Tagged: Cancer Research

Prognostic Markers Identified in Ultra-Rare Adrenal Cancer

January 26, 2022

Researchers demonstrated the overexpression of the protein APOBEC3B in adrenocortical carcinoma. They also identified the transcription factor, known as GATA3, that directly regulates APOBEC3B.

Illustration of kidneys and adrenal glands

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Adrenocortical carcinoma (ACC) is a rare and aggressive cancer that forms in the outer layer of the adrenal gland tissue above the kidneys. According to the National Institutes of Health, the occurrence of ACC in the United States is believed to only affect one to two people per million, per year. This highly-rare disease also challenges patients and researchers due to its post-diagnosis five-year survival rate of a mere 51%.

At this time, there are no known external factors that cause this disease. Most adrenocortical tumors that have been found produce symptoms including abdominal pain and higher levels of certain hormones, inclusive of cortisol, aldosterone, testosterone, and estrogen. Any of these hormones produced in excess can have numerous troubling effects on the body and, most alarmingly, the cancer cells in the adrenal glands have the potential to travel to other organs.

Researchers—from the National Cancer Institute, Stanford University, Medical College of Wisconsin, Frederick National Laboratory for Cancer Research, and Salubris Biotherapeutics—conducted a study to learn more about ACC and the mechanisms that lead to the biological materialization of this ultra-rare disease. In 2020, their research paper was published by Oncotarget and entitled, “GATA3 and APOBEC3B are prognostic markers in adrenocortical carcinoma and APOBEC3B is directly transcriptionally regulated by GATA3.”

APOBEC3B In ACC

Previously, recent evidence confirmed the overexpression of a protein that is rightfully abbreviated as APOBEC3B (fully known as Apolipoprotein B mRNA editing enzyme catalytic subunit 3B) as a source of mutations occurring in breast, bladder, cervical, lung, head, and neck cancers. In this study the researchers used two publicly available datasets to analyze APOBEC3B gene expression in 21 normal adrenal cortices, 69 benign adrenocortical tumors and 38 ACC samples. They found that APOBEC3B is significantly overexpressed in ACC. The effects of this overexpression, in addition to a tumor mass, were consequently associated with DNA damage, reduced number of cells in S-phase arrest and increased alterations and gene mutations (particularly in the TP53 gene).

To assess the association between APOBEC3B and adrenocortical tumor growth, the team used mouse models to perform a “knockdown” or reduction, in APOBEC3B and measured the effects this had on the tumor tissue. The mice were divided into three groups of eight, and at weeks six and eight of the APOBEC3B knockdown, the researchers found significantly reduced cell proliferation and more cells in S-phase arrest.

GATA3 and APOBEC3B In ACC

The team was able to successfully knockdown APOBEC3B in mice and demonstrated that this caused a significant reduction in tumor volume. They also found in their analysis that tumors with higher expressions of APOBEC3B presented with a higher number of TP53 gene mutations. Given that the researchers were now confident that APOBEC3B is the protein that coincides with the growth of tumors in ACC, they sought to identify the mechanism responsible for regulating this protein.

After a thorough process of tests distinguishing between 90 different cancer-associated transcription factors, the team observed that the transcription factor GATA3 directly binds to the promoter region of APOBEC3B and transcriptionally regulates its gene expression in ACC.

Conclusion

In this study, the team successfully demonstrates that the protein APOBEC3B is overexpressed in ACC and causes DNA damage, alterations and mutations, and also, for the first time, that GATA3 directly regulates the expression of APOBEC3B. This confirms that the higher expression levels of both APOBEC3B and GATA3 are prognostic markers for patients with ACC.

This new information may be used in further research to develop treatments and interventions to improve the prognosis for those affected by adrenocortical carcinoma and other related disorders.

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

Go Behind the Study with co-author, Dr. Monica Varun Tyagi.

Testimonial: Dr. Tyagi describes her experience publishing with Oncotarget.

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Oncotarget’s Top 10 Most-Viewed Papers in 2021

January 21, 2022

Read the 10 most-viewed oncology-focussed papers on Oncotarget.com in 2021.

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#10: Metformin and berberine, two versatile drugs in treatment of common metabolic diseases

Authors: Haoran Wang, Chen Zhu, Ying Ying, Lingyu Luo, Deqiang Huang, and Zhijun Luo

Institutions: The First Hospital of Nanchang University, Nanchang University and Boston University School of Medicine

Quote: “Metformin has been used as a glucose lowering drug for several centuries and is now a first-line drug for type 2 diabetes mellitus (T2DM). Since the discovery that it activates AMP-activated protein kinase (AMPK) and reduces risk of cancer, metformin has drawn great attentions. Another drug, berberine, extracted from berberis vulgaris L. (root), was an ancient herbal medicine in treating diarrhea.”

#9: Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects

Author: Yuri Lazebnik

Institution: Lerna Consulting

Quote: “A distinctive feature of the SARS-CoV-2 spike protein is its ability to efficiently fuse cells, thus producing syncytia found in COVID-19 patients. This commentary proposes how this ability enables spike to cause COVID-19 complications as well as side effects of COVID-19 vaccines, and suggests how these effects can be prevented.”

#8: Physical activity and telomere length: Impact of aging and potential mechanisms of action

Authors: Nicole C. Arsenis, Tongjian You, Elisa F. Ogawa, Grant M. Tinsley, and Li Zuo

Institutions: University of Massachusetts Boston, Texas Tech University and The Ohio State University College of Medicine

Quote: “Based on the significance of telomere length in aging and the need to understand the potential association with physical activity, the purpose of this systematic review is to investigate whether physical activity and exercise influence telomere length and to discuss possible mechanisms of action.”

#7: Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer

Authors: Jayati Chakrabarti, Loryn Holokai, LiJyun Syu, Nina G. Steele, Julie Chang, Jiang Wang, Syed Ahmed, Andrzej Dlugosz, and Yana Zavros

Institutions: University of Cincinnati, University of Cincinnati College of Medicine, University of Cincinnati Cancer Institute, University of Michigan

Quote: “Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation.”

#6: cGAS-STING pathway in oncogenesis and cancer therapeutics

Authors: Brandon Yi Da Hoong, Yunn Hwen Gan, Haiyan Liu, and Ee Sin Chen

Institutions: National University of Singapore and National University Health System (NUHS) Singapore

Quote: “The host innate immunity offers the first line of defense against infection. However, recent evidence shows that the host innate immunity is also critical in sensing the presence of cytoplasmic DNA derived from genomic instability events, such as DNA damage and defective cell cycle progression. This is achieved through the cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon (IFN) genes (STING) pathway. Here we discuss recent insights into the regulation of this pathway in cancer immunosurveillance, and the downstream signaling cascades that coordinate immune cell recruitment to the tumor microenvironment to destroy transformed cells through cellular senescence or cell death programs.”

#5: Anti-aging: senolytics or gerostatics (unconventional view)

Author: Mikhail V. Blagosklonny

Institution: Roswell Park Cancer Institute

Quote: “Based on lessons of cancer therapy, here I suggest how to exploit oncogene-addiction and to combine drugs to achieve selectivity. However, even if selective senolytic combinations will be developed, there is little evidence that a few senescent cells are responsible for organismal aging. I also discuss gerostatics, such as rapamycin and other rapalogs, pan-mTOR inhibitors, dual PI3K/mTOR inhibitors, which inhibit growth- and aging-promoting pathways.”

#4: Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment

Authors: Gennady M. Zharinov, Oleg A. Bogomolov, Irina V. Chepurnaya, Natalia Yu. Neklasova, and Vladimir N. Anisimov

Institutions: N.N. Petrov National Medical Research Center of Oncology

Quote: “The antitumor and immunomodulating activities of melatonin are widely known. These activities are based upon the multifactorial mechanism of action on various links of carcinogenesis. In the present paper, the long-term results of the clinical use of melatonin in the combined treatment of patients with prostate cancer of various risk groups were evaluated.”

#3: Scent test using Caenorhabditis elegans to screen for early-stage pancreatic cancer

Authors: Ayumu Asai, Masamitsu Konno, Miyuki Ozaki, Koichi Kawamoto, Ryota Chijimatsu, Nobuaki Kondo, Takaaki Hirotsu, and Hideshi Ishii

Institutions: Osaka University and Hirotsu Bio Science Inc.

Quote: “Although early detection and diagnosis are indispensable for improving the prognosis of patients with pancreatic cancer, both have yet to be achieved. Except for pancreatic cancer, other cancers have already been screened through scent tests using animals or microorganisms, including Caenorhabditis elegans.”

#2: Inflammatory responses and inflammation-associated diseases in organs

Authors: Linlin Chen, Huidan Deng, Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Yinglun, Xun Wang, and Ling Zhao

Institution: Sichuan Agricultural University

Quote: “Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.”

#1: The goal of geroscience is life extension

Author: Mikhail V. Blagosklonny

Institution: Roswell Park Cancer Institute

Quote: “Although numerous drugs seemingly extend healthspan in mice, only a few extend lifespan in mice and only one does it consistently. Some of them, alone or in combination, can be used in humans, without further clinical trials.”

Click here to read the latest papers published by Oncotarget in Volume 13.

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Can Purified Cholera Stop Obesity?

December 31, 2021

In this 2019 study, researchers investigated the effects of purified elements of cholera toxin in age-associated weight gain.

In recent years, scientists have made significant advancements to improve our understanding of the gut microbiome. This diverse environment—of somewhere around 39 trillion microorganisms living within the digestive tracts of vertebrates (including humans, and even insects)—includes bacteria, archaea, viruses, and fungi. However, a “healthy” gut microbiota remains difficult to define in humans. The contents of the gut microbiome are not only different between women and men, microbiomes differ between… everyone. Among unrelated humans, no more than 30% of the same bacterial strains are shared in the gut microbiome.

Different microbiomes can present with different biological reactions to outside factors, including infections and medications, and can even display different symptoms reacting to cancer and other diseases. Studies have repeatedly found that the gut microbiome plays important roles in human mood, sleep, metabolism, digestion, the immune and nervous systems, and in chronic inflammatory disorders, such as obesity.

“Indeed, earlier studies have shown that gut microbe-immune interactions contribute to smoldering inflammation, adiposity, and weight gain.”

The Hygiene Hypothesis

Researchers continue to find evidence to support the “hygiene hypothesis.” The hygiene hypothesis postulates that a lack of beneficial early-life microbe exposures can result in a dysregulated immune system later in life. This lack of early-life microbe exposures followed by immune imbalances may be responsible for the increase in obesity and other chronic inflammatory disorders over the past forty years.

“Systemic immune imbalances arising from the gut have been proposed as a probable cause of obesity [8].”

In 2019, researchers from Massachusetts Institute of Technology (MIT) and Aristotle University of Thessaloniki conducted a study to test using purified elements of the otherwise dangerous cholera toxin as a vaccination in mouse models. Their theory was that this safe and well-established cholera-based immune adjuvant would cause an immune system reaction that reduces the inflammation associated with age-related obesity. Their research paper was published by Oncotarget and entitled, “Consuming cholera toxin counteracts age-associated obesity.” (Go Behind the Study to learn why the researchers decided to use the cholera toxin.)

The Study

First, the researchers used both inbred and outbred mouse models to test the effects of the cholera-toxin subunit B (ctB)—a component of the Dukoral® vaccine used in humans for cholera diarrhea prevention. For each mouse model tested in the study, four different groups of eight mice each were examined: a female control group, a vaccinated female group, a male control group, and a vaccinated male group. At four weeks of age, the study mice were given three doses every-other-week of ctB at 10 micrograms. The control mice were given sham doses. The researchers found that in ctB vaccinated mice, the oral vaccination prevented age-associated weight gain compared to the control mice in both models.

Next, the researchers used an obese mouse model to test the effects of ctB dosing in early-life and to test the effects of transfering their gut flora into another mouse. The researchers found that the obese-mouse microbiome was sufficient to trigger obesity and inflammation in other mice when compared to sham-dosed control mice. In the obese mouse model, ctB dosing in early life also inhibited age-associated weight gain. This probiotic inhibited weight gain in mice dosed in early-life, and also in mice dosed in adulthood.

“Although we discovered dramatic benefit after early-life exposures to ctB, mice were also significantly slimmer when dosed with ctB for the first time during adulthood at 12-wks-of-age or 24-wks-of-age.”

Conclusion

The researchers found that purified elements of the cholera toxin stabilized immunity, through the gut microbiome, and inhibited age-associated obesity in multiple mouse models. Further studies are necessary to determine the degree to which an early-life microbe exposure such as this impacts immunity versus first-time adulthood exposures. Humans have been taking pre- and probiotics for quite some time without a strong grasp of exactly how these microbe infusions work. This research contributed to a better understanding of how humans can modulate our own gut microbiome to improve many aspects of our health and well-being.

“This type of microbe-immune re-programming may ultimately target other diseases linked with obesity and inflammation such as diabetes [19], multiple sclerosis [64], and cancer [25].”

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

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Could Metformin and Rapamycin Replace Maintenance Chemotherapy?

December 16, 2021

Researchers explored metformin with or without rapamycin as maintenance therapy in patients with metastatic pancreatic adenocarcinoma.

Malignant fluid cytology; Malignant cells of adenocarcinoma may spread to fluid of pleural or peritoneal cavity in cancer from the breast, lung, colon, pancreas, ovary, endometrium or other sites. — Malignant cells of adenocarcinoma

Maintenance chemotherapy has previously been recommended for patients with metastatic pancreatic ductal adenocarcinoma (mPDA)—as PDA is an aggressive cancer at all stages, and treatment options are limited for later-stage mPDA. However, maintenance chemotherapy regimens often lead to toxicity and are not viable long-term options. Therefore, researchers are exploring alternative maintenance therapies for mPDA patients. In preclinical studies, the therapeutic combination of metformin and rapamycin demonstrated a potential synergy of anti-tumor activity in PDA.

“A synergistic effect of the combination of metformin with rapamycin was suggested by preclinical studies demonstrating enhanced inhibition of mTOR in a pancreatic cancer cell line and better growth inhibition of pancreatic cancer cells in a xenograft tumor model with the combination than either agent alone [21].”

Metformin is an antihyperglycemic drug that is frequently prescribed for patients with diabetes to help control blood sugar levels. Rapamycin is an immunosuppressive drug that has historically been prescribed to prevent organ rejection in kidney transplant patients. (Today, rapamycin is also being considered for its potential use in anti-aging and longevity interventions.) In animals, metformin and rapamycin both inhibit the major biological regulator of growth, named the mammalian target of rapamycin (mTOR). mTOR is thought to be a main driver of many (if not all) aging-related diseases, including cancers such as PDA.

“Mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase which acts as a signaling node downstream of several oncogenic pathways including KRAS/MEK/ERK and PI3K/Akt, both of which are thought to be relevant drivers in a majority of PDAs [6–9].”

The Study

Given its promising potential, researchers—from Johns Hopkins University School of Medicine, Virginia Piper Cancer Center at HonorHealth, Translational Genomics Research Institute (TGen), and Shanghai Jiao Tong University School of Medicine—conducted a study exploring metformin, plus or minus rapamycin, in patients with metastatic PDA. Their priority research paper was published by Oncotarget in 2020, and entitled, “An exploratory study of metformin with or without rapamycin as maintenance therapy after induction chemotherapy in patients with metastatic pancreatic adenocarcinoma”.

A total of 22 unselected patients with mPDA were included in this randomized open-label phase 1b study between June 2014 and December 2017. Patients were at least 18 years of age and had previously been treated with chemotherapy for mPDA. At the beginning of the study, patients had either stable mPDA or responding mPDA for at least six months after induction chemotherapy. Half of the patients were randomly assigned to study Arm A, and the other 11 patients were assigned to study Arm B. Of note, the average age of the participants in Arm B was older (52–72; 66) than the participants in Arm A (34-73; 58). Otherwise, baseline characteristics between the study groups were relatively well-balanced.

Participants in study Arm A were assigned to take 850 milligrams of metformin orally, two times per day, for at least 12 months. Participants in study Arm B were assigned to take metformin and four milligrams of rapamycin once per day, for at least 12 months. The researchers conducted PET/CT scans, immunologic and metabolic analyses, statistical analysis, and continuously recorded and monitored for safety, patient tolerance, toxicity, and treatment-related adverse events.

“Treatment was continued until disease progression, intolerance of study treatments, or study closure, which occurred only after all remaining patients received a minimum of 12 months of treatment.”

Results and Conclusion

“In conclusion, the administration of metformin with or without rapamycin in patients with mPDA who achieve a response to chemotherapy is well-tolerated and was associated with better than expected overall survival in this study.”

The researchers observed “remarkably longer than expected” progression free survival and overall survival in this typically poor-prognosis population of patients. In this cohort, a low neutrophil-to-lymphocyte ratio and decreased fluorodeoxyglucose-avidity and/or decreased CA19-9 from baseline predicted improved outcomes among the long-term survivors. Overall, metformin and rapamycin were well-tolerated and their safety profiles were found to be comparable to previous reports. The researchers were forthcoming about limitations of their study—as their cohort was relatively small and the study was not powered to detect differences in clinical activity between the treatment arms.

“To this end, we identified several factors which may be used to select for patients with improved outcomes; however, whether good prognosis patients need any further treatment at all and whether poor prognosis patients will benefit from continued chemotherapy rather than a maintenance approach are not known and additional prospective studies are needed to answer these questions.”

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

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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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Oncotarget

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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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.

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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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Oncotarget

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.

YOU MAY ALSO LIKE: More Oncotarget Videos on LabTube

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