Oncotarget Archives | Page 10 of 12 | Mikhail Blagosklonny Oncotarget

Oncotarget Uses TrendMD to Expand Research Impact

July 15, 2021

Oncotarget began using TrendMD—a platform that recommends relevant content to a large network of research readers.

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Oncotarget has started a new venture to expand our reach and connect with other relevant platforms using TrendMD. The TrendMD widget has been applied at the bottom of all research papers on Oncotarget.com to serve recommended content to our readers, and readers on thousands of other high-traffic websites and scholarly platforms. Recommended content is based on the content currently being viewed, content that has been viewed in the past, and content other similar readers are viewing.

“[TrendMD’s] recommendation algorithms continuously optimize the placements of links to your content for the right audience while readers are actively looking for something interesting to discover.” —Source: TrendMD.com

This platform uses algorithms similar to those that Amazon uses to help bring fresh new relevant content to interested readers. The TrendMD widget recommends content both derived from Oncotarget.com and from other biomedical journals and articles publishing similar content. They also use collaborative filtering and track user behavior to learn how to suggest the right content for the right people.

Oncotarget uses TrendMD to help our authors better circulate their research to targeted audiences around the world, cross-promote papers in adjacent fields, and increase paper citations. In a research study by Scientometrics, TrendMD was shown to outperform PubMed related citations by 272%. By joining this platform, Oncotarget publications are now incorporated into the TrendMD network—with 100 million total monthly users. Papers published by Oncotarget will now be recommended on hundreds of other leading peer-reviewed journals and scholarly websites.

“TrendMD is the world’s leading discovery platform, delivering over 1 billion recommendations to over 100 million unique users each month on 4,500 websites from over 300 scholarly publishers.” —Source: TrendMD.com

Since papers are recommended based on algorithms aiming to share specific content with readers who are most likely to be interested in the content, readership and engagement on TrendMD is very high. TrendMD statistics show that readers have the lowest bounce rate and view more content on TrendMD compared to Google AdWords, Google Scholar, Twitter, and PubPeer. Oncotarget is proud to offer this service for our authors and the scientific research community.

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Oncotarget

Trending With Impact: Targeted Treatment for Recurrent Ovarian Cancer

July 15, 2021

In this 2018 paper, researchers studied a new targeted strategy to treat ovarian cancer.

Anatomy and physiology of Ovary under the microscopic in laboratory.

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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Sialyl-Thomsen-nouveau (STn)—a tumor stem cell-associated carbohydrate antigen—is a moiety. “Moiety” is a term used to name molecular particles identified among multiple types of molecules. STns have been found on protein markers of cancer stem cells (CSCs) in pancreatic, colon, and gastric malignancies. Researchers hypothesize that CSCs can survive adjuvant chemotherapy and are responsible for tumor resurgence in many cancers, including recurrent ovarian cancer (OvCa).

“Unfortunately, despite aggressive surgery and adjuvant chemotherapy, most women with OvCa develop recurrent disease that is ineffectively treated with current therapies. Novel treatment strategies are urgently needed to target chemoresistant disease.”

Researchers from Massachusetts General Hospital, Siamab Therapeutics, Inc., and Harvard Medical School conducted a novel research study in 2018 and authored a paper published by Oncotarget, entitled, “Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau.”

“Accumulating research has revealed not only the importance of CSCs in tumor initiation, metastasis, recurrence, and chemoresistance, but also the potential of CSC-directed therapies to impact patient survival.”

The Study

Researchers often use CD133 (a cell surface antigen) as a marker to detect and sequester CSCs in various solid tumors. In this study, the team analyzed the expression of STn and CD133 in ovarian cancer cell lines, their colony and sphere formation capacity, response to cytotoxic chemotherapy, and STn’s response to two targeted antibody drug conjugate (anti-STn-ADC) treatments in vivo and in vitro.

“Analyses of colony and sphere forming capacity and of response to standard-of-care cytotoxic therapy suggest a subset of OvCa STn+ cells display some CSC features.”

In a subset of human OvCa cell lines, the researchers found that STn and CD133 were co-expressed. They also found that STn+ and CD133+ cells have increased colony formation capacity and elevated levels of STn increases sphere formation. Both of the anti-STn-ADC treatments had anti-cancer effects in the OvCa cell lines in vivo and in vitro. These findings show that STn demonstrates some stem-like properties and may be a viable therapeutic target in ovarian cancer.

“In summary, STn+ cells demonstrate some stem-like properties and specific therapeutic targeting of STn in ovarian tumors may be an effective clinical strategy to eliminate both STn+ CSC and STn+ non-CSC populations.”

Conclusion

“Our finding that targeting STn+ cells in vivo with a highly specific antibody conjugated to auristatin resulted in marked decreases in tumor burden without any obvious toxicity suggests that an anti-STn ADC approach may serve as a viable option in eliminating non-CSC as well as some CSC populations.”

Click here to read the full scientific study, published by Oncotarget.

Oncotarget

Trending With Impact: ONC201 Induces Apoptosis in Breast Cancer

July 1, 2021

A novel therapeutic combination converts anti-proliferative effects in breast cancer cells to pro-apoptotic.

Trending With Impact: ONC201 Induces Apoptosis in Breast Cancer — 3D illustration of the stages of cell apoptosis.

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In the 1990s, Dr. Wafik El-Deiry’s cancer research laboratory discovered a gene that encodes a protein, called death receptor 5, or TRAIL receptor 2. TRAIL is a protein that induces the process of cell death, or apoptosis. This pathway activates the body’s innate immune system and is capable of suppressing cancer cells by inducing apoptosis.

After this discovery, researchers from the same lab considered the notion that increasing the production of TRAIL to enhance the body’s own immune response may have a safe therapeutic benefit in the treatment of cancer. The team searched for small molecules capable of upregulating the TRAIL gene and discovered the therapeutic compound TIC10, also known as ONC201. ONC201 is a well-tolerated drug currently being evaluated in advanced clinical trials for the treatment of various malignant solid tumors, including refractory metastatic breast cancer.

Researchers in Dr. El-Deiry’s laboratory have continued to investigate this drug in order to learn more about how it works, and what tactics or combinations may be used to produce better results for cancer patients. In a 2016 study, the researchers learned that ONC201 produces heterogeneous results in different tumor types.

“The question is, with this specific drug, what is the pattern of response, what determines that, and how can we get it to work a little bit better,” Dr. El-Deiry said in a recent Oncotarget interview.

Based out of Temple University, Fox Chase Cancer Center, Brown University, and the El-Deiry Cancer Research Laboratory, researchers wrote a paper detailing their latest study on ONC201. The paper was published by Oncotarget in 2020 and entitled, “TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic.”

THE STUDY

Led by first-author Dr. Marie Ralff, the researchers in this study found that ONC201 induces differential responses across various breast cancer tumor subtypes. Few breast cancers are responsive to TRAIL, and one subtype that is responsive to TRAIL is triple-negative breast cancer.

“We saw that in some of these tumor types (the triple-negative breast cancer type in particular) the compound was having a pro-apoptotic effect, and in other [breast cancer] tumor types, it was having an anti-proliferative effect,” said Dr. Ralff.

When comparing in vivo and in vitro results of the drug, the team found that the pro-apoptotic effects translated to efficacy, while the anti-proliferative effects did not. The researchers then decided to investigate strategies to convert breast cancer cell response to ONC201 from anti-proliferative to apoptotic. ONC201 affects two known mechanisms of TRAIL resistance in breast cancer: death receptor 5 and anti-apoptotic proteins. This fact led the researchers to introduce a TRAIL receptor agonist antibody in combination with ONC201.

“If we pretreat TRAIL resistant breast cancer cells with ONC201, the level of surface death receptor 5 goes up and the intracellular levels of anti-apoptotic proteins go down, thereby priming the cells to undergo death through the TRAIL pathway. So, if we then add in a TRAIL receptor agonist, it induces apoptosis in a very potent way,” Dr. Ralff said.

CONCLUSION

“The concept is when cells are treated with the small molecule compound, not a whole lot happens. When cells are treated with TRAIL, not a whole lot happens. When you put them together, it’s like flipping a switch. The cells now undergo potent cell death,” Dr. El-Deiry said.

The potential efficacy of this therapeutic combination was strengthened by results in the study showing that ONC201 paired with the TRAIL receptor agonist antibodies is non-toxic to fibroblasts. The researchers also showed that the natural killer cells are only active against the breast cancer cells that have been exposed to ONC201. In vivo studies reaffirmed the safety of this combination in mouse models.

Click here to read the full research study, 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.

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

Oncotarget

Trending With Impact: Low-Dose Chemo Inhibits Resistant Breast Cancer

June 18, 2021

In this trending in vitro study, researchers assessed the efficacy of low-dose 6-mercaptopurine and 5-azacitidine to inhibit high resistance triple-negative breast cancer cells.

Photomicrograph of a breast cancer (grade 3 invasive ductal carcinoma) with frequent mitoses (mitotic figures), including a large central atypical mitoses.

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Triple-negative breast cancer (TNBC) accounts for 10-15% of all breast cancers. “Triple-negative” in this subtype of breast cancer cell refers to the lack of HER2 protein and estrogen and progesterone receptors. This means that TNBC cannot be treated with hormone inhibition and must be treated with conventional chemotherapy. In addition, many of these breast cancer cells can opportunistically switch between proliferation and quiescence—a difficult phenotype to treat. Patients diagnosed with this highly adaptable cancer frequently relapse and develop resistance to treatments.

In 2021, researchers from The University of Texas MD Anderson Cancer Center conducted a research study in hopes of developing a safe and effective therapeutic combination to treat resistant triple-negative breast cancer. Their paper, published in Oncotarget’s Volume 12, Issue 7, was entitled: “Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine.”

The Study

“Evidence suggests that SUM149-metabolic adaptable (MA) cells are a suitable model of resistant human triple-negative breast cancer (TNBC) cells that can survive bottlenecks in the body, including therapeutic interventions, by opportunistically switching between quiescence and cell proliferation [5, 7, 8].”

In this in vitro study, researchers cultured three highly drug-resistant and metastatic progenitor-like TNBC cell lines with opportunistic switching between quiescence and proliferation. Researchers focused on designing a safe treatment that is effective in both low- and high-risk patients. The researchers note that it was critical to their study that the regimen is proven safe to administer to patients for early use in the minimal residual disease (MRD) stage after surgery, and before clinical metastasis is detected.

“For a potential therapy to be suitable at the MRD stage, it must be safe (an important criterion prior to clinical relapse) and disrupt heterogeneous progenitor-like cancer cells that evolve into clinical metastases.”

Two chemotherapy and immunosuppressive drugs (ribonucleoside analogues) were tested on the cell lines at low doses for the sake of viability in the MRD stage: 6-mercaptopurine (6-MP) and 5-azacitidine (5-AzaC). Both of these drugs have been clinically proven to be well-tolerated and to have drug-sensitizing, quiescence-stabilizing, and apoptosis-inducing effects in cancer cells.

“We chose 5-AzaC because it could complement 6-MP’s effects on the transcriptome and epigenome, and—as indicated by many Phase 1 clinical trials—5-AzaC is well tolerated [11].”

Results & Conclusion

“Our studies suggest that low-dose 6-MP, which is a purine analogue and very effective in maintaining remission in IBD [9], inhibits highly adaptable TNBC cells in our model, presumably by disrupting their transcriptome and epigenome.”

Researchers found that these low-dose therapeutics take several weeks to become effective. Despite the low dose, 6-MP (complimented by 5-AzaC) was capable of inhibiting highly adaptable TNBC cells. The researchers also point out that, based on decades of 6-MP’s use in patients with inflammatory bowel disease (IBD), this drug may be used regularly to modulate the immune system and prevent disease recurrence through its ability to inhibit chronic inflammation associated with advanced cancers.

“We suggest that low dose 6-MP and other drugs that would complement 6-MP’s action, such as 5-AzaC, could be suitable for preventing recurrence and metastasis in high-risk breast cancers. 6-MP could be taken lifelong if it is necessary for maintaining a long-term remission.”

Click here to read the full scientific study, published by Oncotarget.

Oncotarget

Trending With Impact: Novel Biomarkers in Bladder Cancer

June 4, 2021

Researchers from the University of Houston and UT Southwestern Medical Center conducted a study which aimed to screen urine for potentially useful protein biomarkers of bladder 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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Bladder cancer is four times more common among men than women, and it is the sixth most common cancer diagnosis in the United States. However, researchers have found that cystoscopy—the primary method physicians use to diagnose patients with bladder cancer—is relatively invasive, expensive, and has the potential to cause urinary tract infections.

“In contrast, urine is a noninvasive and readily available biological fluid that can be used for diagnostic tests.”

In 2021, researchers from the University of H ouston and UT Southwestern Medical Center conducted a study which aimed to screen urine for possibly useful protein biomarkers of bladder cancer. The paper they authored was published in Oncotarget’s Volume 12, Issue 8, and entitled: “Urine protein biomarkers of bladder cancer arising from 16-plex antibody-based screens.”

“Urine biomarkers could potentially provide preliminary confirmation of low-grade BC [bladder cancer] before invasive procedures are performed and facilitate surveillance of BC, as reviewed [9].”

The Study

Patients may benefit in a number of different ways by using urine as fluid in diagnostic testing for bladder cancer. Urine is readily bioavailable, non-invasive, and it can also be collected and tested on a regular basis. Patients can even use various cost-effective point-of-care diagnostic tools, including at-home testing. First, the researchers assessed whether there were useful biomarkers of bladder cancer to be found in this fluid. The team used Luminex screening to test for both low and high levels of 16 proteins utilizing highly specific antibody-protein interactions.

“In this study, Luminex screening was used to simultaneously assay the protein abundances of 16 potential biomarkers in different stages of bladder cancer and then compared to urology clinic controls.”

ELISA validation was then used to determine which proteins were significantly elevated in bladder cancer. They found that levels of three urine proteins were capable of distinguishing between control and bladder cancer urine. One protein was also found to be capable of discriminating between high- and low-grade disease, and the successive clinical stages of bladder cancer.

“Upon ELISA validation, urine IL-1α, IL-1ra, and IL-8 were able to distinguish control urine from urine drawn from various bladder cancer stages, with IL-8 being the best discriminator.”

Conclusion

“These studies indicate that urine IL-1α, IL-1ra, and IL-8 are potential biomarkers of BC, two of which re-affirm previous reports.”

The researchers note that these newer urine biomarkers must be analyzed in larger cohorts, in specific clinical contexts, and compared to the performance of current diagnostic tools, such as the Bladderchek and UroVysion FISH assay.

“Looking forward, systematic studies in larger patient cohorts are warranted to establish the specific clinical contexts in which these markers may be used, including the following: (i) for initial diagnosis of BC, (ii) for surveillance of tumor recurrence, and/or (ii) for assessing treatment response following BCG therapy or other therapeutic modalities.”

Click here to read the full scientific study, 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.

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

Oncotarget

Trending with Impact: RNA Modification Regulatory Proteins in Melanoma

May 20, 2021

Researchers analyzed various publicly available datasets and identified two RNA modification regulatory proteins that are not only overexpressed in melanoma, but necessary for melanoma growth.

Malignant melanoma 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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After melanoma of the skin metastasizes, it commonly becomes very difficult for doctors to treat. This is due to melanoma’s problematic tendency to acquire resistance to therapeutic interventions. Despite the development of many new targeted interventions and immunotherapies, five-year survival rates for patients with melanoma continue to be less than 10% for patients with lymph node metastasis and less than 5% for patients with distant metastasis.

“As the number of potential therapeutic DNA targets dwindle, many researchers are turning to RNA to tackle the problem.”

In 2018, researchers from Yale University School of Medicine and the University of Alabama at Birmingham in the United States set their focus on analyzing RNA alterations in melanoma, in hopes of identifying new, and more effective, therapeutic targets. Their research paper was published by Oncotarget in 2019, and entitled: “Dissecting the role of RNA modification regulatory proteins in melanoma.”

“Many studies have shown that these RNA modifications play crucial role in melanoma growth and metastasis [58, 59]. They are also involved in drug resistance mechanism.”

The Study

“Since RNA is a key molecule that drives every cellular process, their deregulation is present in nearly all human disease and play a causative role.”

The researchers explain that alterations among RNAs may arise due to altered activity or expression of the enzymes/proteins which are involved in the modification process. In this study, the team used multiple publicly available bioinformatics platforms to, first, analyze RNA alterations in melanoma samples, and then, to comprehensively analyze RNA modification regulatory proteins among melanoma samples. The publicly available datasets included: The Cancer Genome Atlas, The Human Protein Atlas, Oncomine, and the UALCAN database.

“Our study started with the analysis of various genetic alterations (amplifications, mutations/deletion) as well as RNA overexpression of these RNA modification regulatory proteins in The Cancer Genome Atlas melanoma database.”

Based on their analyses of these databases, reverse transcription quantitative PCR, soft-agar assays, validation by shRNA-mediated knockdown, and statistical analysis, the team identified what they believe are the most relevant RNA modifying proteins that play a crucial role in the development of melanoma. They found that METTL4 and DNMT3A RNA-modifying enzymes/proteins are both necessary for melanoma growth and overexpressed in melanoma.

“Based on this we infer that the upregulated expression of RNA modification regulatory proteins METTL4 and DNMT3A play a key role in melanoma initiation or progression.”

Conclusion

The researchers explained that their studies served the duel purpose of improving their understanding of novel pathways that cause melanoma to become untreatable, and also paving the way “to develop new, effective and sustainable therapeutic tools for optimal drug selection and treatment.”

“Additional future studies are needed to fully determine the role of these RNA modification regulatory proteins in melanoma tumor growth and progression (e.g., metastasis).”

Click here to read the full scientific study, 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.

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

Oncotarget

Trending with Impact: Composite Score May Further Classify HCC

May 7, 2021

In this trending study, the association between IGF/CTP composite scores, overall survival, and progression-free survival of hepatocellular carcinoma patients treated with sorafenib was investigated.

Human liver tissue under the microscope view.

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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Sorafenib was the first systemic therapy approved to treat Child-Turcotte-Pugh (CTP) class A patients with advanced hepatocellular carcinoma (HCC). However, there are no biomarkers known to predict survival, treatment outcomes, or to guide this HCC systemic therapy. The insulin-like growth factor 1 Child-Turcotte-Pugh (IGF-1/CTP) composite score has emerged as a hepatic reserve assessment tool—and potential prognostic biomarker.

“Accurate assessment of the functional hepatic reserve is important to the prognostic and treatment prediction for patients with liver disease [1, 2].”

Researchers from the University of Texas MD Anderson Cancer Center, Massachusetts General Hospital, and Harvard Medical School conducted a study to assess the association of the IGF/CTP score with overall survival (OS) and progression-free survival (PFS) of HCC patients treated with sorafenib. Their paper was published in Oncotarget’s Volume 12, Issue 8 and entitled, “Insulin-like growth factor 1/Child-Turcotte-Pugh composite score as a predictor of treatment outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib.”

The Study

The majority of circulating insulin–like growth factor (IGF) is synthesized and secreted by the liver, and levels of IGF dramatically decrease in chronic liver disease and HCC. IGF can be a helpful tool to determine the prognosis of patients with advanced HCC while undergoing treatment with sorafenib. Researchers also use the Child-Turcotte-Pugh (CTP) qualitative scoring system to assess severity of liver cirrhosis, hepatic reserve, guide treatment decisions, and to stratify patients with HCC into three groups (A, B, and C). CTP class A has a better prognosis compared to classes B and C.

“Assessing liver reserve in HCC is of a great value as a tool for stratification of patients in clinical trials as well as to predict HCC outcome and guide therapy decisions in routine practice [28].”

In the researchers’ prospective study, 171 patients with HCC from the University of Texas MD Anderson Cancer Center were screened and included in this study. Of the patients, 116 were classified in CTP group A. Patient IGF/CTP scores were calculated and the researchers used the Kaplan-Meier method and log-rank test to estimate and compare the time-to-event outcomes between patient subgroups. Based on CTP and the IGF/CTP scores, researchers reclassified group A patients into AA and AB risk groups, which differed significantly in terms of OS and PFS. The researchers followed up with all patients in the study until disease progression or death. Unfortunately, during the follow-up period, 100 patients passed away.

“After IGF/CTP scoring, 87 of 116 CTP class A patients were reclassified as IGF/CTP-A (AA) and 29 patients were reclassified as IGF/CTP-B (AB) (Supplementary Table 1).”

Results & Conclusion

“Our study is the first prospective validation of the IGF/CTP scoring system association with the outcomes among patients with HCC treated with sorafenib.”

This study supported the researchers’ hypothesis that the IGF/CTP score is capable of further distinguishing and refining CTP class A patients. However, for CTP class A patients, due to limited power of the study, researchers were unable to meet the threshold for statistical significance for the OS and PFS durations of the reclassified groups AA and AB.

“Although our study was not powered to determine the predictive value of the IGF/CTP score in regard to median OS and PFS durations in CTP class A patients treated with sorafenib, our subset analyses of OS and PFS at different timepoints were statistically significant and, if independently validated, could change the standard approach to assessing hepatic reserve in patients with HCC.”

Click here to read the full scientific study, 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.

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

Oncotarget

Trending with Impact: Acute Myeloid Leukemia and Midostaurin Response

April 23, 2021

Researchers examined midostaurin resistance or sensitivity in a cohort of patients with acute myeloid leukemia.

Figure 2: Differential gene expression for midostaurin sensitive vs. resistant samples identifies a unique signature. — **Figure 2:** Differential gene expression for midostaurin sensitive vs. resistant samples identifies a unique signature.

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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Acute myeloid leukemia (AML) is a heterogeneous malignancy that most commonly affects older adults, 60 years of age and older. NPM1, DNMT3A, and FLT3 are the most common genomic alterations found within this disease. In about 30% of AML patients, FLT3 is mutated. Midostaurin was the first FDA approved FLT3 inhibitor for AML. While Midostaurin has a successful overall survival benefit, both primary and secondary resistance remains common.

“A subtype of AML, classified by the presence of a FLT3-Internal Tandem Duplication (ITD) mutation, tends to have a worse prognosis with early relapse and death [5].”

Researchers from Oregon Health and Science University and Howard Hughes Medical Institute conducted a study to identify features that may predict response to midostaurin in FLT3 mutant and wild-type samples. They performed an ex vivo drug sensitivity screen on primary and relapsed AML samples, with corresponding targeted sequencing and RNA sequencing. The paper was entitled: “Genomic markers of midostaurin drug sensitivity in FLT3 mutated and FLT3 wild-type acute myeloid leukemia patients.”

The Study

In order to understand the impact that different genomic alterations have on midostaurin response, 214 patients were functionally assessed with midostaurin and their FLT3 status was annotated. Of these patients, the researcher identified 193 primary and 21 relapse AML samples from the Beat AML publicly available dataset. Risk groups within the cohort were as follows: 73 samples were favorable risk, 59 samples were intermediate, and 68 were adverse. The median age of patients in the cohort was 61, with 52% male and 48% female.

“We hypothesized that there are additional genomic alterations and gene expression changes outside of FLT3-ITD mutations that can influence AML sample resistance or sensitivity to midostaurin and aimed to further characterize these factors.”

Drug sensitivity screening, RNA sequencing/expression analysis, custom gene panel (GeneTrails) sequencing and variant detection, exome sequencing and variant detection, internal FLT3-ITD and NPM1 mutation detection, derivation of FLT3-ITD and NPM1 consensus calls, ex vivo functional drug screens, and statistical analysis were the methods used to observe the impact of genomic alterations on midostaurin response.

“Our research explored the multi-targeted nature of midostaurin and suggested a number of molecular mutational patterns that correlated with midostaurin drug sensitivity and resistance in both FLT3-ITD mutated and FLT3-ITD wild-type AML patient samples.”

Results

The researchers observed specific point mutations and gene expression patterns that they believe explain why there is a range of responses to midostaurin treatment. In the FLT3-ITD positive cohort, increased expression of the oncogene RGL4 (and regulator of the Ras-Raf-MEK-ERK cascade) correlated with poorer midostaurin response. In the FLT3-ITD negative cohort, KRAS mutations correlated with a poorer midostaurin response.

“We also observed that 16 / 34 of the most sensitive samples did not harbor a FLT3 mutation and a majority of differentially expressed genes were independent of FLT3 status.”

Conclusion

The authors point out that additional research studies will be needed given that their sample cohort was relatively small. They also note that since there are multiple FLT3 inhibitors available, it is important to understand the sensitivity mechanisms of each intervention in order to better personalize therapy for chemo-refractory or relapsed AML patients.

“Overall, we identify genomic alterations that correlate with midostaurin response independent of FLT3-ITD status, propose that Ras-Raf-MEK-ERK inhibition in combination therapy could limit resistance to midostaurin, and suggest that within the overall AML population there may be therapeutic benefit of midostaurin in patients with certain expression profiles.”

Click here to read the full scientific study, published in 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.

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

Oncotarget

Trending with Impact: The Vitamin D Binding Protein in Thyroid Cancer

April 8, 2021

Researchers compared vitamin D binding protein expression in papillary thyroid cancer tissues among Filipino American and European American patients.

3D rendered medically accurate illustration of thyroid cancer.

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On the basis of ethnicity, different gene variants of the vitamin D binding protein (DBP) are expressed among different populations of people around the world. Little is known about this highly polymorphic protein, though, researchers do know that DBP functions dependently and independently of vitamin D. Many previous research studies have examined the vitamin D-dependent correlation between DBP and cancer, however, few studies have examined DBP’s functionality independent of vitamin D, especially regarding the role of DBP expression in thyroid cancer.

“A systemic review demonstrated that a large number of chronic diseases, including cancers, have been associated with DBP variants [29].”

Filipino Americans are disproportionately affected by thyroid cancer, and researchers from Harbor-UCLA Medical Center, Loma Linda University School of Medicine, and Riverside University Health System conducted a study published in Oncotarget’s Volume 12, Issue #7, entitled, “Differential expression of Vitamin D binding protein in thyroid cancer health disparities.” The researchers compared the expression of DBP in thyroid cancer in Filipino and European Americans. The goal of this research was to further elucidate the functional implications of DBP in different stages of thyroid cancer across ethnicities.

“Although DBP is an essential protein with multifunctional properties, [28, 41–47], very few studies are available on its contribution to thyroid cancer oncogenesis.”

The Study

“Thyroid cancer incidence, recurrence, and death rates are higher among Filipino Americans than European Americans.”

To determine the correlation between differential DBP expression in tumor tissues and cancer staging among Filipino Americans and European Americans, the researchers gathered 200 archival papillary thyroid tissues; 100 from Filipino Americans and 100 from European Americans. They used immunohistochemistry to assay DBP expression in each sample and then analyzed the data with confocal microscopy.

“Since DBP gene variants showed differential expression across ethnicities [25, 40, 48, 49], DBP level in the tumor microenvironment may implicate the difference in TC [thyroid cancer] prognosis between Filipino and European Americans.”

First, the team evaluated whether or not there was any relationship between their DBP staining results and age, gender, or body mass index of the patients. They found no correlation between DBP levels and any of these variables, in either ethnicity. The researchers then analyzed the immunohistochemistry DBP staining results by ethnicity. They found moderate to strong intensity DBP staining across the European American cancer tissues and significantly low to no DBP staining in the Filipino American cancer tissues. The researchers also determined an inverse relationship between DBP expression and cancer stage—the lower the DBP expression, the poorer the prognosis.

“These data implied that DBP’s presence might play protective roles in cancer progression in European Americans compared to Filipino Americans, supporting the aggressive phenotype observed in Filipino Americans.”

Next, to observe the effects on cell migration and proliferation, DBP knockdown and overexpression (almost 90%) was achieved in the papillary thyroid tumor cells. The researchers demonstrated increased cancer cell proliferation and migration after the knockdown of the DBP gene. When the researchers overexpressed DBP, they observed a significant reduction in papillary thyroid cancer cell proliferation and migration.

Conclusion

“In conclusion, we demonstrate that the presence or absence of DBP inversely correlates to thyroid cancer staging in two ethnicities.”

The researchers note that while this study demonstrated low vitamin D binding protein expression in the advanced thyroid tumors of Filipino Americans, they acknowledge the need to determine the progressive loss of DBP throughout the stages of thyroid cancer.

“A future study is underway to determine the DBP regulation and its downstream pathways to elucidate strategies to eliminate the observed thyroid cancer health disparities.”

Click here to read the full scientific study, published in 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.

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

Oncotarget

Oncotarget Participating in Virtual AACR 2021 Annual Meeting

March 26, 2021

Oncotarget, exhibited by its publisher Impact Journals, will be participating virtually at the AACR Annual Meeting this year, from April 10-15 and May 17-21, 2021.

Oncotarget participating in the Annual AACR Meeting 2021 #AACR

Listen to an audio version of this article

The American Association for Cancer Research (AACR) organizes an annual meeting program covering some of the most recent discoveries in cancer research. The conference aims to highlight work from the best minds in research and medicine from institutions all over the world. Oncotarget, exhibited by its publisher Impact Journals, will be participating virtually at the AACR Annual Meeting this year.

As of June 2020, Scopus released their latest 2019 Journal Rankings on Oncology. Oncotarget is among their highest rated (Q1) journals and ranked number one in total citations in oncology. The journal has published outstanding papers and reviews by authors including Bert Vogelstein, Peter K. Vogt, Pier Paolo Pandolfi, Arnold J. Levine, Brian Druker, and Carol Prives. Founding Oncotarget Editorial Board members include Nobel Laureates Andrew V. Schally and Gregg L. Semenza; Lasker Award recipients Alexander Varshavsky, Brian J. Druker, and Gregg L. Semenza; and 16 members of the US National Academy of Sciences. Oncotarget is indexed and archived in PubMed, PubMed Central, Scopus, EMBASE, and META (Chan Zuckerberg Initiative) .

The 2021 AACR conference, a two-week online event, will take place from April 10-15 and May 17-21, 2021. Topics include population science and prevention, cancer biology, translational and clinical studies, survivorship, and advocacy.

In 2019, Oncotarget participated in the AACR Annual Meeting at the Georgia World Congress Center in Atlanta, Georgia, USA, and “AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics,” at the Hynes Convention Center in Boston, Massachusetts, USA. The total registration count from the 2019 AACR Annual Meeting was over 21,000—nearly 16,000 of which were scientific attendees from all over the world. Click here to view photos from Oncotarget’s participation in the 2019 AACR Annual Meeting.

Follow the Oncotarget Twitter account (@Oncotarget) for live updates about the conference using the #AACR21 hashtag.

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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.

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

Category: Oncotarget

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