site, and a double mutation that abolished both interaction sites (BCR(Y177F)-FGFR1(Y766F)).

“These data demonstrate that inhibition of either signaling pathway alone fails to inhibit hematopoietic cell proliferation, and demonstrate a dual requirement for Grb2 and PLCγ1 interactions with BCR-FGFR1 for proliferation.”

When either Grb2 or PLCγ1 signaling pathway was mutated, BCR-FGFR1 activity was decreased, but never abolished. However, when both Grb2 and PLCγ1 interactions were mutated, both cell transformation and proliferation were inhibited. The team demonstrated that BCR-FGFR1 dually relies on Grb2 and PLCγ1 for biological activity and the activation of cell signaling pathways. The researchers also found that the PLCγ1 inhibitor U73122 revealed that PLCγ1 is a potential therapeutic target for BCR-FGFR1-driven hematologic malignancies. In addition, the irreversible FGFR inhibitor futibatinib suppressed downstream signaling and cell transformation. 

“We demonstrate here that BCR-FGFR1 relies dually on the small adapter protein, Grb2, and the phospholipase, PLCγ1, for biological activity and the activation of cell signaling pathways (summarized in Figure 6).”

Figure 6: Signaling pathways activated by BCR-FGFR1.
Figure 6: Signaling pathways activated by BCR-FGFR1.

Conclusion

“Our work highlights the importance of sequencing based, mutation-specific therapies for FGFR1 induced hematologic malignancies.”

This study provides new insight into the potential molecular mechanisms underlying BCR-FGFR1 activity and identifies PLCγ1 as a therapeutic target for leukemia/lymphoma patients with this particular mutation. Future studies will be necessary to validate these findings in animal models and clinical trials. However, this study lays the groundwork for the development of new and more targeted leukemia/lymphoma therapies.

“These data unravel essential roles of Grb2 and PLCγ1 in BCR-FGFR1 mediated oncogenic growth and suggest the importance of further investigation into PLCγ1 as a potential therapeutic target in treating SCLL.”

Click here to read the full research paper published by Oncotarget.

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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.

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Gene Variants Investigated in Polish Bladder and Kidney Cancer

Two gene variants were studied in large-scale cohorts for their potential roles in bladder and kidney cancer among Polish patients.

Genitourinary cancers are a group of cancers that affect components of the urinary tract, including the bladder and kidneys. Worldwide, bladder and kidney cancer impact men at disproportionately higher rates than women. While incidence and mortality rates of bladder cancer in most western European countries have been consistently decreasing, some countries in the region, such as Poland, have seen an increase. Bladder cancer is the 4th most common malignancy in Polish men and the 14th most common malignancy in Polish women. There is currently a need to identify more effective bladder cancer biomarkers and therapeutic targets to develop new effective treatments that improve patient outcomes.

“The association between the NOD2 c.3020insC allele and CDKN2A missense variant c.442G>A (p.P.A148T) and survival of patients with bladder or kidney cancer remains controversial.”

In April of 2022, researchers from Pomeranian Medical UniversityUniversity of Newcastle and NSW Health Pathology published the first larger-scale study in Poland to describe the clinical characteristics and survival of bladder cancer patients and kidney cancer patients associated with variants in NOD2 and CDKN2A. Their research paper was published in Oncotarget on April 22, 2022, and entitled, “Bladder cancer survival in patients with NOD2 or CDKN2A variants.”

The Study

In this study, the researchers investigated two gene variants—the NOD2 c.3020insC variant and the CDKN2A p.A148T polymorphism—and their role in bladder and kidney cancer in Polish cohorts. This NOD2 variant has been shown to occur in 7.3% of the Polish population. The CDKN2A polymorphism has been found in 3.5% of the Polish population. Therefore, these gene variants could be considered genetic risk factors for cancer. To test this hypothesis, the researchers assembled detailed participant data from a cohort of 706 bladder cancer patients and 410 kidney cancer patients. The team compiled control data from over 5,000 unselected, cancer-free individuals.

“To our knowledge, this is the first larger-scale study describing the clinical characteristics and survival of bladder and kidney cancer patients that is associated with the NOD2 c.3020insC allele and the CDKN2A p.A148T polymorphism in Poland.”

After performing the variant analysis in the cohort of Polish patients with bladder cancer, the team found that 8.9% of these patients carried the NOD2 variant and 5.2% carried the CDKN2A variant. However, their analysis revealed that neither the NOD2 nor the CDKN2A variant played a significant role in the survival of patients with bladder cancer. In performing the variant analysis in the cohort of Polish patients with kidney cancer, they found that 7.3% of these patients carried the NOD2 variant and 3.4% carried the CDKN2A variant. The researchers did not observe any statistically significant relationship between kidney cancer and either variant. However, they were not able to perform a survival analysis in the kidney cancer cohort.

Conclusion

The researchers found that the NOD2 c.3020insC variant and the CDKN2A p.A148T polymorphism were not significantly associated with the survival of bladder cancer patients, regardless of age, cancer family history, smoking status, and sex. To date, this is the first larger-scale study to examine these variants in association with clinical characteristics and survival of Polish patients with bladder cancer.

“In summary, the results of this study indicate that neither the NOD2 c.3020insC variant or the CDKN2A p.A148T polymorphism are associated with the survival of bladder cancer patients regardless of age, cancer family history, smoking status, and sex. Thus, the NOD2 c.3020insC or the CDKN2A p.A148T polymorphism cannot be added to the list of genes that are associated with an increased susceptibility to bladder or kidney cancer at this time.”

Click here to read the full research paper published by Oncotarget.

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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.

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Trending With Impact: Analysis of Mutational Burden in NSCLC

Researchers conducted a multi-site cohort study of tumor mutational burden among hundreds of patients diagnosed with stage IV non-small cell lung cancer (NSCLC).

Lung cancer x-ray
Lung cancer x-ray

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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While a high tumor mutational burden (TMB) may seem unfavorable in the midst of battling non-small cell lung cancer (NSCLC), a higher TMB has been associated with a higher number of neoantigens. The presence of more neoantigens can potentially elicit a stronger immune response. Therefore, TMB may be a viable biomarker of tumor response to immunotherapeutic agents. However, the definitions, parameters and units used to measure high- and low-TMB have been inconsistent over the years. Today, the consensus unit for reporting TMB has shifted to mutations per megabase (mut/Mb). The common cut-off for high- vs. low-TMB from tissue samples is >10 mut/Mb in NSCLC.

“Despite inconsistencies with TMB definition and reporting over time, high TMB has consistently been associated with improved clinical benefit among patients receiving immunotherapy for NSCLC [22].”

Researchers—from University of UtahUniversity of Minnesota DuluthHuntsman Cancer InstituteH. Lee Moffitt Cancer Center and Research InstituteBaptist Health Medical GroupMetroHealth Medical CenterRutgers Cancer Institute of New JerseyUniversity of Southern CaliforniaSaint Luke’s Cancer InstituteUniversity of Kentucky, and Bristol Myers Squibb—used the newest consensus unit and common cut-off parameters for TMB expression to measure TMB’s relationship to treatment response and survival outcomes among metastatic NSCLC patients. Their trending research paper was published in Oncotarget’s Volume 13 on January 31, 2022, and entitled, “Real-world survival analysis by tumor mutational burden in non-small cell lung cancer: a multisite U.S. study.”

“The purpose of this study is to evaluate clinical outcomes by TMB among NSCLC patients treated with immunotherapy containing regimens in the first-line setting.”

The Study

Participants in this large cohort study included 667 patients who had been diagnosed with stage IV NSCLC and treated with any NSCLC-related treatment. Patients were recruited from nine different academic and community cancer centers across the United States. The researchers intended to utilize this “real-world” dataset and hoped it would allow them to realistically assess the role of TMB as a potential biomarker of NSCLC response to treatment.

First, the team collected demographic and clinical characteristics and separated them into two groups: TMB greater or less than 10 mut/Mb. Characteristics included age, sex, race, body mass index, smoking history, PD-L1 expression, comorbidities, Eastern Cooperative Oncology Group performance status (ECOG PS) at diagnosis, histology subtype, Stage at metastatic diagnosis, and site of metasteses. Interestingly, a history of smoking was significantly associated with a TMB greater than 10 mut/Mb.

“Smoking status was significantly associated with TMB >10 with 91% of patients reported as current or former smokers compared to 61% in the TMB <10 cohort (p < 0.01, Table 1).”

The Results

The researchers found no association between TMB and age, PD-L1 expression, tumor histology, or cancer stage at diagnosis. Next, the team assessed for significant associations between TMB and 17 genomic alterations. They found that lower TMB was associated with ALK and EGFR alterations. Higher TMB was associated with TP53 alterations. The researchers investigated the association between TMB and treatment patterns and responses. The overall response rate was very similar in both groups. 

A multivariable model was used to analyze overall patient survival and progression-free survival (PFS) for first-line immunotherapy containing regimens based on TMB. The model controlled for the initial patient characteristics and did not demonstrate significantly different results for overall survival in the two groups. However, the researchers found in a subgroup analysis that, of the patients who received TMB testing within 60 days of receiving immunotherapy treatment, those with TMB >10 demonstrated significantly longer overall survival compared to their TMB <10 counterparts. In terms of PFS, they found that PFS was longer among patients with TMB >10 in the cohort and subgroup analyses. PFS was significantly longer when treated with an immunotherapy-containing regimen first-line compared to a first-line treatment of chemotherapy. An association between TMB and PD-L1 expression was not found in this study.

Conclusion

“This study evaluated two broad questions: (1) The distribution of TMB in the real world and its association with baseline clinical and demographic features (n = 677) and (2) the association between TMB and clinical outcomes among NSCLC patients who received first-line immunotherapy (n = 224).”

Results of the study confirmed the association between a higher TMB and smoking history, as well as the benefits of first-line immunotherapy within two months of TMB testing. While the researchers were forthcoming about limitations in their study, metastatic NSCLC patients with TMB>10 who were treated with first-line immunotherapy had improved overall survival and progression-free survival.

“Based on the results in this study and prior research, TMB along with other biomarkers, such as PD-L1, may help identify patients more likely to benefit from first-line immunotherapy.”

Click here to read the full research paper published by Oncotarget.

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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.

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Trending With Impact: Genes Identified in Endocrine Therapy Resistance

Researchers studied the dynamic behavior of gene expression during the development of endocrine therapy resistance in breast cancer.

Figure 4: Tissue-specific protein-protein interaction network for modules 1 and 2 candidate genes.
Figure 4: Tissue-specific protein-protein interaction network for modules 1 and 2 candidate genes.

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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Hormones can cause tumor growth in some subtypes of breast cancer. Endocrine therapy, also known as hormone therapy, is a type of cancer treatment that removes or blocks the hormones which fuel breast cancer growth. This treatment is often given as adjuvant therapy after breast cancer surgery to lower the risk of cancer reoccurrence. In some cases, endocrine therapy may be used as a first-line treatment for hormone receptor-positive breast cancers, such as estrogen receptor-positive (ER-positive) breast cancer. However, ER-positive tumors frequently become unresponsive to endocrine therapy, and tumor regrowth can occur after treatment. The underlying causes of endocrine resistance are mostly undetermined.

“Endocrine therapies have been successful at improving cancer outcomes; however, the development of endocrine resistance, or resistance to inhibition of ER actions, remains a roadblock in breast cancer treatment.”

Recently, researchers—from UTHealth HoustonUniversity of ChicagoUniversity of Texas MD Anderson Cancer Center, and the University of Houston—used a new statistical and computational pipeline method of analysis to study the dynamic behavior of gene expression during the development of endocrine resistance in breast cancer. Their trending research paper published in Oncotarget on April 06, 2022, is entitled, “A novel group of genes that cause endocrine resistance in breast cancer identified by dynamic gene expression analysis.”

The Pipeline

“In this study, we explored the dynamic behavior of the entire gene population to identify novel genes that play fundamental roles in the development and progression of endocrine-resistant breast cancer.” 

Pipeline analysis in biology is a method of studying and analyzing a group of genes or proteins in order to understand their structure and function. The pipeline can be used to determine gene dynamics, clusters, similarities, and networks. In this case, the researchers used it to understand how endocrine resistance develops over time.

“The pipeline provides three main functions. First, statistical hypothesis testing determines a set of dynamic response genes (DRGs) that exhibit significant changes over time. Next, these DRGs are clustered into gene response modules (GRMs), sets of DRGs with similar time course expression patterns. Finally, the GRMs associations and regulatory effect are analyzed as a gene regulatory network using ordinary differential equations.”

The Study

To begin this study, the researchers first aimed to select a cell-based model that represents endocrine resistance in patients as closely as possible. They gathered data from breast cancer patients who were either resistant or sensitive to endocrine therapies and compared them with publicly available gene expression data. Results showed that the LTED MCF7 cell model displayed similar endocrine resistance to patient tumor data.

Next, the researchers observed the development of endocrine therapy resistance in the LTED MCF7 cell model, as well as the changes in gene expression over time. This data was collected and used to develop a mathematical model of gene expression dynamics during endocrine therapy resistance development. After statistical and computational pipeline analysis, the team identified a group of 254 genes whose time course expression significantly changed during the development of endocrine therapy resistance. They then aimed to validate their findings and used multiple bioinformatics approaches to narrow down this group of candidate genes.

“To further refine the genes common to endocrine resistance development and progression, we utilized several bioinformatic approaches designated to rank and prioritize the 254 common genes.”

The Results

Candidate genes were narrowed down to a novel group of 34 genes whose time course expression most significantly changed during LTED MCF7 cell modeling of endocrine-resistant breast cancer development. In addition, microarray analysis also showed that a subset of these genes was differentially expressed in triple-negative breast cancer (TNBC). This suggests that there may be shared genetic mechanisms between endocrine-resistant breast cancer and TNBC.

“As these two subtypes of breast cancer are the most fatal breast cancers with no known effective therapeutic approaches available to date, research on underlying genetic factors is of great importance.”

Conclusion

Their analysis led to the identification of a novel group of 34 genes that may play a role in endocrine resistance. Interestingly, some of these genes were also differentially expressed in TNBC. These findings could potentially lead to the development of new therapeutic strategies to overcome endocrine therapy resistance in some of the most difficult to treat and fatal breast cancers.

“Our analysis identified novel candidate genes with potential significance in endocrine-resistant breast cancer as well as TNBC, which opens new doors for designing novel therapeutic approaches for endocrine-resistant breast cancer and TNBC.”

Click here to read the full research paper published by Oncotarget.

ONCOTARGET VIDEOS: YouTube | LabTube | Oncotarget.com

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.

For media inquiries, please contact media@impactjournals.com.

Trending With Impact: Interrelated Oncogenic Pathways in Osteosarcoma

Researchers evaluated the roles and relationship between two cancer-related signaling pathways in osteosarcoma.

A child x-ray elbow ​Lateral, AP view of the forearm caused by bone cancer(osteosarcoma) of the ulna.
A child x-ray elbow ​Lateral, AP view of the forearm caused by bone cancer(osteosarcoma) of the ulna.

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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Osteosarcoma (OS) is a fairly uncommon type of bone cancer that primarily develops in the long bones found in the arms and legs. While most osteosarcomas occur in patients between the ages of 10 and 30 years old, half of all osteosarcomas develop in children. Osteosarcoma is a genetically diverse cancer that lacks a consistent targetable mutation—saddling patients and researchers with major challenges when it comes to treatment options.

“Despite their high mutation burden, OS has proven surprisingly recalcitrant to the numerous immunotherapies that have revolutionized the treatment of other mutation-high cancers.”

The lack of consistent therapeutic targets in osteosarcoma has driven researchers to investigate the role of oncogenic signaling pathways in this disease. In a trending research paper published in Oncotarget on March 9, 2022, researchers from The University of Texas’ MD Anderson Cancer Center and Rice University evaluated osteosarcoma and two cancer-related signaling pathways: IGF-1/mTOR and YAP/TAZ (the Hippo Pathway). Their paper was entitled, “Correlation of nuclear pIGF-1R/IGF-1R and YAP/TAZ in a tissue microarray with outcomes in osteosarcoma patients.”

The Study

Oncogenic signaling pathways are often deregulated in cancer, which means that these pathways can potentially be targeted and exploited for therapeutic purposes. The insulin/insulin-like growth factor (IGF) signaling pathway to mTOR (IGF-I/mTOR) is a well-known oncogenic pathway that is often deregulated in solid tumors. The YAP/TAZ (Hippo pathway) plays an important role in organ size control and tissue regeneration.

In this study, the researchers retrospectively evaluated the correlation between nuclear pIGF-IR/IGF-IR, YAP/TAZ expression and outcomes in patients with osteosarcoma. Effectors and pathways were investigated among 37 post-treatment human osteosarcoma tumor specimens. The specimens were analyzed using tissue microarray (TMA), confocal imaging, quantitative image analysis, nuclear staining, the Cox proportional hazards model, and Kaplan–Meier analysis. Researchers who evaluated images of de-identified patient samples were blind to patient demographics and outcomes until after analysis was complete.

The Results

Their results demonstrated that nuclear IGF-1R and YAP/TAZ are interrelated in human osteosarcoma. Their findings also showed that high nuclear-phosphorylated IGF-1R and low YAP nuclear-to-cytoplasmic (N:C) ratio are potentially negative prognostic indicators of overall survival in osteosarcoma patients.

“While sole targeting of the IGF/PI3K/mTOR cascade has had limited success in early phase osteosarcoma trials, our study suggests that nuclear pIGF-1R might serve as a prognostic biomarker to identify osteosarcoma patients that have an especially poor prognosis.”

Findings from this study may have revealed a clinically important relationship between these pathways in osteosarcoma. Osteosarcoma is currently treated with a combination of surgery, chemotherapy and radiation therapy. However, this study suggests that therapies targeting the IGF-I/mTOR and/or YAP/TAZ pathways may improve the diagnosis and treatment of patients with osteosarcoma.

Conclusion

The researchers were forthcoming about limitations in their study. They recognized that the sample size was relatively small and the study design only involved post-treatment specimens and retrospective analysis. However, the authors note that the likely crosstalk observed between the YAP/TAZ and IGF/PI3K/mTOR pathways is an important finding. They hypothesize that a dual-targeted pathway approach may have synergistic antineoplastic activity.

“Given the rarity of osteosarcoma, clinical validation of our results will almost certainly require the active participation of national and international high-volume cancer centers.”

Click here to read the full research paper published by Oncotarget.

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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.

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Scientific Integrity

Trending With Impact: Adjunct Virotherapy Fights Multiple Myeloma

Researchers investigated using oncolytic viruses to treat multiple myeloma—alone and in a combination approach.

3D red blood cells in vein
3D red blood cells

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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Multiple myeloma (MM) is a currently incurable cancer of blood plasma cells. Autologous stem cell transplantation (ASCT) has had efficacious results among eligible patients. However, even after ASCT, a significant number of patients continue to relapse and become resistant to current standard therapies.

A promising new method to treat blood cancers is a form of immunotherapy called virotherapyOncolytic viruses are uniquely capable of being reprogrammed to selectively infect and kill various cancer cells without infecting or damaging normal cells in host organisms, including mice and humans. Researchers from Arizona State UniversityEmory University and the Mayo Clinic (in Scottsdale, Arizona) had previously experimented with using the oncolytic myxoma virus (MYXV) to treat MM. In nature, MYXV only affects rabbits and is innocuous in mice and humans. They found that MYXVs delivered through stem cell transplantation can eliminate some residual MM cells in the Balb/c mouse model.

“Recently, we reported that ex vivo virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an autologous-transplant Balb/c mouse model.”

However, the researchers found that Balb/c mice may not be ideal models for MM. They observed that the behavior of MM in Balb/c mice did not quite reflect the development, clinical manifestation and localization of MM observed in human patients. Therefore, the team conducted a new study of MYXVs in the Vk*MYC transplantable C57BL/6 mouse MM model. Their trending research paper was published in Oncotarget on March 3, 2022, and entitled, “Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma.

The Study

“In this study, we used the Vk*MYC MM model because it faithfully recapitulates the localization of the myeloma disease within the bone marrow as well as the clinical manifestation of the disease including bone damage (paralysis), renal failure [912].”

A bortezomib-resistant multiple myeloma murine cell line was examined in this study, named Vk12598. Three different strains of MYXV were tested here: vMyx-M093L-Venus, vMyx-M135KO and vMyx-hTNF. The vMyx-M093L-Venus is a wild-type MYXV that expresses Venus-tagged M093 protein as a virion component. The vMyx-M135KO virus is an unarmed and attenuated recombinant MYXV, in which the M135 gene has been deleted and the green fluorescent protein (GFP) has been inserted. The vMyx-hTNF strain is genetically modified, or “armed”, to express human tumor necrosis factor (TNF). TNF is a cytokine that induces apoptosis in various cancer cells.

First, the researchers examined the in vitro ability of these three MYXVs to bind to the Vk12598 cells in culture media. These results were then tested in vivo by first injecting the C57BL/6 mice with Vk12598 cells. Vk12598 cells were seeded for three weeks to allow the MM to progress in the mice. Then, some mice were treated with either cyclophosphamide (a common chemotherapeutic drug used to treat MM) or the compounds LCL161 and α-PD-1. Next, bone marrow cells were loaded with either vMyx-M135KO or vMyx-hTNF and transplanted into the mice.

The Results

In vitro, the researchers found that all three MYXVs did indeed bind to, infect and compromise the viability of the BOR-resistant MM cells in a relatively short period of time. In vivo, the results demonstrated that, alone, autologous bone marrow leukocytes armed ex vivo with the MYXVs (BM/MYXV) exhibited moderate therapeutic effects against the MM cells. This indicated that BM/MYXV has potential as an adjunct therapy against the MM. While little synergy was observed between Cyclophosphamide (Cy) and BM/MYXV, Cy in combination with BM/vMyx-M135KO delayed the onset of myeloma in the mice more than Cy combined with BM/vMyx-hTNF. The researchers note that these results indicate the TNF transgene may have actually interfered with efficacy.

The authors also observed a better synergistic ability between BM/vMyx-M135KO and LCL161 with α-PD-1 to control the progression of MM. This combination resulted in a significant improvement in survival rates and decreased tumor burden. When surviving mice were re-introduced to Vk12598 cells, the researchers found that they had developed acquired anti-MM immunity.

Conclusion

“Together, we show promising results in terms of therapeutic benefits of delivering oncolytic MYXV via carrier cells from autologous BM transplants, both alone or in combination with LCL161 and α-PD-1 against drug-resistant MM cells in vivo. To our knowledge, these are the first results showing therapeutic benefits of oncolytic MYXV to control and even eradicate established drug-resistant MM cells in a preclinical murine model that has previously shown excellent concordance with predicting clinical efficacy in human MM patients.”

Click here to read the full research paper published by Oncotarget.

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Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Scientific Integrity

A Remote Weight Loss Strategy for Breast Cancer Survivors

Researchers Jennifer Y. Sheng and Vered Stearns discussed the results of a study that compared weight loss interventions among overweight or obese survivors of breast cancer.

Weight loss for survivors of breast cancer
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After being diagnosed with breast cancer, up to 96% of women have reported gaining weight. Medications, inactivity, food choice, and food quantity can all lead to weight gain. Studies have shown that weight gain can increase the risk of breast cancer recurrence by 40–50% and breast cancer-related mortality by 53–60%. Thus, for women with breast cancer and those who have survived breast cancer, weight management is a potentially life-saving intervention.

In an editorial paper published by Oncotarget in 2021, researchers Jennifer Y. Sheng and Vered Stearns from Johns Hopkins School of Medicine and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discussed the results of the 2020 POWER-Remote Trial—a study among breast cancer survivors on the results of a remote-based weight loss program compared with a self-directed approach. Their editorial paper is entitled, “Innovating and expanding weight loss strategies for breast cancer survivors.”

The POWER Intervention

The Practice-based Opportunities for Weight Reduction (POWER) intervention is a 12-week behavioral weight loss program designed for overweight and obese participants. The POWER program strategy focuses on physical activity and behavioral changes, nutrition education and setting individual goals. Researchers developed the POWER-remote intervention to enable participants to engage in this weight loss program remotely through weekly video conferences and phone calls. In the current editorial paper, the researchers discussed the results from a study that adapted the POWER-remote intervention for breast cancer survivors: the POWER-Remote Trial.

“The original Practice-based Opportunities for Weight Reduction (POWER) study in obese individuals with a risk for cardiovascular disease demonstrated equivalent weight loss outcomes between in-person coaching and a remote intervention [24].”

The POWER-Remote Trial

The POWER-Remote Trial was a randomized, controlled comparative effectiveness trial that evaluated the POWER-remote intervention compared to a self-directed weight loss approach among overweight or obese breast cancer survivors. Between 2013 and 2015, 87 overweight or obese women with stage 0-III breast cancer (who completed local therapy and chemotherapy) were evaluable for analysis in this study. Forty-five women were enrolled in the POWER-remote arm of the study and 42 women were enrolled in the self-directed arm.

“Our group compared the remote-based POWER intervention (telephone calls by a coach, access to online learning materials, online self-directed dietary/activity monitoring) to self-directed weight loss in overweight or obese survivors of early-stage breast cancer [25].”

Over the course of the study, the researchers found high adherence in the POWER-remote arm, with only one participant lost in follow-up. At the 12-month mark, 51% of the POWER-remote participants lost greater than or equal to 5% of their baseline body weight. Among the self-directed participants, 17% lost 5% or more of their baseline body weight. The results of this study suggest that the POWER-remote intervention is an effective weight loss strategy. It is a cost-effective, scalable and conscientious solution to assist with weight loss among many breast cancer survivors.

Conclusion

Despite the significant improvements in weight, body composition, fitness, and quality of life seen by over half of the participants in the POWER-remote arm, the researchers also pointed out a problem. The POWER-remote intervention still did not yield significant results in almost half of the other participants. Trouble sleeping was shown as a potential culprit that hindered weight loss, while many other factors inhibiting weight loss in this population are not yet fully understood.

The authors wrote that it may be necessary to further individualize or enhance the POWER intervention to achieve greater success in breast cancer survivors. They also suggested that, in some people, the POWER program may need to be augmented with pharmacological agents to aid in weight loss. In addition, the authors believe that the payer system should be reevaluated to expand coverage for obesity treatments.

“At present, I’m conducting a phase two study to determine whether an adaptor approach with pharmacotherapy can augment obesity treatment in breast cancer survivors. This study is called the A-NEW study, which stands for an Adaptive Nutrition and Exercise Weight Loss Study,” Dr. Jennifer Sheng said in a recent Behind the Study interview with Oncotarget. “We’re also looking forward to analyzing results from the COOIN study, the Cancer, Obesity, Overweight, and Insomnia study, which was led by Dr. Janelle Coughlin.”

Click here to read the full editorial paper published by Oncotarget.

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Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Scientific Integrity

Trending With Impact: Are NOTCH1 Variants Prognostic in Breast Cancer?

Researchers determined the prognostic ability of three NOTCH1 gene variants by incorporating them into two non-tumorigenic breast cell lines.

Breast cancer illustration
Breast cancer illustration

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 genetic changes that occur within the protein-coding gene NOTCH1 have not yet been fully studied or classified. Despite a lack in research, previous studies have suggested that NOTCH1 may be a potential target for novel cancer therapies, particularly against triple-negative breast cancer (TNBC). NOTCH1 variants in TNBC tend to cluster in the PEST region and have previously been linked to gamma secretase inhibitor (GSI) sensitivity and chemotherapy resistance.

“Furthermore, TNBC patients with increased Notch1 expression have demonstrated increased aggressive phenotypes and lower median overall survival [25].”

Since TNBC is well-known for a lack of actionable therapeutic targets, aggressive phenotypes and poor prognoses, there is an important need to develop new targeted therapies—as well as predictive markers for those therapies. Researchers from The Johns Hopkins University School of MedicineVanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center experimented in vitro with NOTCH1 variants and their ability to predict TNBC responsiveness to GSIs and standard of care chemotherapies. Their trending research paper was published by Oncotarget on February 16, 2022, and entitled, “NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model.”

The Study

The researchers used three publicly available tumor-associated variant databases to identify three NOTCH1 variants that are commonly mutated in breast cancers; two variants were located in the A2441 site on NOTCH1 and the third variant was located in the PEST region of NOTCH1. To investigate the role of these NOTCH1 variants in TNBC in vitro, the team cultured two non-tumorigenic breast epithelial cell lines. Uniquely, they used an adeno-associated virus (AAV) vector to isogenically incorporate the NOTCH1 variants into the two cell lines. The researchers also developed a wildtype vector for the control arm of the study.

“In addition to the NOTCH1 variants, a targeted wildtype (TWT), which underwent the same gene targeting mechanism with a wildtype vector, was generated for both parental cell lines to act as a control.”

A standard growth factor supplemented media was used to determine if the NOTCH1 variants caused increased proliferation in the non-tumorigenic cell lines. Compared to the controls, no significant change in proliferation was observed. They also removed the epidermal growth factor (EGF) from the cells to determine if these NOTCH1 variants impart a ligand-independent proliferative advantage. In both cell lines, their results demonstrated that the A2441 variants exhibited EGF-independent growth, while the PEST NOTCH1 variant did not. Immunoblot analyses suggested that, in the absence of EGF, the A2441 NOTCH1 variants activated the MAPK pathway. These EGF-independent NOTCH1 variants (not the PEST NOTCH1 variant) conferred an invasive growth phenotype, increased migratory potential, had dysregulated 3D morphology, and significantly altered gene expression in cancer pathway genes.

Next, to measure the responsiveness and susceptibility of these variants to therapeutic agents, the cells were treated with six chemotherapeutic agents and nirogacestat—a GSI drug. Interestingly, none of the three variants demonstrated significantly different responses to the treatments when compared to one another. Furthermore, all of the variants showed sensitivity to these standard therapies used against TNBC. This suggests that these specific genetic changes within NOTCH do not have a large impact on tumor behavior and may not be useful as predictive markers for therapy response.

Conclusion

“Taken together, these data suggest that the oncogenic potential of NOTCH1 PEST domain variants depends on both variant type and amino acid location.”

Contrary to previous studies, the researchers found that the three NOTCH variants did not demonstrate significantly different responses to the GSI or the chemotherapies despite demonstrating distinct phenotypes. The lack of differential responses demonstrated by the variants in this study suggests that there is high variability among NOTCH1 variants. The prognostic potential of NOTCH1 may be dependent on the type of variant and its location, but more expansive research is necessary.

“Future studies involving meticulous characterization of an expansive panel of NOTCH1 variants in a similar model may provide mechanistic insight and predictive and/or prognostic value that is both variant type and site dependent.”

Click here to read the full research paper published by Oncotarget.

ONCOTARGET VIDEOS: YouTube | LabTube | Oncotarget.com

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.

Scientific Integrity