Author: Kathryn Atkins

Trending With Impact: Promising Non-Small Cell Lung Cancer Prodrug

Researchers examined the preclinical prodrug LP-184 and its efficacy in treating non-small cell lung cancers that lack actionable targets or resistance-related genes.

3D illustration of lung 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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Between 20 and 40% of adults with non-small cell lung cancer (NSCLC) eventually go on to develop brain metastases. Over 40% of patients with NSCLC have limited treatment options due to a lack of actionable therapeutic targets. Treatment for such patients has been limited to non-targeted chemotherapy—an approach which increases the risk of developing drug-resistance due to underlying resistance-associated mutations. 

“Newer drugs that will be more potent and remain efficacious in NSCLC with such mutations could lead to better alternate or combinatorial therapies.”

Lantern Pharma (a pharmaceutical company developing targeted cancer therapies) created a new drug candidate and next generation member of the acylfulvene class of prodrugs, named LP-184. Researchers from Lantern Pharma and REPROCELL (a commercial contract research organization) conducted a study to test the anti-tumor activity of this preclinical compound in a variety of NSCLC cell lines. In 2021, Oncotarget published team’s pape, entitled, “The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations.”

The Study

Despite LP-184’s highly-synthetic sounding name, the lead product in this acylfulvene prodrug (Illudins) is derived from, you guessed it, Jack-o-Lantern mushrooms. 

“Acylfulvenes have been derived from cytotoxic agents called Illudins, isolated from Jack-o-Lantern mushroom (Omphalotus illudens), that retain and improve the cytotoxicity of parent Illudins for use as anticancer agents.”

The anti-tumor activity of this compound is based on activation through reductive mechanisms, mediated by enzymes such as Prostaglandin Reductase 1 (PTGR1). PTGR1 is known to be upregulated in some tumors, including in tumors with mutations in KEAP1. LP-184 sensitivity was investigated in NSCLC cell lines with individual or combined mutations in KEAP1, KRAS, TP53, and STK11. 

“There is a high unmet need for effective therapies for NSCLC harboring mutations in these genes that have not only been considered undruggable till date but also are associated with loss of efficacy or resistance to multiple therapeutic strategies, at least in frontline regimens.”

The researchers tested LP-184 in vitro in 19 primary and metastatic NSCLC cell lines to determine the range of NSCLC settings that this compound might work best in. Clinical data analyses were also conducted by the researchers to predict tumor responsiveness to LP-184. In addition, the compound was examined in two mouse models of primary lung cancer. Mouse models were tested for sensitivity to LP-184 in both two- and three-dimensional culture systems.

“We sought to assess LP-184 activity in a panel of selected NSCLC adenocarcinoma cell lines, determine associations between genomic and transcriptomic profiles and responses of cell lines tested, and compare in vitro potency of LP-184 with that of approved chemotherapy agents.”

Conclusion

Among their many findings, the researchers demonstrated that LP-184 has high nanomolar potency in 11 of the 19 NSCLC cell lines tested—indicating broad NSCLC anti-tumor activity. In vivo, LP-184 showed efficacy in terms of tumor regression in one of the two mouse models.

“We propose further evaluation of LP-184 in multiple PTGR1 high NSCLC settings that may not necessarily be mutually exclusive, including in highly prevalent KEAP1 and KRAS mutant tumors (Figure 6), and in patients with lack of actionable targets or resistance-related genes with no effective therapy options available.”

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

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Trending With Impact: Analysis of Breast Cancer in Nigerian Women

In this trending paper published by Oncotarget in 2021, a cohort of Nigerian women were assessed for a useful biomarker in aggressive molecular subtypes of breast 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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Forms of cancer can vary in prevalence and aggression in different populations of people around the world. For instance, incidence rates of breast cancer (BC) have been rising in Africa over the past few decades. Research finds that Nigerian women have the highest age-standardized mortality rate of breast cancer on the African continent. This population in particular also faces disproportionately aggressive molecular subtypes of breast cancer.

“BC in Nigeria is characterized by disproportionately aggressive molecular subtypes, with exceptionally high rates of triple-negative (TN) BC [4], similar to BC in other countries in West Africa [5] and among African American women in the United States [6].”

In order to develop better treatment strategies, there is a distinct need to identify biomarkers that indicate, and even predict, these aggressive subtypes of breast cancer in Nigerian women. In 2021, a new study was conducted by researchers from Duke UniversityUniversity of LagosObafemi Awolowo University Teaching HospitalUniversity of IbadanFederal Medical Center AbeokutaUNC Gillings School of Global Public HealthOur Lady of Apostle Catholic Hospital in IbadanUniversity of Alabama at BirminghamUniversity of Kentucky, and University of Kansas Medical Center. Their trending research paper was published by Oncotarget and entitled, “Association of high-sensitivity C-reactive protein and odds of breast cancer by molecular subtype: analysis of the MEND study.”

C-Reactive Protein

“C-reactive protein (CRP) is associated with risk and aggressiveness for several types of cancer.”

When there is inflammation in the body, levels of the C-reactive protein (CRP) increase. This easily measurable protein can be a useful biomarker of systemic inflammation, infection, or tissue damage. Previous studies show that circulating CRP has been elevated in various types of cancers; it has also been associated with tumor prognosis. Past studies about CRP’s association in breast cancer subtypes have been notably few, and none have focused on isolating subpopulations in Africa.

“Additionally, it is worth noting that most of these past studies have been conducted in populations from the United States and Europe, among mostly White study populations, and to our knowledge, none have been conducted in populations from Africa.”

The Study

In this study, 555 Nigerian participants were assembled—of which 296 were confirmed breast cancer cases, and 259 were controls. The researchers collected clinical and reproductive characteristics of each participant, including the controls. In their first analysis, the researchers observed that newly diagnosed cases of Nigerian breast cancer were significantly more likely to have high levels of highly-sensitive CRP (hsCRP) compared to the controls. After adjusting for socio-demographic, clinical, and reproductive variables, the team still observed significant statistical significance for high levels of hsCRP associated with Nigerian BC. The findings from this cohort study also showed that high hsCRP was associated with a four-fold increased odds of BC.

“We also provide novel evidence of associations between hsCRP and BC molecular subtypes, with significant associations observed for luminal A, TN, and HER-enriched subtypes.”

Conclusion

“In conclusion, our analysis revealed a positive association between hsCRP and odds of BC, overall and for all molecular subtypes. Because CRP is an easily measured biomarker in the blood, it may represent a useful predictor of BC in the Nigerian context. We urge larger studies, preferably prospective cohort studies, among women of African descent to further characterize this association.”

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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The Ride for Roswell: Rolling Around The Track August 7

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The Ride for Roswell is one of the nation’s largest cycling events—hosted by Roswell Park Comprehensive Cancer Center—with ambitious goals to raise awareness and funds for cancer research and patient care. This charity bike ride, based out of Buffalo, New York, has brought people together for 25 years to celebrate cancer survivors, pay tribute to lives that have been lost, and to work together to support research and find a cure.

When it opened its doors in Buffalo in 1898, Roswell Park Comprehensive Cancer Center was the first cancer research-focused institution in the world. Today, this institution is one of only four National Cancer Institute-designated comprehensive cancer centers in the state of New York. Roswell Park Comprehensive Cancer Center is ranked by U.S. News & World Report as one of the best cancer hospitals in the United States.

The Origin of The Ride

The Ride for Roswell started in 1989, when Mitch Flynn, owner of the advertising agency Flynn & Friends, met Katherine Gioia. Katherine was a four-year-old patient battling a rare form of cancer. After Katherine’s death, less than a year after her diagnosis, Katherine’s mother, Anne Gioia, and aunt, Donna Gioia, founded the Roswell Park Alliance Foundation in her memory to raise money for cancer research and treatment. On June 29, 1996, Mitch and Alliance Foundation staff launched the first Ride for Roswell.

In the 25 years since then, thanks to many thousands of riders and generous donations, the Ride for Roswell has raised over $60 million to fund cancer research. The event has become one of the largest single-day charity rides in the United States. 

This Year

Traditionally (excluding last year’s COVID-19 inspired “Summer of The Ride”), teams of bicyclists register to ride in a one-day event and raise money to support their participation. This summer, there are two ways to ride. Riders can join in-person at various locations (socially distanced) throughout the Western New York area on Saturday, August 7, 2021. Participants can also ride on their own throughout the month of August.

Impact Journals has been sponsoring the Ride for Roswell since 2018. The Impact Journals peloton, Team Open Access (named after the open-source online medical journals OncotargetAgingGenes & Cancer, and Oncoscience), is captained by Sergei Kurenov. Sergei (who has been riding in the event since 2016) works at the Roswell Park Comprehensive Cancer Center to create, develop, and implement innovative diagnostic and surgical pre-planning software used in cancer treatment.

“Roswell Park Comprehensive Cancer Center is dedicated to providing a high level of care for cancer patients,” Sergei said. “By contributing to the Ride for Roswell, we are helping our patients to fight this most dangerous disease.”

Join Us!

There is still time to join Team Open Access and the Ride for Roswell this summer. You can also support the team by giving a donation of any size. Any avenue of support you may choose to donate to the Ride for Roswell will make a difference and change lives. 

“Finding a cure for cancer is something we are all incredibly passionate about, and we are so thankful and grateful for your support,” Sergei said. “Together, we can make a difference!”

Visit our team page to join or donate today.

Click here to learn more about the Ride for Roswell.

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2021 Ride for Roswell
2021 Ride for Roswell

Oncotarget Uses TrendMD to Expand Research Impact

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

Earth
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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.

Click here to learn more about TrendMD.

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Trending With Impact: Targeted Treatment for Recurrent Ovarian Cancer

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

Anatomy and physiology of Ovary under the microscopic in laboratory.
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.

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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.

Trending With Impact: ONC201 Induces Apoptosis in Breast Cancer

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.

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.

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 UniversityFox Chase Cancer CenterBrown 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.

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

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

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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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 [578].”

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.

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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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Trending With Impact: Novel Biomarkers in Bladder Cancer

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.

3D Illustration of the urinary bladder.
3D Illustration of the urinary bladder.

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 Houston 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.

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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Trending with Impact: RNA Modification Regulatory Proteins in Melanoma

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.
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 [5859]. 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 AtlasThe Human Protein AtlasOncomine, 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

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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Trending with Impact: Composite Score May Further Classify HCC

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 [12].”

Researchers from the University of Texas MD Anderson Cancer CenterMassachusetts 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.

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.

Oncotarget is a proud participant of the AACR Annual Meeting 2021 #AACR21
Oncotarget is a proud participant of the AACR Annual Meeting 2021 #AACR21

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