A new research perspective was published in Oncotarget's Volume 14 on June 19, 2023, entitled, “Targeting GITR in cancer immunotherapy – there is no perfect knowledge.”

In this new perspective, researchers Diwakar Davar and Roberta Zappasodi from the University of Pittsburgh Medical Center (UPMC), University of Pittsburgh, Weill Cornell Medical College, and Weill Cornell Graduate School of Medical Sciences discuss the glucocorticoid-induced TNFR-related protein (GITR), belonging to the TNFR superfamily (TNFRSF) and stimulating both the acquired and innate immunity. GITR is broadly expressed on immune cells, particularly regulatory T cells (Tregs) and natural killer (NK) cells. 

“Given its potential to promote T effector function and impede Treg immune suppression, GITR is an attractive target for cancer immunotherapy.”

Preclinically, GITR agonists have demonstrated potent anti-tumor efficacy singly and in combination with a variety of agents, including PD-1 blockade. Multiple GITR agonists have been advanced into the clinic, although the experience with these agents has been disappointing. Recent mechanistic insights into the roles of antibody structure, valency, and Fc functionality in mediating anti-tumor efficacy may explain some of the apparent inconsistency or discordance between preclinical data and observed clinical efficacy.

Overall, the clinical results obtained so far with GITR agonist agents have demonstrated specific immune effects in the expected immune cell populations based on preclinical studies. However, these effects have not produced substantial therapeutic activity in human cancer patients. A maturing understanding of the immune responses to GITR agonism in human cancer has clarified novel issues specific to drug development in this space including Ab structure (monospecific and bispecific mAbs and co-stimulatory GITR ligands), Ab valency, and Fc functionality.

“This improved understanding of the immune responses to GITR agonism in patients should be kept in consideration for the design of novel rational combinations or treatment regimens in earlier disease settings where immunotherapy is gradually becoming the treatment of choice.”

DOI - https://doi.org/10.18632/oncotarget.28461

Correspondence to - Diwakar Davar - davard@upmc.edu

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Keywords - cancer, immunotherapy, programmed death-1 (PD-1), cytotoxic T-lymphocyte Antigen-4 (CTLA-4), glucocorticoid-induced TNFR-related protein (GITR)

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Targeting GITR in Cancer Immunotherapy – There Is No Perfect Knowledge

BUFFALO, NY- June 18, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on June 13, 2024, entitled, “When does a melanoma metastasize? Implications for management.”

In this new perspective, researchers John F. Thompson and Gabrielle J. Williams from The University of Sydney, Royal Prince Alfred Hospital, and the University of Western Australia discussed melanoma and timing treatment. Selecting which patients with clinically localized melanoma require treatment other than wide excision of the primary tumor is based on the risk or presence of metastatic disease. This in turn is linked to survival. 

“Knowing if and when a melanoma is likely to metastasize is therefore of great importance.” 

Several studies employing a range of different methodologies have suggested that many melanomas metastasize long before the primary lesion is diagnosed. Therefore, waiting for dissemination of metastatic disease to become evident before making systemic therapy available to these patients may be less effective than giving them post-operative adjuvant therapy initially if the metastatic risk is high. The identification of these high-risk patients will assist in selecting those to whom adjuvant systemic therapy can most appropriately be offered. 

“Further studies are required to better identify high-risk patients whose primary melanoma is likely to have already metastasized.”

DOI - https://doi.org/10.18632/oncotarget.28591

Correspondence to - John F. Thompson - john.thompson@melanoma.org.au

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Keywords - cancer, melanoma, metastasis, time, adjuvant systemic therapy, tumor doubling time

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Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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When Does a Melanoma Metastasize? Implications for Management

BUFFALO, NY- June 19, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 11, entitled, “Dietary sucrose determines the regulatory activity of lithium on gene expression and lifespan in Drosophila melanogaster.”

The amount of dietary sugars and the administration of lithium both impact the lifespan of the fruit fly Drosophila melanogaster. It is noteworthy that lithium is attributed with insulin-like activity as it stimulates protein kinase B/Akt and suppresses the activity of glycogen synthase kinase-3 (GSK-3). However, its interaction with dietary sugar has largely remained unexplored. 

In this new study, researchers Katharina Jans, Kai Lüersen, Jakob von Frieling, Thomas Roeder, and Gerald Rimbach from the University of Kiel investigated the effects of lithium supplementation on known lithium-sensitive parameters in fruit flies, such as lifespan, body composition, GSK-3 phosphorylation, and the transcriptome, while varying the dietary sugar concentration. 

“Based on this proposed overlapping bioactivity of dietary sugar and lithium in the female fruit fly, we decided to investigate the extent of these similarities and whether a joint mechanism lies at their root.”

For all these parameters, the researchers observed that the efficacy of lithium was significantly influenced by the sucrose content in the diet. Overall, they found that lithium was most effective in enhancing longevity and altering body composition when added to a low-sucrose diet. Whole-body RNA sequencing revealed a remarkably similar transcriptional response when either increasing dietary sucrose from 1% to 10% or adding 1 mM LiCl to a 1% sucrose diet, characterized by a substantial overlap of nearly 500 differentially expressed genes. 

“Hence, dietary sugar supply is suggested as a key factor in understanding lithium bioactivity, which could hold relevance for its therapeutic applications.”

DOI - https://doi.org/10.18632/aging.205933

Corresponding author - Katharina Jans - jans@foodsci.uni-kiel.de

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Keywords - aging, lithium, longevity, glycogen synthase kinase 3, fruit fly, trace element

About Aging (Aging-US):

Aging aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Aging (Aging-US)

Dietary Sucrose Determines Activity of Lithium on Gene Expression and Lifespan in Drosophila Melanogaster

Sucrose Modulates Lithium's Effects on Gene Expression and Lifespan in Drosophila melanogaster

BUFFALO, NY- June 19, 2024 – A new research paper was published in Oncotarget's Volume 15 on June 13, 2024, entitled, “Assessment of serum tumor markers CEA, CA-125, and CA19-9 as adjuncts in non-small cell lung cancer management.”

Conventional tumor markers may serve as adjuncts in non-small cell lung cancer (NSCLC) management. In this new study, researchers Scott Strum, Mark Vincent, Meghan Gipson, Eric McArthur, and Daniel Breadner from the Schulich School of Medicine and Dentistry, London Health Sciences Centre, and Royal College of Surgeons in Ireland analyzed whether three tumor markers (CEA, CA19-9, and CA-125) held associations with radiographic and clinical outcomes in NSCLC. 

“The aim of this retrospective study was to provide additional evidence for the clinical use of conventional serum tumor markers CEA, CA19-9, and CA-125 in NSCLC management.”

It constituted a single-center study of NSCLC patients treated with systemic therapy at the London Regional Cancer Program. Serum tumor markers were analyzed for differences in radiographic responses (RECIST v1.1 or iRECIST), associations with clinical characteristics, and all-cause mortality. A total of 533 NSCLC patients were screened, of which 165 met inclusion criteria. A subset of 92 patients had paired tumor markers and radiographic scans. 

From the latter population, median (IQR) fold-change from nadir to progression was 2.13 (IQR 1.24–3.02; p < 0.001) for CEA, 1.46 (IQR 1.13–2.18; p < 0.001) for CA19-9, and 1.53 (IQR 0.96–2.12; p < 0.001) for CA-125. Median (IQR) fold-change from baseline to radiographic response was 0.50 (IQR 0.27, 0.95; p < 0.001) for CEA, 1.08 (IQR 0.74, 1.61; p = 0.99) for CA19-9, and 0.47 (IQR 0.18, 1.26; p = 0.008) for CA-125. 

“In conclusion, tumor markers are positioned to be used as adjunct tools in clinical decision making, especially for their associations with radiographic response (CEA/CA-125) or progression (CEA/CA-125/CA-19-9).”

DOI - https://doi.org/10.18632/oncotarget.28566

Correspondence to - Daniel Breadner - daniel.breadner@lhsc.on.ca

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Keywords - cancer, tumor marker, biomarker, lung cancer; NSCLC, translational research

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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Assessment of CEA, CA-125, and CA19-9 as Adjuncts in Non-small Cell Lung Cancer Management

Applications of AR in Interventional Oncology

Breast cancer immunotherapy has shown promise, but its clinical efficacy remains limited, especially for hormone receptor positive (HR+)/HER2-negative breast cancer. While immune checkpoint inhibitors combined with chemotherapy have benefitted some early-stage and metastatic triple-negative breast cancer patients, HR+/HER2-negative cases have seen fewer improvements.

Recent neoadjuvant trials indicate that early-stage HR+/HER2-negative breast cancers might respond better to immunotherapy strategies that amplify tumor-infiltrating lymphocytes (TILs) through dual PD-(L)1/CTLA-4 checkpoint inhibition before surgery and chemotherapy. This approach could enhance the immune response in the tumor microenvironment and improve outcomes for this challenging breast cancer subtype.

Increased TILs are associated with improved neoadjuvant chemotherapy (NACT) responses across breast cancer subtypes. Recently, researchers Haven R. Garber, Sreyashi Basu, Sonali Jindal, Zhong He, Khoi Chu, Akshara Singareeka Raghavendra, Clinton Yam, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, Elizabeth A. Mittendorf, and Jennifer K. Litton from the University of Texas MD Anderson Cancer Center, Brigham and Women’s Hospital, Dana-Farber Brigham Cancer Center, and Harvard Medical School hypothesized that amplifying TILs via dual checkpoint blockade would enhance the response to subsequent NACT in breast tumors.

Full blog - https://www.oncotarget.org/2024/06/20/impact-of-dual-immunotherapies-before-surgery-in-hr-her2-negative-breast-cancer/

Paper DOI -https://doi.org/10.18632/oncotarget.28567

Correspondence to - Haven R. Garber - hrgarber@mdanderson.org

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Keywords - cancer, breast cancer, ER positive,  immunotherapy, neoadjuvant chemotherapy, tumor microenvironment

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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Impact of Dual Immunotherapies Before Surgery in HR+/HER2-negative Breast Cancer

BUFFALO, NY- June 24, 2024 – A new editorial paper was published in Oncotarget's Volume 15 on June 14, 2024, entitled, “Leveraging gold nanostars for precision laser interstitial thermal therapy.”

In this new editorial, researchers Aden P. Haskell-Mendoza, Ethan S. Srinivasan, Tuan Vo-Dinh and Peter E. Fecci from Duke University discuss laser interstitial thermal therapy (LITT). Over the past decade, LITT has become an important tool for the neurosurgical treatment of a variety of intracranial pathologies, including focal epilepsies, vascular malformations, and central nervous system (CNS) tumors [1]. LITT involves the minimally invasive, stereotactically-guided placement of a laser catheter into a target lesion for subsequent thermal ablation via the delivery of infrared radiation, typically at wavelengths of 980–1064 nm [1, 2]. Following transfer of the patient to a scanner, real-time magnetic resonance (MR) thermometry is employed to track tissue hyperthermal ablation. 

“For patients with primary and metastatic brain tumors who are suboptimal candidates for craniotomy due to clinical status, wound healing concerns, or tumor location, LITT represents a particularly favorable option for reducing tumor burden.” 

However, successful ablation is limited by the (1) inability to precisely sculpt heat to cover or conform to large (typically, ≥3 cm) or irregular lesions, (2) the presence of various intracranial heat sinks, including cerebrospinal fluid (CSF) spaces and blood vessels, and (3) the sensitivity of uninvolved white and gray matter structures to inadvertent thermal damage [1–3]. 

“To aid in the performance of more efficient, conformal, and accordingly, safe ablations, we recently developed procedures for the use of gold nanostars (GNS, Figure 1) [2]."

DOI -  https://doi.org/10.18632/oncotarget.28592

Correspondence to - Peter E. Fecci - peter.fecci@duke.edu

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Keywords - cancer, laser interstitial thermal therapy, gold nanostars, brain tumors, thermal ablation, immunotherapy

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Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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Leveraging Gold Nanostars for Precision Laser Interstitial Thermal Therapy

BUFFALO, NY- June 25, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 11, entitled, “Associations of childhood, adolescence, and midlife cognitive function with DNA methylation age acceleration in midlife.”

Prior studies showed increased age acceleration (AgeAccel) is associated with worse cognitive function among old adults. In this new study, researchers Junyu Chen, Leah Moubadder, Elizabeth S. Clausing, Katrina L. Kezios, Karen N. Conneely, Anke Hüls, Andrea Baccarelli, Pam Factor-Litvak, Piera Cirrillo, Rachel C. Shelton, Bruce G. Link, and Shakira F. Suglia from Emory University, University of Nebraska, Columbia University, Public Health Institute, Washington, DC, and the University of California Riverside examined the associations of childhood, adolescence and midlife cognition with AgeAccel based on DNA methylation (DNAm) in midlife.

“To the best of our knowledge, this is the first study to show the association of cognition at younger age with midlife age acceleration, and associations between midlife age acceleration measures and cognitive function that are independent of childhood and adolescent cognition.”

Data are from 359 participants who had cognition measured in childhood and adolescence in the Child Health and Development study, and had cognition, blood based DNAm measured during midlife in the Disparities study. Childhood cognition was measured by Raven’s Progressive Matrices and Peabody Picture Vocabulary Test (PPVT). Adolescent cognition was measured only by PPVT. Midlife cognition included Wechsler Test of Adult Reading (WTAR), Verbal Fluency (VF), Digit Symbol (DS). AgeAccel measures including Horvath, Hannum, PhenoAge, GrimAge and DunedinPACE were calculated from DNAm. Linear regressions adjusted for potential confounders were utilized to examine the association between each cognitive measure in relation to each AgeAccel.

There are no significant associations between childhood cognition and midlife AgeAccel. A 1-unit increase in adolescent PPVT, which measures crystalized intelligence, is associated with 0.048-year decrease of aging measured by GrimAge and this association is attenuated after adjustment for adult socioeconomic status. Midlife crystalized intelligence measure WTAR is negatively associated with PhenoAge and DunedinPACE, and midlife fluid intelligence measure (DS) is negatively associated with GrimAge, PhenoAge and DunedinPACE. AgeAccel is not associated with VF in midlife.

“In conclusion, our study showed the potential role of cognitive functions at younger ages in the process of biological aging. We also showed a potential relationship of both crystalized and fluid intelligence with aging acceleration.”

DOI - https://doi.org/10.18632/aging.205943

Corresponding author - Junyu Chen - junyu.chen@emory.edu

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The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.

The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

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Childhood, Adolescence, and Midlife Cognitive Function Linked to Age Acceleration in Midlife

BUFFALO, NY- June 26, 2024 – A new editorial paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 11, entitled, “Global consensus for sarcopenia.”

In this new editorial, researchers Ben Kirk, Peggy M. Cawthon, and Alfonso J. Cruz-Jentoft from the University of Melbourne and Western Health discuss the global societal issue of skeletal muscle loss and weakness, termed Sarcopenia. Low muscle mass or low strength/function increases the susceptibility to poor outcomes such as fragility, hip fractures, disability, and low quality of life in older people [1–4]. Skeletal muscle also acts as an endocrine organ and interacts with local and distal tissues; for instance, muscle cells secrete molecules involved in bone fracture healing and the same molecules help regulate distal tissues such as the brain, heart, and kidneys [5, 6]. This may partially explain why low muscle mass is a strong predictor of disease-specific mortality (dementia, cancer, heart failure, kidney/liver disease) as well as all-cause mortality in aging [7]. 

“Until now, there has been no universal agreement on a definition for Sarcopenia.”

Previous definitions were continent- and region-specific: Asia, Europe, North America, and Australia/New Zealand [8]. These definitions were certainly important in drawing attention to, and understanding of, this muscle disease. However, these definitions led to wide estimates in disease prevalence/incidence as well as heterogeneity when comparing treatments results of randomised trials [9]. The lack of a single definition likely impacted the identification of or treatment for sarcopenia in research and clinical practice (i.e., caused confusion for scientists, physicians and health care professionals on which definition, cutpoints, and muscle assessment tools to employ). 

“To address this, the Global Leadership Initiative in Sarcopenia (GLIS) [9] was formed to create a unified global definition for use in research and clinical settings.”

DOI - https://doi.org/10.18632/aging.205919

Corresponding author - Ben Kirk - ben.kirk@unimelb.edu.au

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Keywords - aging, sarcopenia, global definition, GLIS, skeletal muscle

About Aging-US

The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.

The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

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Global Consensus for Sarcopenia

BUFFALO, NY- June 26, 2024 – A new research perspective was published in Oncotarget's Volume 15 on June 20, 2024, entitled, “Starving cancer cells to enhance DNA damage and immunotherapy response.”

Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies, including chemotherapy, radiotherapy, and hormonal treatments, often fail due to toxicities, off-target effects, and acquired resistance. In this new research perspective, researchers Aashirwad Shahi and Dawit Kidane from Howard University define an alternative therapeutic strategy focusing on the metabolic vulnerabilities of PCa cells, specifically their reliance on non-essential amino acids such as cysteine. 

“In this prospective, we will rise the driving questions and potential possibilities how amino acid depletion induced oxidative stress associated DNA damage exploited for DNA repair targeted and immune checkpoint blockade therapy [...].”

Using an engineered enzyme cyst(e)inase to deplete the cysteine/cystine can induce oxidative stress and DNA damage in cancer cells. This depletion elevates reactive oxygen species (ROS) levels, disrupts glutathione synthesis, and enhances DNA damage, leading to cancer cell death. The combinatorial use of cyst(e)inase with agents targeting antioxidant defenses, such as thioredoxins, further amplifies ROS accumulation and cytotoxicity in PCa cells. 

“Overall, this perspective provides a compressive overview of the previous work on manipulating amino acid metabolism and redox balance modulate the efficacy of DNA repair-targeted and immune checkpoint blockade therapies in prostate cancer.”

DOI - https://doi.org/10.18632/oncotarget.28595

Correspondence to - Dawit Kidane - dawit.kidane-mulat@howard.edu

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Keywords - cancer, amino acid depletion, DNA damage, DNA repair, Immunotherapy, tumor immunity

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Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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Starving Cancer Cells to Enhance DNA Damage and Immunotherapy Response

Cellular quality control mechanisms like mitophagy, a specialized form of autophagy that eliminates dysfunctional mitochondria, play a pivotal role in various physiological processes. Defects in mitophagy have been linked to neurodegeneration, heart failure, cancer, and aging.

A recent study, by researchers Marta Mauro-Lizcano, Federica Sotgia, and Michael P. Lisanti from the University of Salford, has shed light on the intricate link between mitophagy and cancer stem cells (CSCs). In this study, the researchers developed an innovative fluorescence-based approach to enrich subpopulations of cancer cells exhibiting high basal levels of mitophagy. Their findings reveal that elevated mitophagy activity enhances CSC properties, including self-renewal, ATP production, proliferation, and cell migration, underscoring the potential of targeting mitophagy as a therapeutic strategy for cancer treatment. 

On June 4, 2024, their research paper was published on the cover of Aging’s Volume 16, Issue 11, entitled, “Mitophagy and cancer: role of BNIP3/BNIP3L as energetic drivers of stemness features, ATP production, proliferation, and cell migration.”

Full blog - https://aging-us.org/2024/06/targeting-mitophagy-as-a-therapeutic-strategy-for-cancer-treatment/

Paper DOI - https://doi.org/10.18632/aging.205939

Corresponding authors - Federica Sotgia - fsotgia@gmail.com, and Michael P. Lisanti - michaelp.lisanti@gmail.com

Video short - https://www.youtube.com/watch?v=n872jCkc-q8

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Keywords - aging, mitophagy, BNIP3, BNIP3L(NIX), cancer stem cells (CSCs), flow cytometry (FACS)

About Aging-US

The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.

The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

Please visit our website at https://www.Aging-US.com​​ and connect with us:

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Targeting Mitophagy as a Therapeutic Strategy for Cancer Treatment

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form and then quickly released to Pubmed.

Oncotarget is now indexed by MEDLINE, PubMed and PMC/PubMed.

Read about the Oncotarget Scientific Integrity Process: https://www.oncotarget.com/scientific_integrity/

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