Oncotarget

A new research paper was published in Oncotarget's Volume 14 on March 21, 2023, entitled, “Attenuation of cancer proliferation by suppression of glypican-1 and its pleiotropic effects in neoplastic behavior.”

Glypicans (GPC1-6) are associated with tumorigenic processes and their involvement in neoplastic behavior has been discussed in different cancer types. In this recent cancer-wide GPC expression study, researchers Fang Cheng, Victor Chérouvrier Hansson, Grigorios Georgolopoulos, and Katrin Mani from Lund University and Genevia Technologies used clinical cancer patient data in The Cancer Genome Atlas to reveal net upregulation of GPC1 and GPC2 in primary solid tumors. On the other hand, GPC3, GPC5 and GPC6 displayed lowered expression patterns compared to normal tissues.

“[...] we identify and propose a mechanism where GPC1 interacts with extracellular matrix mediating signal transduction by mitogenic molecules involving TGF-β and p38 MAPK.”

Focusing on GPC1, the researchers conducted survival analyses of the clinical cancer patient data that revealed a statistically significant correlation between high expression of GPC1 and poor prognosis in 10 particular cancer types: bladder urothelial carcinoma, brain lower grade glioma, liver hepatocellular carcinoma, colon adenocarcinoma, kidney renal clear cell carcinoma, lung adenocarcinoma, mesothelioma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, and uveal melanoma.

In vitro studies targeting GPC1 expression by CRISPR/Cas9 or siRNA or treatment with an anti-GPC1 antibody resulted in attenuation of proliferation of cancer cells from bladder carcinoma, glioma and hepatocellular carcinoma patients (T24, U87 and HepG2 cells). Further, GPC1 overexpression exhibited a significant and negative correlation between GPC1 expression and proliferation of T24 cells. Their attempt to reveal the mechanism through which downregulation of GPC1 leads to attenuation of tumor growth using systematic Ingenuity Pathway Analysis indicated that suppression of GPC1 results in ECM-mediated inhibition of specific pro-cancer signaling pathways involving TGF-β and p38 MAPK. The team also identified differential expression and pleiotropic effects of GPCs in specific cancer types. This emphasizes their potential as novel diagnostic tools and prognostic factors, and open doors for future GPC targeted therapy.

“It is plausible to measure circulating GPCs in serum, plasma or urine using a variety of methods including ELISA, urine cell sediments or exosome isolation [13, 24]. Further, detection and quantification of GPC1 by histopathological and immunohistochemical methods in tumor biopsies could be a new way to predict the biological outcome. The results of this investigation would also emphasize the potential of GPCs as novel tumor antigens, and open for GPC targeted immunotherapy. GPC targeted immunotherapy would be of high value, especially as we move into an era of precision and personalized cancer therapy.”

DOI: https://doi.org/10.18632/oncotarget.28388

Correspondence to: Katrin Mani - [email protected]

Keywords: Glypican-1, TCGA, bladder carcinoma, hepatocellular carcinoma, glioma

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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A new editorial paper was published in Oncotarget's Volume 14 on February 11, 2023, entitled, “Unlocking the potential of molecular-driven stratification for osteosarcoma treatment and prognosis.”

Over the last 40 years, the complex genetic landscape, the heterogeneity of the microenvironment and the cell plasticity of Osteosarcoma (OSA) tumors have delayed the therapeutic and prognostic stratification of patients and the introduction of new efficient treatments.

As a direct consequence, the vast majority of trials still don’t benefit from a selection of OSA patient-based on molecular evidence before drug administration. This lack of stratification leads to difficult interpretation of outcome, especially with targeted agents such as multikinase inhibitors or anti-osteoclastic drugs.

“Meanwhile, fortunately, the accumulation of numerous sparse but converging observations from many research and clinical teams have progressively drawn a portrait of the resistant osteosarcoma that’s paved the way to new translational discoveries.”

In their new editorial, researchers Gaël Moquin-Beaudry, Maria Eugenia Marques da Costa, Nathalie Gaspar, and Antonin Marchais from Université Paris-Saclay discussed their recent study using unsupervised machine learning algorithms to classify OSA at diagnosis based on gene expression modules functionally enriched for immune microenvironment and tumor phenotypic traits.

“Recently, several important studies have described OSA molecularly at an unprecedent[ed] level of detail taking advantage of multiomics approaches and artificial intelligence [1–3].”

Read the full editorial: DOI: https://doi.org/10.18632/oncotarget.28364

Correspondence to: Antonin Marchais - [email protected]

Keywords: multiomics, osteosarcoma, bone sarcoma,

stratification

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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Blog summary of an editorial perspective published in Oncotarget on entitled, “Leakage? or Secretion? unconventional protein secretion in cancer.”

________________________________________

Conventional protein secretion is fairly well understood in this day and age. Proteins that are secreted through the classical, secretory vesicle-related pathway contain a signal peptide that guides them to the endoplasmic reticulum (ER), where they are further processed and transported to the Golgi apparatus. From there, the Golgi apparatus modifies, sorts and packages proteins for transport to their final destinations within the cell or for secretion outside of the cell.

However, in recent years, it has become clear that not all secreted proteins follow this conventional pathway. Instead, some proteins are secreted through unconventional pathways that do not require a signal peptide or the involvement of the ER or Golgi apparatus. In a recent editorial perspective published in Oncotarget on February 20, 2023, “Leakage? or Secretion? unconventional protein secretion in cancer,” researchers Kohji Yamada and Kiyotsugu Yoshida from The Jikei University School of Medicine in Tokyo, Japan, discuss unconventional protein secretion (UPS) and its significance in the progression of cancer.

“In contrast, the secretion of proteins that do not code for signal peptides may occur via two or more mechanisms, often collectively referred to as unconventional protein secretion (UPS).”

Full blog - https://www.oncotarget.org/2023/03/16/unconventional-protein-secretion-ups-in-cancer/

DOI - https://doi.org/10.18632/oncotarget.28368 (PDF Download)

Correspondence to - Kohji Yamada - [email protected], and Kiyotsugu Yoshida - [email protected]

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Keywords - unconventional protein secretion, cancer, endoplasmic reticulum

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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A new research paper was published in Oncotarget's Volume 14 on March 11, 2023, entitled, “Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss.”

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) upregulates de novo synthesis of purine (DNSP) and increases the proliferation of neoplastic cells. This increases the sensitivity of breast cancer cells to DNSP inhibitors such as methotrexate, L-alanosine and pemetrexed. In their recent study, Maroun Bou Zerdan, Prashanth Ashok Kumar, Elio Haroun, Nimisha Srivastava, Jeffrey Ross, and Abirami Sivapiragasam from SUNY Upstate Medical University and Foundation Medicine, Inc. analyzed 7,301 metastatic breast cancer (MBC) patients that underwent hybrid-capture based comprehensive genomic profiling (CGP).

“We provide one of the first large analyses of the spectrum of GA [genomic alterations] occurring in MTAP deleted MBC with the hope that this would enable identifying potential therapeutic agents in the future.”

Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). 208 (2.84%) of MBC featured MTAP loss. MTAP loss patients were younger (p = 0.002) and were more frequently ER− (30% vs. 50%; p < 0.0001), triple negative (TNBC) (47% vs. 27%; p < 0.0001) and less frequently HER2+ (2% vs. 8%; p = 0.0001) than MTAP intact MBC.

Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p < 0.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p < 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% vs. 4%; p < 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB >20 mut/Mb levels in the MTAP intact MBC (p < 0.0001) and higher PD-L1 low expression (1–49% TPS) in the MTAP loss MTAP (p = 0.002) were observed.

“MTAP loss in MBC has distinct clinical features with genomic alterations (GA) affecting both targeted and immunotherapies. Further efforts are necessary to identify alternative means of targeting PRMT5 and MTA2 in MTAP-ve cancers to benefit from the high-MTA environment of MTAP-deficient cancers.”

Read the full research paper: DOI: https://doi.org/10.18632/oncotarget.28376

Correspondence to: Abirami Sivapiragasam - [email protected]

Keywords: breast cancer, metastatic, MTAP loss

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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A new review paper was published in Oncotarget's Volume 14 on March 11, 2023, entitled, “Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells.”

Cancer therapy is limited by toxicity in normal cells and drug-resistance in cancer cells. In his latest review, Mikhail V. Blagosklonny, M.D., Ph.D., from Roswell Park Comprehensive Cancer Center discusses the theory that cancer resistance to certain therapies can be exploited for protection of normal cells—simultaneously enabling the selective killing of resistant cancer cells by using antagonistic drug combinations, which include cytotoxic and protective drugs.

“No cancer cell, no matter how resistant it is, can survive chemotherapy in a cell culture. In the organism, however, therapy of cancer is limited by killing or damaging normal cells. Selective protection of normal cells from chemotherapy would increase the therapeutic window, improving the therapeutic outcome. Needless to say, reduction of side effects and better quality of life are very important for a cancer patient.”

Depending on the mechanisms of drug-resistance in cancer cells, the protection of normal cells can be achieved with inhibitors of CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases. When normal cells are protected, the selectivity and potency of multi-drug combinations can be further enhanced by adding synergistic drugs, in theory, eliminating the deadliest cancer clones with minimal side effects.

“I also discuss how the recent success of Trilaciclib may foster similar approaches into clinical practice, how to mitigate systemic side effects of chemotherapy in patients with brain tumors and how to ensure that protective drugs would only protect normal cells (not cancer cells) in a particular patient.”

Read the full review: DOI: https://doi.org/10.18632/oncotarget.28382

Correspondence to: Mikhail V. Blagosklonny - [email protected], [email protected]

Keywords: oncology, resistance, cyclotherapy, trilaciclib, rapamycin

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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A new editorial paper was published in Oncotarget's Volume 14 on February 25, 2023, entitled, “Mitochondria engage the integrated stress response to promote tumor growth.”

In this new editorial, researchers Dillon P. Boulton and M. Cecilia Caino from the University of Colorado School of Medicine discussed prostate cancer (PCa)—the most diagnosed and second deadliest cancer among men in the United States, with an estimated 268,490 new cases and 34,500 deaths in 2022 (ACS Cancer Facts and Figures 2022).

“While the prognosis for men with early-stage disease remains extremely favorable (>99% 5-year overall survival, OS), men diagnosed with metastatic PCa have a 30% 5-year OS, clearly demonstrating a need for therapeutic options for these patients (ACS Cancer Facts and Figures 2022).”

Due to a strong reliance on androgens to drive PCa, first and second courses of therapy involve androgen deprivation therapy or targeting the androgen receptor directly in combination with several other cytotoxic agents [1–3]. Unfortunately, some tumors develop resistance to these androgen axis therapies and progress to castrate resistant and metastatic PCa, which drives the majority of PCa deaths. This underscores a strong need to identify and characterize actionable targets within these tumors. Of interest, mitochondria are emerging as critical organelles that promote tumorigenesis and metastasis.

“​​Along this line, we have recently described a novel signaling pathway where mitochondria promote castrate resistant metastatic PCa growth by acting as a signaling platform to facilitate efficient stress signaling [11]. This pathway is centered around mitochondrial Rho GTPase 2 (MIRO2), an outer-mitochondrial membrane protein in the Ras superfamily of GTPases [12, 13].”

Full editorial: DOI: https://doi.org/10.18632/oncotarget.28372

Correspondence to: M. Cecilia Caino - [email protected]

Keywords: mitochondria, prostate cancer, integrated stress response

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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A new review paper was published in Oncotarget's Volume 14 on February 25, 2023, entitled, “What is hemoglobin, albumin, lymphocyte, platelet (HALP) score? A comprehensive literature review of HALP’s prognostic ability in different cancer types.”

Since its inception, the Hemoglobin, Albumin, Lymphocyte, Platelet (HALP) Score has gained attention as a new prognostic biomarker to predict several clinical outcomes in a multitude of cancers.

“HALP is a novel immune-nutritional marker that integrates several routinely collected indicators of immune status, such as the platelet and lymphocyte count, nutritional status, such as albumin, and hemoglobin, a marker for anemia.”

In this new review, researchers Christian Mark Farag, Ryan Antar, Sinan Akosman, Matthew Ng, and Michael J. Whalen from George Washington University School of Medicine searched PubMed for articles on HALP, from the first paper in 2015 through September 2022. Their search yielded a total of 32 studies that evaluated HALP's association with various cancers, including Gastric, Colorectal, Bladder, Prostate, Kidney, Esophageal, Pharyngeal, Lung, Breast, Cervical cancers, and others.

“This review highlights the collective association HALP has with demographic factors such as age and sex in addition to TNM staging, grade, and tumor size.”

Furthermore, this review summarizes HALP's prognostic ability to predict overall survival, progression-free survival and recurrence-free survival, among other outcomes. In some studies, HALP has also been able to predict response to immunotherapy and chemotherapy. Their review article also aims to serve as a comprehensive and encyclopedic report on the literature that has evaluated HALP as a biomarker in various cancers, highlighting the heterogeneity surrounding HALP's utilization.

“Because HALP requires only a complete blood count and albumin - already routinely collected for cancer patients - HALP shows potential as a cost-effective biomarker to aid clinicians in improving outcomes for immuno-nutritionally deficient patients.”

Full review: DOI: https://doi.org/10.18632/oncotarget.28367

Correspondence to: Christian Mark Farag - [email protected]

Keywords: HALP score, biomarker, prognosis, cancer, survival

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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A new editorial paper was published in Oncotarget's Volume 14 on February 11, 2023, entitled, “Unveiling the non-canonical functions of EZH2 in prostate cancer.”

Prostate cancer (PCa) is ranked as the second leading cause of cancer-related death among American men excluding skin cancer. In this new editorial, researchers Yang Yi, Yanqiang Li, Kaifu Chen, and Qi Cao from Northwestern University’s Feinberg School of Medicine discuss a well-known oncogenic driver in PCa: enhancer of zeste homolog 2 (EZH2)—canonically known for the functions as the catalytic subunit of Polycomb Repressive Complex 2 (PRC2) that deposes histone H3 lysine 27 mono, di-, and tri-methylation (H3K27me1-3) and represses transcription.

“Although the oncogenic role of EZH2 mainly relies on its enzymatic activity and the PRC2, accumulating evidence suggests that targeting the lysine methyltransferase activity of EZH2 alone is ineffective in treating EZH2-dependent malignancies including PCa [4, 5].”

Hence, deeply investigating the multifaceted tumorigenic functions of EZH2 will shed new light on understanding the etiology of PCa. It is noteworthy that two recent studies published in Nature Cell Biology and Oncogene by Yi et al. described previously unrecognized roles of EZH2 in regulation of translation and coactivation of transcription, respectively. In both cases, EZH2 exerts oncogenic functions independently of PRC2 and H3K27me3 to promote tumorigenesis and aggressiveness in PCa.

“In summary, both articles by Yi et al. emphasized the significance of non-canonical functions of EZH2 during PCa development, which may provide novel insights into the advancement of EZH2-targeting strategies to treat PCa patients. In fact, a new wave has been ushed for the discovery of EZH2 inhibitors to eliminate both the catalytic and non-catalytic activities of EZH2 [12–14]. Will these newly developed EZH2 degraders be successfully applied in PCa therapy? Will additional noncanonical functions of EZH2 be characterized in the PCa model? Let’s eagerly wait and see.”

Full editorial: DOI: https://doi.org/10.18632/oncotarget.28357

Correspondence to: Qi Cao - [email protected]

Keywords: EZH2, prostate cancer, FBL, CDCA8, E2F1

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Keywords - EZH2, prostate cancer, FBL, CDCA8, E2F1

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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Blog summary of an editorial published in Volume 14 of Oncotarget, entitled, “The role of Kras and canonical Wnt pathways for tumorigenesis of extrahepatic biliary system.”

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The extrahepatic biliary system is a network of tubes and ducts that carry bile from the liver to the small intestine, where it helps digest fats. Biliary tract cancers, including gallbladder cancer and cholangiocarcinoma, are rare but aggressive cancers that arise from this system. Understanding the molecular mechanisms that drive these cancers is crucial for developing effective therapies.

“Despite advances in diagnosis and therapy, 5-year survival rate of biliary cancer is only 5% to 15% [7, 8].”

In a new editorial, researchers Munemasa Nagao, Akihisa Fukuda and Hiroshi Seno from Kyoto University Graduate School of Medicine discuss the latest research on the role of Kras and the canonical Wnt pathway in the development of biliary tract cancers. On January 26, 2023, their paper was published in Oncotarget’s Volume 14, entitled, “The role of Kras and canonical Wnt pathways for tumorigenesis of extrahepatic biliary system.”

Full blog - https://www.oncotarget.org/2023/03/01/the-role-of-kras-and-canonical-wnt-pathways-in-biliary-tract-cancers/

DOI - https://doi.org/10.18632/oncotarget.28349 (PDF Download)

Correspondence to - Akihisa Fukuda - [email protected]

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Keywords - ICPN, BilIN, biliary cancer, Kras, Wnt

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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A new research perspective was published in Oncotarget's Volume 14 on February 7, 2023, entitled, “WNT-pathway medulloblastoma: what constitutes low-risk and how low can one go?”

Novel biological insights have established that medulloblastoma is a heterogenous disease comprising four broad molecular subgroups - WNT, SHH, Group 3, and Group 4 respectively, resulting in the incorporation of molecular/genetic information in 5th edition of WHO classification and contemporary risk-stratification. Concerns regarding therapy-related late toxicity in long-term survivors have led to systematic attempts at treatment de-intensification in good-risk medulloblastoma.

Given the excellent survival (>90%) of WNT-pathway medulloblastoma, prospective clinical trials have focused on optimization of therapy to balance survival versus quality of survival. The currently accepted definition of low-risk WNT-pathway medulloblastoma includes children <16 years of age with residual tumour <1.5 cm2 and no evidence of metastases. This systematically excludes adolescents and young adults who have been perceived to have worse outcomes.

In a previous study, researchers Shakthivel Mani, Abhishek Chatterjee, Archya Dasgupta, Neelam Shirsat, Sridhar Epari, Girish Chinnaswamy, and Tejpal Gupta from Homi Bhabha National Institute (HBNI) in Mumbai, India, reported long-term survival of an adolescent and young adult cohort that was largely comparable to childhood medulloblastoma. In their current research perspective, the researchers now report on molecularly characterized WNT-subgroup patients treated between 2004–2020 with risk-stratified multi-modality therapy to identify differences between childhood (<15 years) versus adolescent and young adults (>15 years).

Despite modest differences in disease status at presentation and treatment modality, there were no significant differences in patterns of failure or survival between childhood versus adolescent and young adult WNT-pathway medulloblastoma. Two de-intensification trials in low-risk WNT-pathway medulloblastoma – first testing omission of upfront craniospinal irradiation and second a primary chemotherapy approach after surgery – had to be terminated prematurely due to unacceptably high relapse rates suggesting that craniospinal irradiation remains an integral component of treatment. The presence of TP53 mutations and OTX2 gains have recently been reported as independent negative prognostic factors in a multi-institutional cohort of WNT-pathway medulloblastoma, raising questions on eligibility of such patients for de-escalation trials.

“Concerns regarding therapy-related late toxicity have prompted systematic attempts at treatment de-intensification in good-risk MB over the last four decades. However, results of prior studies should be used to inform and guide controlled de-intensification of therapy even in low-risk and favourable biology disease. The definition of low-risk WNT-MB may need to be further refined in light of recent clinical data and newer biological information.”

DOI: https://doi.org/10.18632/oncotarget.28360

Correspondence to: Tejpal Gupta - [email protected]

Keywords: de-intensification, medulloblastoma, molecular, survival, toxicity

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Keywords - de-intensification, medulloblastoma, molecular, survival, toxicity

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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