Oncotarget

BUFFALO, NY- March 4, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 22, 2024, entitled, “Sacituzumab govitecan plus platinum-based chemotherapy mediates significant antitumor effects in triple-negative breast, urinary bladder, and small-cell lung carcinomas.”

Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2-directed antibody conjugated with the topoisomerase I inhibitory drug, SN-38, via a proprietary hydrolysable linker. SG has received United States Food and Drug Administration (FDA) approval to treat metastatic triple-negative breast cancer (TNBC), unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and accelerated approval for metastatic urothelial cancer (mUC).

In this new study, researchers Thomas M. Cardillo, Maria B. Zalath, Roberto Arrojo, Robert M. Sharkey, Serengulam V. Govindan, Chien-Hsing Chang, and David M. Goldenberg from Gilead Sciences and the Center for Molecular Medicine and Immunology investigated the utility of combining SG with platinum-based chemotherapeutics in TNBC, urinary bladder carcinoma (UBC), and small-cell lung carcinoma (SCLC).

“Given recent FDA approval of SG in mTNBC and accelerated approval in mUC [metastatic urothelial cancer], as well as its demonstrated clinical activity in SCLC [11], we investigated the possibility of expanding use of SG through combinations with currently utilized chemotherapeutics for these disease indications.”

SG plus carboplatin or cisplatin produced additive growth-inhibitory effects in vitro that trended towards synergy. Immunoblot analysis of cell lysates suggests perturbation of the cell-cycle and a shift towards pro-apoptotic signaling evidenced by an increased Bax to Bcl-2 ratio and down-regulation of two anti-apoptotic proteins, Mcl-1 and survivin. Significant antitumor effects were observed with SG plus carboplatin in mice bearing TNBC or SCLC tumors compared to all controls (P < 0.0062 and P < 0.0017, respectively) and with SG plus cisplatin in UBC and SCLC tumor-bearing animals (P < 0.0362 and P < 0.0001, respectively). These combinations were well tolerated by the animals.

“Combining SG with platinum-based chemotherapeutics demonstrates the benefit in these indications and warrants further clinical investigation.”

DOI - https://doi.org/10.18632/oncotarget.28559

Correspondence to - Thomas M. Cardillo - [email protected]

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Keywords - cancer, sacituzumab govitecan, Trop-2, SN-38, carboplatin, cisplatin

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- February 28, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 22, 2024, entitled, “Prevalence and spectrum of germline BRCA1 and BRCA2 in a cohort of ovarian cancer patients from the Salento peninsula (Southern Italy): a matter of preventive health.”

In this new exploratory and descriptive study, researchers Elisabetta De Matteis, Maria Rosaria Tumolo, Paolo Tarantino, Mariangela Ciccarese, Tiziana Grassi, Francesco Bagordo, Maria Rita De Giorgio, Emanuele Rizzo, and Graziana Ronzino from Vito Fazzi Hospital, University of Salento, Strategic Regional Agency for Health and Social of Puglia, and University of Bari Aldo Moro aimed to characterize the deleterious BRCA1 and BRCA2 variants evaluated by genetic testing in a group of Ovarian cancer patients living in the Salento peninsula (Southern Italy).

From June 2014 to July 2023, patients with histologically confirmed high-grade serous carcinoma, fallopian tube, or primary peritoneal cancer who were referred to Lecce Familial Cancer Clinic were considered. BRCA-mutation genetic testing was performed on these patients. Socio-demographic data and cancer epidemiology were assessed, and Next Generation Sequencing and Sanger DNA sequencing were performed.

The median age at the diagnosis of 332 ovarian cancer patients collected was 57 years. The pedigree analyses showed that 28.6% had familial cases and 39.7% had sporadic cases. Of the 319 patients submitted to genetic testing, 29.8% were carriers of BRCA1/2 mutation, 75.8% at BRCA1 and 24.2% at BRCA2 gene. Of the 21 BRCA1 mutations, the variant c.5266dupC was the most frequent alteration (28.4%). With respect to BRCA2, 13 mutations were found and the variant c.9676delT was the most frequently recorded (6.3%).

“This study reveals that the prevalence of germline mutations in the BRCA1 and BRCA2 genes was higher than reported by other studies. A broader understanding of the prevalence and role of BRCA mutations in development, response to treatment, and prognosis represents an exciting and developing area of ovarian cancer treatment and prevention.”

DOI - https://doi.org/10.18632/oncotarget.28561

Correspondence to - Maria Rosaria Tumolo - [email protected]

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Keywords - cancer, ovarian cancer, BRCA1, BRCA2, mutation

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BUFFALO, NY- February 26, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 8, 2024, entitled, “GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells.”

In this new study, researchers Michael R. Booth, Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated the therapeutic agent GZ17-6.02, composed of curcumin, harmine and isovanillin.

“Combined with our curcumin findings, we believe that isovanillin can complex with curcumin and harmine to create an entity with unique biology when compared to the three individual agents.”

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not previously been studied. The researchers found that GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells.

“All three components are necessary for optimal killing of MF cells.”

GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing.

Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, the team wrote that GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.”

“We discovered that GZ17-6.02 containing harmine, isovanillin and curcumin caused more tumor cell killing than any of the agents individually or in pairs, and that it could interact in an additive fashion with standard of care MF drugs such as bexarotene and vorinostat to cause additional tumor cell death.”

DOI - https://doi.org/10.18632/oncotarget.28557

Correspondence to - Paul Dent - [email protected]

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Keywords - cancer, autophagy, ER stress, GZ17-6.02, bexarotene, vorinostat

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Betel quid chewing, a traditional custom widely practiced in South Asia, Southeast Asia, the Asia-Pacific region, and East Africa for centuries, involves the consumption of raw areca nut mixed with slaked lime and wrapped in a betel leaf. This habit is particularly popular in certain regions, including Northeast India, where the areca nut is raw, wet, and consumed unprocessed. The act of chewing and swallowing this mixture leads to the release of alkaloids, polyphenols, and tannins. However, the consumption of raw areca nut betel quid has been strongly associated with the development of oral, esophageal, and gastric cancers, and has adverse consequences on oral health. Several studies have shown a significant relationship between periodontitis and betel quid chewing habits in many countries, including India.

In this context, esophageal cancer is a devastating disease that affects millions of people around the world. Recent research has shed light on the role of the Mad2 gene in the development and progression of esophageal cancer, a disease strongly associated with the consumption of raw areca nut betel quid. In a new study, researchers Chongtham Sovachandra Singh, Nabamita Boruah, Atanu Banerjee, Sillarine Kurkalang, Pooja Swargiary, Hughbert Dakhar, and Anupam Chatterjee from The Assam Royal Global University, University of Pennsylvania, LN Mithila University, University of Chicago Medicine, Nazareth Hospital, Laitumkhrah, and North-Eastern Hill University provide valuable insights into the molecular mechanisms underlying Mad2 gene deregulation in esophageal cancer. On February 5, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “Differential expression of Mad2 gene is consequential to the patterns of histone H3 post-translational modifications in its promoter region in human esophageal cancer samples.”

Full blog - https://www.oncotarget.org/2024/02/22/raw-areca-nut-betel-quid-consumption-and-esophageal-cancer/

Paper DOI - https://doi.org/10.18632/oncotarget.28554

Correspondence to - Anupam Chatterjee - [email protected], [email protected]

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Keywords - cancer, Mad2 gene, histone methylation, histone acetylation, Rb-phosphorylation; esophageal cancer

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BUFFALO, NY- February 21, 2024 – A new research #perspective was #published in Oncotarget's Volume 15 on February 8, 2024, entitled, “Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.”

As discussed in this new paper, researchers Alberto Moscona-Nissan, Karl J. Habashy, Victor A. Arrieta, Adam M. Sonabend, and Crismita Dmello from Universidad Panamericana School of Medicine, Northwestern University and Universidad Nacional Autónoma de México recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment.

“To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680).”

The validation of novel biomarkers of susceptibility to therapy is critical to elucidate the efficacy signal of therapeutic agents. This is especially important in the context of glioblastoma, where therapeutic benefit is variable and unpredictable, leading to negative trials, yet the outcome of subset of patients has outperformed expectations.

“Precision and personalized medicine can lead to a transition from a stochastic treatment response into predictable scenarios. Further identification of predictive biomarkers, validation, and study of combinations as predictive models is critical to generate a greater impact that can be translated to the bedside of patients.”

DOI - https://doi.org/10.18632/oncotarget.28549

Correspondence to - Crismita Dmello - [email protected], and Adam M. Sonabend - [email protected]

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Keywords - cancer, glioblastoma, predictive biomarker, CRISPR screen, paclitaxel

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BUFFALO, NY- February 19, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Neurotrophic-tyrosine receptor kinase gene fusion in papillary thyroid cancer: A clinicogenomic biobank and record linkage study from Finland.”

Selective tropomyosin receptor kinase (TRK) inhibitors are approved targeted therapies for patients with solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Country-specific estimates of NTRK gene fusion frequency, and knowledge on the characteristics of affected patients, are limited.

In this new study, researchers Wei Zhang, Arndt A. Schmitz, Roosa E. Kallionpää, Merja Perälä, Niina Pitkänen, Mikko Tukiainen, Erika Alanne, Korinna Jöhrens, Renate Schulze-Rath, Bahman Farahmand, and Jihong Zong from Bayer HealthCare Pharmaceuticals Inc., University of Turku, Turku University Hospital, Technical University Dresden, and Western Finland Cancer Centre identified patients with histologically-confirmed papillary thyroid cancer (PTC) from Finland’s Auria Biobank.

“The study objectives were to determine the frequency of NTRK gene fusion in patients with PTC in Finland, and to describe co-occurring genetic alternations, clinical characteristics, disease progression, and treatment pathways in NTRK gene fusion positive patients.”

TRK protein expression was determined by pan-TRK immunohistochemistry. Immuno-stained tumor samples were scored by a certified pathologist. Gene fusions and other co-occurring gene alterations were identified by next generation sequencing. Patient characteristics and vital status were determined from linked hospital electronic health records (EHRs).

Patients were followed from 1 year before PTC diagnosis until death. 6/389 (1.5%) PTC patients had an NTRK gene fusion (all NTRK3); mean age 43.8 years (and none had comorbidities) at PTC diagnosis. Gene fusion partners were EML4 (n = 3), ETV6 (n = 2), and RBPMS (n = 1). Of 3/6 patients with complete EHRs, all received radioactive iodine ablation only and were alive at end of follow-up (median observation, 9.12 years).

“In conclusion, NTRK gene fusion is infrequent in patients with PTC. Linkage of biobank samples to EHRs is feasible in describing the characteristics and outcomes of patients with PTC and potentially other cancer types.”

DOI - https://doi.org/10.18632/oncotarget.28555

Correspondence to - Jihong Zong - [email protected]

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Keywords - cancer, NTRK gene fusion, papillary thyroid cancer, clinicogenomic, epidemiology, biobank

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Crossref is a non-profit organization that logs and updates citations for scientific publications. Each month, Crossref identifies a list of the most popular Oncotarget papers based on the number of times a DOI is successfully resolved.

Below are Crossref’s Top 10 Oncotarget DOIs published in 2023.

10: Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)

DOI: https://doi.org/10.18632/oncotarget.28355

Authors: Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Taylor Powell, Landon Goodreau, Emily K. Daniel, Xiaohua Rong, Tara Moore-Medlin, Alok R. Khandelwal, and Cherie-Ann O. Nathan

9: Novel inflammation-combined prognostic index to predict survival outcomes in patients with gastric cancer

DOI: https://doi.org/10.18632/oncotarget.28353

Authors: Noriyuki Hirahara, Takeshi Matsubara, Shunsuke Kaji, Hikota Hayashi, Yohei Sasaki, Koki Kawakami, Ryoji Hyakudomi, Tetsu Yamamoto, and Yoshitsugu Tajima

8: Crosstalk between triple negative breast cancer and microenvironment

DOI: https://doi.org/10.18632/oncotarget.28397

Authors: Karly Smrekar, Artem Belyakov and Kideok Jin

7: Systemic AL amyloidosis: current approach and future direction

DOI: https://doi.org/10.18632/oncotarget.28415

Authors: Maroun Bou Zerdan, Lewis Nasr, Farhan Khalid, Sabine Allam, Youssef Bouferraa, Saba Batool, Muhammad Tayyeb, Shubham Adroja, Mahinbanu Mammadii, Faiz Anwer, Shahzad Raza, and Chakra P. Chaulagain

6: Deciphering the mechanisms of action of progesterone in breast cancer

DOI: https://doi.org/10.18632/oncotarget.28455

Authors: Gaurav Chakravorty, Suhail Ahmad, Mukul S. Godbole, Sudeep Gupta, Rajendra A. Badwe, and Amit Dutt

5: Targeting cellular respiration as a therapeutic strategy in glioblastoma

DOI: https://doi.org/10.18632/oncotarget.28424

Authors: Enyuan Shang, Trang Thi Thu Nguyen, Mike-Andrew Westhoff, Georg Karpel-Massler, and Markus D. Siegelin

4: Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells

DOI: https://doi.org/10.18632/oncotarget.28382

Author: Mikhail V. Blagosklonny, M.D., Ph.D.

3: The immunoregulatory protein CD200 as a potentially lucrative yet elusive target for cancer therapy

DOI: https://doi.org/10.18632/oncotarget.28354

Authors: Anqi Shao and David M. Owens

2: Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss

DOI: https://doi.org/10.18632/oncotarget.28376

Authors: Maroun Bou Zerdan, Prashanth Ashok Kumar, Elio Haroun, Nimisha Srivastava, Jeffrey Ross, and Abirami Sivapiragasam

1: Using cancer proteomics data to identify gene candidates for therapeutic targeting

DOI: https://doi.org/10.18632/oncotarget.28420

Authors: Diana Monsivais, Sydney E. Parks, Darshan S. Chandrashekar, Sooryanarayana Varambally, and Chad J. Creighton

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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BUFFALO, NY- February 14, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Genetic and therapeutic landscapes in cohort of pancreatic adenocarcinomas: next-generation sequencing and machine learning for full tumor exome analysis.”

About 7% of all cancer deaths are caused by pancreatic cancer (PCa). PCa is known for its lowest survival rates among all oncological diseases and heterogenic molecular profile. Enormous amount of genetic changes, including somatic mutations, exceeds the limits of routine clinical genetic laboratory tests and further stagnates the development of personalized treatments.

In this new study, researchers P.A. Shatalov, N.A. Falaleeva, E.A. Bykova, D.O. Korostin, V.A. Belova, A.A. Zabolotneva, A.P. Shinkarkina, A. Yu Gorbachev, M.B. Potievskiy, V.S. Surkova, Zh V. Khailova, N.A. Kulemin, Denis Baranovskii, A.A. Kostin, A.D. Kaprin, and P.V. Shegai from the Ministry of Health of the Russian Federation, Pirogov Russian National Research Medical University, Federal Medical-Biological Agency, Moscow, and the Peoples Friendship University of Russia (RUDN University) aimed to build a mutational landscape of PCa in the Russian population based on full exome next-generation sequencing (NGS) of the limited group of patients.

“Applying a machine learning model on full exome individual data, we received personalized recommendations for targeted treatment options for each clinical case and summarized them in the unique therapeutic landscape.”

DOI - https://doi.org/10.18632/oncotarget.28512

Correspondence to - Denis Baranovskii - [email protected]

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Keywords - cancer, pancreatic cancer, tumor mutation burden, somatic mutations, artificial intelligence, machine learning

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BUFFALO, NY- February 12, 2024 – A new research paper was published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Differential expression of Mad2 gene is consequential to the patterns of histone H3 post-translational modifications in its promoter region in human esophageal cancer samples.”

Raw areca nut (AN) consumption increases esophageal squamous cell carcinoma (ESCC) due to overexpression of securin (pituitary tumor transforming gene1), causing chromosomal instability. Mitotic arrest deficient protein 2 (Mad2), a crucial spindle assembly checkpoint protein, is at risk of aneuploidy and tumor development when overexpressed or underexpressed. In this new study, researchers Chongtham Sovachandra Singh, Nabamita Boruah, Atanu Banerjee, Sillarine Kurkalang, Pooja Swargiary, Hughbert Dakhar, and Anupam Chatterjee from The Assam Royal Global University, University of Pennsylvania, LN Mithila University, University of Chicago Medicine, Nazareth Hospital, Laitumkhrah, and North-Eastern Hill University evaluated Mad2 status in human ESCC with AN consumption habits, revealing unclear molecular mechanisms.

Human ESCC samples (n = 99) were used for loss of heterozygosity analysis at 4q25-28, while 32 samples were used for expression analysis of Mad2, E2F1 genes, and Rb-phosphorylation. Blood samples were used for metaphase preparation. The Mad2 deregulation was assessed using chromatin immunoprecipitation-qPCR assay in the core promoter region, establishing its association with the pRb-E2F1 circuit for the first time.

“The study revealed overexpression and underexpression of Mad2, premature anaphase, and chromosome missegregation in all the samples.”

LOH pattern identified a deletion in D4S2975 in 40% of ESCC samples. The study reveals the deregulation of pRb-E2F1 circuit in all samples. 4q27 disruption could be a factor for Mad2 underexpression in AN-induced esophageal carcinogenesis, while overexpression may be due to the deregulation of the Rb-E2F1 circuit and consequently elevation of H3K4me3 and H3K9ac.

“Mad2 expression levels with chromosomal abnormalities can be a clinical biomarker, but further research is needed to understand pRb’s role in Mad2 down-regulation.”

DOI - https://doi.org/10.18632/oncotarget.28554

Correspondence to - Anupam Chatterjee - [email protected], [email protected]

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Keywords - cancer, Mad2 gene, histone methylation, histone acetylation, Rb-phosphorylation; esophageal cancer

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Thyroid cancer is a complex disease with various subtypes and clinical presentations. While some cases can be successfully treated with standard therapy, others present challenges due to resistance to treatment and the development of aggressive forms of the disease. In a new research perspective, researchers Mark Lee and Luc GT Morris from New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center discuss the recent research that has shed light on the role of genetic alterations in mediating both resistance to BRAF inhibition and anaplastic transformation in thyroid cancer. On January 24, 2024, their paper was published in Oncotarget, entitled, “Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.”

“An improved understanding of the molecular basis of thyroid cancer has led to the development of new targeted agents.”

Full blog - https://www.oncotarget.org/2024/02/08/genetic-alterations-in-thyroid-cancer-resistance-to-brafi-and-anaplastic-transformation/

DOI - https://doi.org/10.18632/oncotarget.28544

Correspondence to - Luc GT Morris - [email protected]

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Keywords - cancer, thyroid cancer, drug resistance, anaplastic transformation, BRAF inhibitors, PIK3CA

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