Tagged: Cancer Research

New Study: ALK Rearrangement Among Lung Cancer Patients

November 10, 2021

In Oncotarget’s Volume 12, Issue 23, cover paper, researchers retrospectively assessed the prevalence of anaplastic lymphoma kinase (ALK) gene rearrangement among nearly 20,000 patients with advanced non-small cell lung cancer.

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The identification of an actionable gene mutation or translocation in patients with cancer can give researchers a target for new drug therapies. One such mutation, found in some patients with non-small cell lung cancer (NSCLC), is anaplastic lymphoma kinase (ALK) gene rearrangement. However, the exact population of patients that present with ALK rearrangement has not been fully characterized. Identifying the subpopulation of patients who present with ALK rearrangement may lead to better overall treatment outcomes.

Researchers—from University of Mississippi Medical Center, Roche Information Solutions, Roche Diagnostics Corporation, Genesis Research, and Houston Methodist Hospital—conducted a retrospective study of nearly 20,000 patients with advanced NSCLC (aNSCLC). The researchers assessed ALK rearrangement prevalence in the cohort overall and then categorized the data using patient characteristics. Their paper was published on the cover of Oncotarget’s Volume 12, Issue 23, and entitled, “Anaplastic lymphoma kinase rearrangement prevalence in patients with advanced non-small cell lung cancer in the United States – retrospective real world data”.

“We performed a retrospective study of a database to acquire real-world clinical data on the frequency of the translocation in a large pool of patients drawn primarily from community hospitals and practices.”

The Study

This cross-sectional, observational study used de-identified data from Flatiron Health’s database, which included 19,895 patients who were diagnosed with aNSCLC in the United States between 2015 and 2019. The average age of patients was 68.5, plus or minus 10 years. The distribution of gender was nearly equal, with men comprising 50.4% (10,029) of the patient cohort, and 68.4% of patients were Caucasian. A large proportion of patients had a non-squamous histology type (80.5%) and smoking history (85.5%).

“Prevalence of ALK rearrangement was assessed overall and then stratified by patient characteristics such as age, gender, race, smoking status and histology.”

The researchers used descriptive statistics to summarize patient characteristics. Characteristics included age, gender, race, geographic location, smoking status, histology, practice type (community or academic), PD-L1 status, prevalence of ALK rearrangement and other biomarkers.

“Regardless of documented histology, a higher ALK rearrangement rate (8.9%) was observed among patients who had no smoking history compared to patients with a smoking history (1.5% ALK positivity) which represent the largest number of patients in this cohort (17,003).”

Conclusion

Results from the study concluded that ALK rearrangement was present in 2.6% of the total cohort, or 517 patients. The researchers found that ALK rearrangement prevalence varied based on the patients’ demographic characteristics. The rate of ALK rearrangement was the highest among patients younger than 40 years old, and decreased with age. Researchers found no significant difference in ALK rearrangement between men and women. However, when compared to other patients, Asian patients had a higher ALK rearrangement rate (39 out of 623, or 6.3%). Interestingly, the ALK positivity rate was greatest (9.3%) among non-smoking patients with non-squamous histology.

“In summary, this retrospective review of nearly 20,000 patients with aNSCLC and tested for ALK in the United States confirms that ALK rearrangements are found more commonly in younger nonsmokers and patients of Asian descent.”

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

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New Study: Vaccine Enhances Breast Cancer Treatment

October 27, 2021

Researchers conducted a study to examine the efficacy of adding the P10s-PADRE vaccine to chemotherapy treatments for patients with HR+/HER2− breast cancer.

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The most common type of breast cancer in the United States is HR+/HER2− breast cancer. Patients with HR+/HER2− breast cancer often face the threat of distant recurrence—long after the completion of their treatment. Previous studies have found that high levels of tumor infiltrating lymphocytes (TILs) were associated with improved outcomes and recurrence-free survival in patients with HR+/HER2− breast cancer. These studies and many others have prompted researchers to further develop and test cancer vaccinesin an effort to elicit anti-tumor immune responses in these patients.

“Therefore, a rational combination therapy that enhances the immune-stimulatory properties of NAC [neoadjuvant chemotherapy], can provide long-term survival benefits for this patient population.”

Researchers from University of Arkansas for Medical Sciences, University of Texas Southwestern, Highlands Oncology Group, and Université Claude Bernard Lyon 1 conducted a new single-arm Phase Ib clinical trial. Early-stage HR+/HER2− breast cancer patients were treated with carbohydrate-mimetic peptides, the P10s-PADRE vaccine, in combination with chemotherapy treatments. Their paper was chosen as the cover of Oncotarget’s Volume 12, Issue 22, and entitled, “P10s-PADRE vaccine combined with neoadjuvant chemotherapy in ER-positive breast cancer patients induces humoral and cellular immune responses.”

“The main objective of our study was to determine an appropriate schedule to be used for adding the P10s-PADRE vaccine to cancer chemotherapy in the neoadjuvant setting considering the ability of the vaccine to elicit adequate antibody response.”

The Study

After meeting the study’s detailed inclusion/exclusion criteria, a total of 25 patients with HR+/HER2− breast cancer were selected to partake in this single-arm Phase Ib clinical trial. Patients were divided into five cohorts (five patients per cohort): A, B, C, D, and E. Each patient was treated with a combination of four therapies over the course of 22-25 weeks, including three doses of thepeptide-based P10s-PADRE cancer vaccine, four doses of Cyclophosphamide (chemotherapy), four doses of Doxorubicin (chemotherapy) and four doses of Docetaxel (chemotherapy). Using a cohort-specific treatment schedule for the previously stated combination of therapies, the researchers assessed the feasibility, safety and immunogenicity achieved in each cohort and each patient.

Additionally, patients underwent surgery between weeks 26 and 33 (four to eight weeks after their last chemotherapy treatment). Each cohort also had a cohort-specific blood draw schedule—blood was drawn at eight different times in the 73-week time frame. Blood draws were used to conduct flow cytometry, measure the concentration of cytokines, natural killer (NK) cells and antibodies, and to determine the presence of anti-peptide antibody response and the percentage of TILs. The researchers observed that all five cohorts saw a significant reduction in tumor size.

“The data suggest that subjects enrolled in schedule C generated a more consistent and robust antibody response, therefore schedule C appears as the schedule of choice for future combination therapy.”

Their findings concluded that, in combination with chemotherapy, P10s-PADRE immunization in HR+/HER2− breast cancer patients induced “acceptable” antibody responses in study cohorts C and E. The treatment schedule in cohort C demonstrated the strongest antibody response by affecting the expression levels of NK-cell markers, stimulating the production of cytokines, T-cells and TILs. However, the researchers note that continued analysis of the blood samples collected could show serum antibodies may begin to appear later on in patients enrolled in the other treatment schedules.

Conclusion

“This Phase Ib clinical trial of the P10s-PADRE vaccine shows that immunization in combination with a standard-of-care NAC is feasible and well-tolerated. Combination therapy induces antibody response, stimulates activation of NK cells, and is associated with infiltration of T cells in tumor microenvironment. Randomized phase II trials focusing on treatment schedule C are needed to validate current findings and evaluate clinical efficacy.”

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

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Oncotarget

EMT Resistance in Cancer Cells and Two Potential Causes

October 21, 2021

Researchers used mathematical modeling to investigate mechanisms that drive the elusive phenomenon of cancer cell resistance to epithelial-mesenchymal transition (EMT).

Epithelial–mesenchymal transition (EMT): losing cell polarity and cell adhesion to gain migratory and invasive properties.

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Cancer cells have been known to use sagacious methods of evading apoptosis and mysteriously overcoming powerful anti-cancer therapies. One such method of evasion has recently been identified as the process of epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET). These transitions enable epithelial cells (structural/fixed) to gain mesenchymal cell (differentiating/mobile) functions, and vice versa. Researchers believe that epithelial-mesenchymal plasticity (EMP) allows cancers to become therapy resistant, determines cancer aggressiveness and allows metastatic cancer to mobilize and spread.

“Such dynamic and reversible switching can help tumor cells to overcome various challenges during disease progression such as anoikis [6], and assaults by the immune system [7].”

These processes and their characterization in cancer have been studied, however, questions remain about their molecular determinants and degree of reversibility, or irreversibility, in different cell populations and environments. To further elucidate EMT, researchers from Rice University, Northeastern University and the Indian Institute of Science used mechanistic mathematical models to identify possible mechanisms that may drive EMT response to an EMT-inducing signal in a given isogenic cell population. Their paper was published by Oncotarget in 2020, and entitled, “Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT.”

EMT/MET Reversibility/Irreversibility

In the introduction of this paper, the authors discuss results from previous research about the reversibility and irreversibility of EMT/MET. EMT can be triggered by various EMT-inducing external signals, such as TGFβ or by adjusting the levels of EMT-specific transcription factors (EMT-TFs). They report that, in cells stimulated over shorter durations (between two and six days), cells may revert back to an epithelial state after withdrawal of the signal/stimulus. They also explain that cells that have been stimulated over longer durations (10+ days) may render EMT irreversible and to become “locked” in a mesenchymal state.

Researchers suspect the existence of a “tipping point” after continued signal/stimulus exposure is what results in irreversible EMT. Multiple mechanisms have been proposed as responsible for this tipping point, including epigenetic alterations and self-stabilizing feedback loops in regulatory circuits. However, there remains a need for studies to investigate the mechanistic basis that causes epithelial cells to be resistant to undergoing EMT, or the irreversibility of MET.

“Some sporadic observations about the resistance of epithelial cells to undergo EMT have been reported [14, 24], but a causative mechanistic understanding still remains elusive.”

The Study

To investigate the mechanisms that enable the irreversibility of MET, or lack of EMP, the researchers in this study used mechanism-based mathematical modeling. Their experimental observations indicated that a global epigenetic program limiting the action of ZEB1 was found to underlie epithelial trait retention in cells exposed to persistent Twist1 activation for 21 days. They demonstrated a possible underlying mechanism by which GRHL2 overexpression can resist EMT. Importantly, the researchers found that, from a single isogenic cell population, two subpopulations of cells emerged and responded differently to the EMT-signalling.

“Here, we propose two independent mechanism[s] that may explain the resistance of epithelial tumor cells to undergo EMT: 1) epigenetic feedback mediated via GRHL2—an MET-inducing transcription factor (MET-TF) [25–27]; and 2) stochastic partitioning of parent cell biomolecules among the daughter cells at the time of cell division [28–30].”

Aside from epigenetic mediation involving GRHL2, the researchers believe varying EMT-signal responses within isogenic cell populations are caused by stochastic partitioning of molecules during cell division. The researcher described this phenomenon as a type of incongruent “noise” that takes place when cells divide.

“Such noise in the distribution of molecules may affect cell-fate and drive non-genetic heterogeneity [28–30], leading to different phenotypic distributions in terms of EMT [3].”

Conclusion

The team concluded that MET should not only be considered the reverse process of EMT, as important and distinct processes may be involved in both EMT and MET transformations. The authors are forthcoming about limitations in their study—indicating that a more detailed molecular mechanism-based epigenetic model would provide better insights into EMT. They also note that they did not consider spatial effects in their model, where more dense or spread out cell populations and access to signal strength, nutrients and oxygen may change outcomes.

“Future efforts should decode the molecular mechanisms of any such epigenetic feedback of GRHL2 on ZEB1 expression as well as track the distribution of molecules during cell divisions happening while cells are being induced to undergo EMT/MET.”

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

Watch, read or listen to an Oncotarget Interview with Drs. Herbert Levine and Mohit Kumar Jolly as they discuss this paper.

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Trending With Impact: Unconventional Method Effectively Targets NSCLC

October 4, 2021

Researchers developed a divergent strategy to treat non-small cell lung cancer (NSCLC).

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 mammalian target of rapamycin (mTOR) operates within two distinct protein complexes—mTOR complex 1 (mTORC1) and complex 2 (mTORC2). These protein complexes are not yet fully understood, as they were only recently identified in humans in 1994. What researchers do know is that mTORC1 is involved in the regulation of many cellular processes and is a key mediator of cell growth and proliferation. mTORC1 is activated by growth factor receptor signals through the PI3K–AKT and RAS–ERK mitogen-activated protein kinase (MAPK) pathways.

The PI3K/AKT/mTOR pathway may be an efficacious target in the treatment of patients with non-small cell lung cancer (NSCLC). This theory is based on the identification of particular gene mutations in NSCLC that are associated with the PI3K/AKT/mTOR pathway. However, previous studies have not yet succeeded in defining an effective monotherapy or combination of therapies that targets this pathway while improving NSCLC patient outcome.

Researchers from Institut Curie, PSL University, Xentech, BioPôle Alfort, Hôpital Foch, and Centre Léon Bérard designed a study using a new methodology to test treatment combinations based on specific targets identified as biomarkers of resistance to PI3K-targeting treatments, and not based on the NSCLC mutations themselves. Their trending research paper was published by Oncotarget in 2021 and entitled, “High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.”

“Our main strategy was therefore, using a panel of NSCLC PDXs, (i) to define predictive markers of response to RAD001 therapy and (ii) to identify possible combinations of treatments that may be able to reverse RAD001 resistance.”

THE STUDY

Researchers tested RAD001/Everolimus (an mTORC1 inhibitor) in vivo using NSCLC Patient-Derived Xenografts (PDXs), which demonstrated high antitumor efficacy. They next aimed to define predictive markers of response to RAD001 using real-time quantitative RT-PCR assays.

“In order to define predictive markers of response to RAD001, we used real-time quantitative RT-PCR assays to quantify the mRNA expression of a large number of selected genes.”

The team found three significantly highly expressed and targetable genes in NSCLC tumors resistant to RAD001: PLK1, CXCR4 and AXL. They then analyzed these genes for their prognostic value among NSCLC patients that were found in the publicly available database KMPLOT. This analysis revealed that of the three genes evaluated, only one high-gene expression was correlated with a negative impact on overall survival of patients with adenocarcinoma: PLK1. Given this data, the researchers next evaluated the in vivo efficacy of RAD001 combined with a PLK1 inhibitor, volasertib, in four PDX models. The RAD001 + volasertib combination demonstrated dramatic efficacy in three of the four models.

“In all tested PDXs, except LCF29, we have observed a significant, but variable, improvement of the antitumor efficacy of RAD001 + volasertib in comparison to each monotherapy (Figure 2A).”

To define this RAD001 + volasertib drug combination’s mechanism of action, the researchers conducted a pharmacodynamics (PD) study. The team then evaluated post-therapeutic proteins involved in the cell cycle, vascularization and carbonic anhydrase IX expression. These results were then validated using in vitro studies.

CONCLUSION

“Our determination of relevant Pi3K-based therapeutic combination(s) was not supported, by the presence of actual molecular abnormalities, nor by physician therapeutic practices, but by the identification of predictive markers of resistance to Pi3K-based monotherapies.”

In summary, the researchers conclude that their study demonstrates that inhibiting both mTORC1 and PLK1 proteins induces synergistic antitumor activity in multiple models of NSCLC. In the discussion section of this paper, the authors detailed the divergent methodology they used to come to their conclusion.

“This methodology may promote more relevant clinical trials and avoid non-efficient combinations, inacceptable toxicities, and expensive and time-consuming studies.”

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

Read the press release here

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Captain of Team Open Access Rides Again for Cancer Research

August 18, 2021

For the past four summers, Impact Journals has sponsored Team Open Access in the Ride for Roswell. The peloton has been captained by Sergei Kurenov, who is the Director of Surgical Simulation at Roswell Park Comprehensive Cancer Center — one of the leading cancer treatment and research centers in the nation. This year, Team Open Access was one of the many teams that participated to raise more than $5 million to help find a cure for cancer.

Prior to the 2021 Ride for Roswell (#RFR21) on August 7, we asked Sergei for his thoughts on the experience and motivation for riding.

Please tell us how you got started in the Ride for Roswell event and what pushes you to participate each year.

Kurenov: When I started working at Roswell Park Comprehensive Cancer Center, I saw how enthusiastically people supported this event and made a lot of contributions of their time in fundraising, patient care support, and cancer research. I wanted to be a part of this community.

This will be your fourth year as team captain and sixth year participating in the Ride for Roswell. What has been your most memorable year or moment since you’ve started?

Kurenov: My first year of the Ride is the most memorable. More than a few thousand riders performed the National Anthem. Then, all the riders cheered on the cancer survivors, reminding us of exactly why we participate.

During last year’s Summer of the Ride, you were a part of over 600 teams that rode to raise more than $3.6 million in the fight against cancer amid a global pandemic. Looking back, how has that specific Ride impacted your outlook on this year’s event and cancer research?

Kurenov: The pandemic has highly affected cancer research. Physicians and researchers are working very hard to minimize pandemic impact and get life back to normal for our patients.

This year, we already raised [more than] $5 million, which will be provided to the development of cancer treatments and cancer research.

Sponsored by Impact Journals, Team Open Access is once again captained by Sergei Kurenov who explains his motivation to participate in the Ride for Roswell. — (Photo Courtesy of Roswell Park Comprehensive Cancer Center)

Tell us a little bit about the 2021 Open Access team.

Kurenov: The 2021 Open Access team has grown again and now we have nine team members, ranging in ages from 13 to 65. Most of the members are scientists in the cancer research field.

Who is the fastest team member? The longest tenured teammate of yours? And, why do you think you make the perfect captain for this team?

Kurenov: Andrei is a great rider and I believe he is the fastest team member.

Liliya and Elena are the longest-tenured teammates for the last six years. They provide a tremendous help in the fundraising and in team organizing. They are also great photographers, making memorable images during the Ride. Each year, they create special Open Access team t-shirts which we are proud to wear during the Ride.

Who, or what, will you be focusing on as team captain this time around?

Kurenov: This year, Sofia joined the Open Access team. She is 13 years old and wants to ride 10 miles. Sofia and the rest of our team will ride together. Perhaps I will join the team or will have a barbecue for the whole team to celebrate afterwards.

How do you generally celebrate following the Ride?

Kurenov: After the Ride, all team members and many of our friends from Buffalo are planning to join a barbecue party in our backyard. Everyone is very welcome to the party.

Please give us your best pitch for people to start or continue donating to cancer research.

Kurenov: Earlier this year, I lost a very close friend who had fought against cancer for the last 17 years. When he was diagnosed, doctors predicted around 10 years of his survival after the initial treatment. However, thanks to the cancer research and new treatment developments in oncology, he almost doubled the doctors’ predictions. And, until this year, he lived a full life, working on cancer research, organizing scientific conferences, traveling around the world and making great photographs. His example shows that the constant cancer research and new technologies can help oncological patients. So, please continue donating to cancer research. This certainly will help to cure cancer more efficiently and save more lives.

Just like we requested of you last year, give us your best pitch for folks to join Team Open Access in 2022.

Kurenov: I am proud to announce that our team is supported again by Impact Journals – which publishes open-source, cancer-related scientific journals Oncotarget, Aging, Genes & Cancer and Oncoscience. These journals include high-impact research papers of general interest and biological significance in all fields of cancer research. As an example, I would like to mention the studies published by Impact Journals that cycling is linked to a substantial decrease in the risk of developing and dying from cancer or heart disease.

Join our team and help us reach our goal or donate to our efforts! No matter how you choose to support us, YOU are making a difference in the lives of the thousands of patients who turn to Roswell Park Comprehensive Cancer Center for hope each year.

Click here to learn more about the Ride for Roswell.

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Oncotarget

The Ride for Roswell: Rolling Around The Track August 7

July 28, 2021

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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 Oncotarget, Aging, Genes & 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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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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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.

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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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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.

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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

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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