Oncotarget

BUFFALO, NY- December 13, 2023 – A new #editorial paper was #published in Oncotarget's Volume 14 on December 1, 2023, entitled, “Therapeutic potentials and challenges of cytostatic persister cancer cells.”

Cancer cells that remain viable despite treatment constitute a persister condition that is implicated in residual diseases and a source from which resistant clones and relapses can emerge. Unlike resistant cells that are capable of cycling under therapy, persister cancer cells stay viable but assume a quiescent or non-proliferating state that is reversible upon treatment discontinuation. A source of persisters that has been under extensive study is drug-tolerant persisters, a small cancer cell population that can withstand the selection pressure of cytotoxic treatment and have been attributed to failure in achieving complete response.

It is well-recognized that many targeted therapeutic agents possess cytostatic effects that suppress growth without directly inducing cell death. While representing favorable responses, treatment-mediated cytostatic conditions require continual maintenance and intrinsically confer an obligate persister population throughout therapy. However, few efforts have focused on understanding the properties of such cytostatic persisters and exploring their therapeutic potentials.

In their new editorial, researchers Paul Y. Kim and Cheuk T. Leung from the University of Minnesota Medical School discuss recent studies from their group exploring the cellular controls in persister cancer cells under treatment-mediated cytostatic conditions and devised strategies for targeting to reduce cancer recurrence. Findings shed light on the cellular controls in cytostatic persisters and highlighted that treatment-mediated cytostatic condition before resistance emerges is a viable targeting venue to reduce cancer recurrence.

“The distinct vulnerabilities of cytostatic and drug-tolerant persisters imply that administering multiple targeted regimens would be necessary to effectively deplete the persister reservoirs in patients under cancer treatments.”

DOI - https://doi.org/10.18632/oncotarget.28488

Correspondence to - Cheuk Leung - [email protected]

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Keywords - cancer, persister cancer cells, cytostatic therapy, cancer recurrence, PTEN/PI3K/AKT, proteasome inhibitor

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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BUFFALO, NY- December 11, 2023 – A new #review paper was #published in Oncotarget's Volume 14 on December 1, 2023, entitled, “Risk factors for long-term arm morbidities following breast cancer treatments: A systematic review.”

In this review, researchers Ifat Klein, Michael Friger, Merav Ben David, and Danit Shahar from Assuta Medical Center and Ben-Gurion University of the Negev in Israel aimed to examine the risk factors for arm morbidity following breast cancer treatments. The team took a broad view of all types of physical morbidity, including prolonged pain, lymphedema, decreased range of motion, and functional limitations.

“A systematic literature review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines.”

Studies exploring the risk factors for prolonged arm morbidity following breast cancer surgery and treatments were included. The studies were assessed independently according to pre-eligibility criteria, following data extraction and methodological quality assessment. 1,242 articles were identified. After removing duplicates, the full texts of 1,153 articles were examined. Sixty-nine of these articles met the criteria and were included in the review.

These 69 articles identified 29 risk factors for arm morbidity following treatments for breast cancer. The risk of bias was evaluated using NIH study quality assessment tools. The studies reviewed were published between 2001 and 2021 and included a total of 22,886 patients who were followed up for between three months and 10 years. The main risk factors for long-term morbidity are removal of lymph nodes from the axilla, body mass index >30, having undergone a mastectomy, the stage of the disease, radiation therapy, chemotherapy, infection and trauma to the affected arm after surgery.

“An understanding of the risk factors for prolonged arm morbidity after surgery can help doctors and therapists in making personalized decisions about the need and timing of rehabilitation treatments.”

DOI - https://doi.org/10.18632/oncotarget.28539

Correspondence to - Ifat Klein - [email protected]

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Keywords - cancer, risk factors, arm morbidity, physical rehabilitation, breast cancer

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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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BUFFALO, NY- December 6, 2023 – A new #researchpaper was #published in Oncotarget's Volume 14 on December 1, 2023, entitled, “Plasma levels of BCMA-positive extracellular vesicles correlate to response and side effects in myeloma patients treated with belantamab-mafodotin.”

In myeloma patients, high levels of soluble B-cell maturation antigen (sBCMA) can limit the efficacy of BCMA-directed therapies. Belantamab-mafodotin is a BCMA antibody-drug conjugate and shows good overall response rates in heavily pretreated patients, but progression-free survival data are poor. In this new study, researchers Carsten Springer, Jürgen Krauter and Arne Trummer, from Städtisches Klinikum Braunschweig and Heidekreis-Klinikum in Germany, investigated whether sBCMA in blood plasma includes extracellular vesicles (EV) carrying BCMA or other myeloma antigens and if these BCMA-EV levels show a significant change during therapy with belantamab-mafodotin.

“As the drug induces apoptosis, we hypothesized that sBCMA includes extracellular vesicles (EV) and thus evaluated numbers of BCMA-EV before and during belantamab therapy in 10 myeloma patients.”

BCMA-EV were significantly higher in patients prior to Belantamab (median: 3227/μl; p = .013) than in other myeloma patients before therapy (n = 10; 1082/μl) or healthy volunteers (n = 10; 980/μl). During therapy, BCMA-EV showed a significant increase to a maximum of 8292/μl (p = .028). Maximal changes in BCMA-EV (Δmax = BCMA-EV at C1/maximal BCMA-EV) showed a strong inverse, logarithmic correlation (r = −.950; p < .001) with FLC ratio changes (Δmax = FLC ratio at C1/minimal FLC ratio) and BCMA-EV peaks often preceded FLC progression. Correlating increase of LDH and BCMA-EV levels, together with clinical symptoms, point to a mafodotin-induced eryptosis. In summary, BCMA-EV are a part of sBCMA, peak levels precede progression, and their measurement might be helpful in identifying resistance mechanisms and side effects of BCMA-targeted therapies.

“To the best of our knowledge, we demonstrate for the first time that BCMA-positive extracellular vesicles can be found in blood plasma from myeloma patients and that BCMA expression on EV is 10 to 100 times higher than that of other well-known antigens of myeloma cells.”

DOI - https://doi.org/10.18632/oncotarget.28538

Correspondence to - Arne Trummer - [email protected]

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Keywords - cancer, myeloma, b cell maturation antigen, extracellular vesicles, belantamab-mafodotin, eryptosis

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BUFFALO, NY- December 4, 2023 – A new #researchpaper was #published in Oncotarget's Volume 14 on December 1, 2023, entitled, “Osteopontin induces mitochondrial biogenesis in deadherent cancer cells.”

Metastasizing cells display a unique metabolism, which is very different from the Warburg effect that arises in primary tumors. Over short time frames, oxidative phosphorylation and ATP generation are prominent. Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected.

In this new study, researchers Gulimirerouzi Fnu and Georg F. Weber from the University of Cincinnati’s James L. Winkle College of Pharmacy hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms.

“Here, we report that autocrine Osteopontin does indeed stimulate an increase in mitochondrial size, with the splice variant -c being more effective than the full-length form -a.”

Osteopontin-c achieves this via its receptor CD44v, jointly with the upregulation and co-ligation of the chloride-dependent cystine-glutamate transporter SLC7A11. The signaling proceeds through activation of the known mitochondrial biogenesis inducer PGC-1 (which acts as a transcription coactivator). Peroxide is an important intermediate in this cascade, but surprisingly acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation. In vivo, suppression of the biogenesis-inducing mechanisms leads to a reduction in disseminated tumor mass.

“This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis – both are induced by Osteopontin-c. The results imply possible mechanisms and targets for treating cancer metastasis.”

DOI - https://doi.org/10.18632/oncotarget.28540

Correspondence to - Georg F. Weber - [email protected]

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Keywords - cancer, metastasis, metabolism, anchorage independence, mitochondrial mass, peroxide

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Hair follicles are dynamic structures that undergo cyclic phases of growth, regression and quiescence. The growth phase, known as anagen, lasts for several years, followed by a short regression phase called catagen. During catagen, most cells within the follicle undergo programmed cell death, but a small population of stem cells remains viable to replenish the follicle during the subsequent growth phase. Understanding the mechanisms involved in hair follicle regression is not only important for elucidating normal tissue homeostasis but also for studying pathological conditions such as cancer and aging.

In a recent study, researchers Bradley D. Keister, Kailin R. Mesa and Krastan B. Blagoev from the National Science Foundation, The Jane Coffin Childs Memorial Fund for Medical Research, Yale School of Medicine, Johns Hopkins University, Bulgarian Academy of Sciences, and Sorbonne Université shed light on the role of apoptotic cells in hair follicle regression and cell death. Their research paper was published in Oncotarget on October 19, 2023, entitled, “Apoptotic cells may drive cell death in hair follicles during their regression cycle.”

“Here, we use a quantitative analysis of the length of hair follicles during their regression cycle.”

Full blog - https://www.oncotarget.org/2023/11/29/can-mechanisms-of-hair-loss-shed-light-on-cancer-and-aging/

Paper DOI - https://doi.org/10.18632/oncotarget.28529

Correspondence to - Krastan B. Blagoev - [email protected]

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Keywords - cancer, hair follicle, stem cells, regression cycle, mathematical model, analysis

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BUFFALO, NY- November 28, 2023 – A new #editorial paper was #published in Oncotarget's Volume 14 on November 27, 2023, entitled, “The double-edge sword of CRISPR application for in vivo studies.”

In this new paper, researcher Martin K. Thomsen from Aarhus University begins his editorial by discussing a hallmark paper that was published a decade ago by Platt et al. on the in vivo application of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to generate cancer in different organs of mice.

This hallmark paper outlines the advancement of delivering sgRNA’s to the target tissue to create loss or gain of function mutations without the need for timely intercrossing of genetic mouse strains. Furthermore, the study showed that multiplexing was possible, thereby enabling the method to target multiple sites simultaneously [1]. It was foreseen that this technology would change the way mouse models of cancer were generated, but even after 10 years, only few studies have relied on this methodology [2].

“The double-edged sword of in vivo application of CRISPR is the imperfection of mutations generated in the target sequence.”

As CRISPR introduces mutations, they do not always occur, resulting in cells being present without the desired mutation. This is further complicated by the different types of indels, which can result in a functional protein with only changes in a few amino acids, without the introduction of a premature stop codon. This introduces clone-to-clone variation and results in tumors with a different mutation profile [3, 4]. However, this is also an advantage of CRISPR for generating in vivo cancer models as natural selection will occur, resulting in a cancer Darwinian evolution.

“Altogether, the in vivo application of CRISPR will become more common, even though the technique has challenges, it will only become more feasible in the future, allowing more researchers to apply this technology.”

DOI - https://doi.org/10.18632/oncotarget.28459

Correspondence to - Martin K. Thomsen - [email protected]

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Keywords - cancer, CRISPR, in vivo, mouse models, Adenoassociated virus

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BUFFALO, NY- November 27, 2023 – A recent #review paper was #published in Oncotarget's Volume 14 on July 1, 2023, entitled, “Targeting Ras with protein engineering.”

Ras proteins are small GTPases that regulate cell growth and division. Mutations in Ras genes are associated with many types of cancer, making them attractive targets for cancer therapy. Despite extensive efforts, targeting Ras proteins with small molecules has been extremely challenging due to Ras’s mostly flat surface and lack of small molecule-binding cavities.

These challenges were recently overcome by the development of the first covalent small-molecule anti-Ras drug, sotorasib, highlighting the efficacy of Ras inhibition as a therapeutic strategy. However, this drug exclusively inhibits the Ras G12C mutant, which is not a prevalent mutation in most cancer types. Unlike the G12C variant, other Ras oncogenic mutants lack reactive cysteines, rendering them unsuitable for targeting via the same strategy. In this review, researchers Atilio Tomazini and Julia M. Shifman from The Hebrew University of Jerusalem discuss protein engineering as a promising emergent method to target Ras, since engineered proteins have the ability to recognize various surfaces with high affinity and specificity.

“While the development of small-molecule Ras inhibitors has been reviewed elsewhere [40], we focus our review on protein-based Ras inhibitors, describing the methods for their engineering, various scaffolds used for inhibitor design, and prospects for delivery of the designed Ras inhibitors into the cellular cytoplasm, where Ras is located.”

Over the past few years, scientists have engineered antibodies, natural Ras effectors, and novel binding domains to bind to Ras and counteract its carcinogenic activities via a variety of strategies. These include inhibiting Ras-effector interactions, disrupting Ras dimerization, interrupting Ras nucleotide exchange, stimulating Ras interaction with tumor suppressor genes, and promoting Ras degradation. In parallel, significant advancements have been made in intracellular protein delivery, enabling the delivery of the engineered anti-Ras agents into the cellular cytoplasm.

“These advances offer a promising path for targeting Ras proteins and other challenging drug targets, opening up new opportunities for drug discovery and development.”

DOI - https://doi.org/10.18632/oncotarget.28469

Correspondence to - Julia M. Shifman - [email protected]

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Keywords - Ras oncogene, anti-Ras therapeutics, Ras targeting, protein engineering, protein design

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BUFFALO, NY- November 22, 2023 – A new #research paper was #published in Oncotarget's Volume 14 on October 4, 2023, entitled, “Determination of genetic predisposition to early breast cancer in women of Kazakh ethnicity.”

Breast cancer (BC) is the most common type of cancer among women in Kazakhstan. To date, little data are available on the spectrum of genetic variation in Kazakh women with BC.

In this new study, researchers Gulnur Zhunussova, Nazgul Omarbayeva, Dilyara Kaidarova, Saltanat Abdikerim, Natalya Mit, Ilya Kisselev, Kanagat Yergali, Aigul Zhunussova, Tatyana Goncharova, Aliya Abdrakhmanova, and Leyla Djansugurova from the Institute of Genetics and Physiology, Kazakh Institute of Oncology and Radiology, Al-Farabi Kazakh National University, and Asfendiyarov Kazakh National Medical University aimed to identify population-specific genetic markers associated with the risk of developing early-onset BC and test their association with clinical and prognostic factors.

“To our knowledge, this is the first study using NGS [next-generation sequencing] technology to study the genetic predisposition to early-onset BC women from Kazakhstan and assess their impact on the patients’ clinical outcomes.”

The study included 224 Kazakh women diagnosed with BC (≤40 age). Entire coding regions (>1700 exons) and the flanking noncoding regions of 94 cancer-associated genes were sequenced from blood DNA using MiSeq platform. The researchers identified 38 unique pathogenic variants (PVs) in 13 different cancer-predisposing genes among 57 patients (25.4%), of which 6 variants were novel. In total, 12 of the 38 distinct PVs were detected recurrently, including BRCA1 c.5266dup, c.5278-2del, and c.2T>C, and BRCA2 c.9409dup and c.9253del that may be founder in this population. BRCA1 carriers were significantly more likely to develop triple-negative BC (OR = 6.61, 95% CI 2.44–17.91, p = 0.0002) and have family history of BC (OR = 3.17, 95% CI 1.14–8.76, p = 0.03) compared to non-carriers.

“This study allowed the identification of PVs specific to early-onset BC, which may be used as a foundation to develop regional expertise and diagnostic tools for early detection of BC in young Kazakh women.”

DOI - https://doi.org/10.18632/oncotarget.28518

Correspondence to - Gulnur Zhunussova - [email protected], and Nazgul Omarbayeva - [email protected]

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Keywords - cancer, breast cancer, early-onset breast cancer, triple negative breast cancer, next-generation sequencing, pathogenic variant, Kazakh population

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BUFFALO, NY- November 20, 2023 – A new editorial #paper was #published in Oncotarget's Volume 14 on August 30, 2023, entitled, “Predicting the molecular functions of regulatory genetic variants associated with cancer.”

Some of inherited human genetic variation can contribute to important phenotypic diversity, such as the varying degrees of individual susceptibility to developing certain health conditions and individual response to therapeutic interventions. To date, over 490,000 genotype-phenotype associations have been discovered through large-scale genome-wide association studies (GWAS); however, molecular functions of most of these discovered GWAS variants remain unknown.

In their recent editorial, researchers Jun S. Song and Mohith Manjunath from the University of Illinois at Urbana-Champaign discuss computational methods of genetic analysis using expression quantitative trait loci, frameworks for predicting regulatory genetic functions, application to transcription factors involved in cancer development and progression, and future implications for their methods in cancer research and precision medicine.

“There are several technical challenges hindering our understanding [...].”

First, the effect size of a typical genetic variant, as measured in terms of the odds ratio of genotype occurrence in case versus control populations, is very small, suggesting that macroscopic systems-level phenotypic differences modulated by each variant may also be small and difficult to detect. Next, most reported variants reside in non-protein-coding regions of the human genome, indicating that they are likely affecting the regulation of some unknown target genes’ expression. Finally, the discovered variants may not be functional themselves, but be merely in genetic linkage disequilibrium with other functional variants.

“A promising approach to address these challenges is to integrate genomic, epigenomic, transcriptomic and machine learning methods to identify functional genetic variants and characterize their mode of action in regulating target genes.”

DOI - https://doi.org/10.18632/oncotarget.28451

Correspondence to - Jun S. Song - [email protected]

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Keywords - cancer, genome-wide association studies, cancer risk, regulatory variants, functional genomics

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Pancreatic ductal adenocarcinoma (PDA), a common type of pancreatic cancer, has proven to be largely resistant to immunotherapy, a treatment that uses the body’s immune system to fight cancer. Despite numerous successful pre-clinical trials using sophisticated PDA mouse models, clinical trials have failed to show a significant improvement in survival.

In a recent editorial, researchers Brian Diskin, Sarah Schwartz and George Miller from Trinity Health of New England shed light on the complex interplay between the immune system and pancreatic cancer. Their paper was published in Oncotarget on April 24, 2023, and entitled, “The critical immune basis for differential responses to immunotherapy in primary versus metastatic pancreatic cancer.”

Tumor Microenvironment and Liver Metastasis: Challenges in Pancreatic Cancer

The authors attribute PDA immunotherapy resistance to the unique characteristics of the tumor microenvironment (TME). The TME is often hypoxic and fibrotic, making it inaccessible to immune cells. Furthermore, the immune cells that do infiltrate the TME often have tolerogenic features, meaning they are more likely to tolerate the presence of cancer cells rather than attack them.

PDA most commonly metastasizes to the liver, an organ known for its immune tolerance. The liver is home to a diverse array of innate immune populations, including NK cells, Kupfer cells, NKT cells, and double negative T cells. Despite this, the liver is the most common location for metastasis from gastrointestinal cancers.

“It is an unfortunate fact that all failed clinical trials assessing immunotherapeutic efficacy were conducted in metastatic PDA, whereas basic preclinical investigations are usually performed in primary PDA using genetically engineered mouse models. We postulated that this dichotomy may explain the gap between preclinical promise and ultimate clinical failure.”

Full blog - https://www.oncotarget.org/2023/11/16/immunotherapy-response-in-primary-vs-metastatic-pancreatic-cancer/

Paper DOI - https://doi.org/10.18632/oncotarget.28373

Correspondence to - George Miller - [email protected]

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Keywords - cancer, pancreatic cancer, liver metastasis, immunnotherapy

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