Oncotarget

A new research paper was published in Oncotarget’s Volume 13 on November 2, 2022, entitled, “MK256 is a novel CDK8 inhibitor with potent antitumor activity in AML through downregulation of the STAT pathway.”

Acute myeloid leukemia (AML) is the most lethal form of AML due to disease relapse. Cyclin dependent kinase 8 (CDK8) is a serine/threonine kinase that belongs to the family of Cyclin-dependent kinases and is an emerging target for the treatment of AML. MK256, a potent, selective, and orally available CDK8 inhibitor was developed to target AML.

In this new study, researchers Jen-Chieh Lee, Shu Liu, Yucheng Wang, You Liang, and David M. Jablons from the University of California San Francisco and Touro University sought to examine the anticancer effect of MK256 on AML.

“In CD34+/CD38- leukemia stem cells, we found that MK256 induced differentiation and maturation.”

Treatment of MK256 inhibited proliferation of AML cell lines. Further studies of the inhibitory effect suggested that MK256 not only downregulated phosphorylated STAT1(S727) and STAT5(S726), but also lowered mRNA expressions of MCL-1 and CCL2 in AML cell lines. Efficacy of MK256 was shown in MOLM-14 xenograft models, and the inhibitory effect on phosphorylated STAT1(S727) and STAT5(S726) with treatment of MK256 was observed in vivo.

Pharmacologic dynamics study of MK256 in MOLM-14 xenograft models showed dose-dependent inhibition of the STAT pathway. Both in vitro and in vivo studies suggested that MK256 could effectively downregulate the STAT pathway. In vitro ADME, pharmacological kinetics, and toxicity of MK256 were profiled to evaluate the drug properties of MK256.

“Our results show that MK256 is a novel CDK8 inhibitor with a desirable efficacy and safety profile and has great potential to be a promising drug candidate for AML through regulating the STAT pathway.”

DOI: https://doi.org/10.18632/oncotarget.28305

Correspondence to: Jen-Chieh Lee [email protected], Shu Liu - [email protected]

Keywords: AML, CDK8, kinase inhibitor, STAT pathway, xenograft

Video: https://www.youtube.com/watch?v=8bRgqTg9-c8

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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A new research paper was published in Oncotarget's Volume 13 on October 20, 2022, entitled, “Nectin-4 is widely expressed in head and neck squamous cell carcinoma.”

Nectin-4 has been successfully established as a target molecule in locally advanced and metastatic bladder cancer. An antibody-drug conjugate (enfortumab-vedotin) directed against nectin-4 has shown marked tumor remission rates in this tumor type, which is known for high expression rates of nectin-4.

As head and neck cancer and urothelial carcinomas share morphological and molecular similarities, researchers Christine Sanders, Jan-Frederic Lau, Dimo Dietrich, Sebastian Strieth, Peter Brossart, and Glen Kristiansen from University Medical Center Bonn and University Hospital Bonn aimed to evaluate Nectin-4 expression in head and neck squamous cell carcinoma (HNSCC).

A previously described and clinically characterized cohort of HNSCC (n = 159) was analyzed by immunohistochemistry for Nectin-4 expression. The expression data was correlated to clinico-pathological parameters including patient outcome.

Nectin-4 was found in 86.2% of HNSCC, with medium/high expression seen in 32.7% of cases. Non smokers and p16 positive HNSCC showed a higher expression of Nectin-4 (p < 0.005). There was no correlation of Nectin-4 with grading or tumor stage. Nectin-4 positive tumors showed significantly better survival (log rank p = 0.006).

“Similar to urothelial carcinoma, Nectin-4 is found in the majority of HNSCC, which clearly warrants further studies to clarify if HNSCC also respond to targeted therapy with enfortumab-vedotin. Moreover, expression of Nectin-4 is associated with HPV infection and may serve as a prognostic marker in HNSCC.”

DOI: https://doi.org/10.18632/oncotarget.28299

Correspondence to: Glen Kristiansen - Email: [email protected]

Video - https://www.youtube.com/watch?v=tDY21YpFsKc

Keywords: Nectin-4, enfortumab-vedotin, HNSCC, p16

About Oncotarget:

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Listen to a blog summary about a research perspective published in Volume 13 of Oncotarget, entiutled, "FSP1, a novel KEAP1/NRF2 target gene regulating ferroptosis and radioresistance in lung cancers."

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Ferroptosis is a type of cell death caused by the accumulation of iron and lipid peroxides in cells. Cancer cells are often resistant to ferroptosis, which allows them to survive and proliferate. Radioresistance is another common feature of cancer cells that allows them to resist the effects of radiation therapy.

A new research paper (published on April 22, 2022) identified ferroptosis suppressor protein 1 (FSP1) as a novel KEAP1/NRF2 target gene and demonstrated that FSP1 plays an essential role in NRF2-mediated ferroptosis resistance and radioresistance in KEAP1-deficient lung cancer cells.

Recently, researchers Nsengiyumva Emmanuel, Hongen Li, Jing Chen, and Yilei Zhang from Xi’an Jiaotong University, Ruyang People’s Hospital and Shaanxi Jiuzhou Biomedical Science and Technology Group wrote a paper about the implications of these findings. On October 19, 2022, their research perspective was published in Oncotarget’s Volume 13, entitled, “FSP1, a novel KEAP1/NRF2 target gene regulating ferroptosis and radioresistance in lung cancers.”

“In a recent study by Pranavi Koppula et al. from The University of Texas MD Anderson Cancer Center, FSP1 was demonstrated as a novel target of NRF2 and to play a vital role in KEAP1/NRF2-mediated ferroptosis regulation [13], which reveals the important role of genetic regulation of FSP1 in cancer development.”

Full blog - https://www.oncotarget.org/2022/11/02/new-target-fights-ferroptosis-and-radio-resistance-in-lung-cancers/

DOI - https://doi.org/10.18632/oncotarget.28301

Correspondence to - Yilei Zhang - [email protected]

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Keywords - KEAP1/NRF2, lung cancer, ferroptosis, radioresistance, therapy

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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BUFFALO, NY- October 27, 2022 – On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by MEDLINE/PubMed and PubMed Central/PubMed.

***

The United States government is firmly committed to making credible biomedical research available to the public. In operation since 1996, PubMed is an online biomedical literature database operated by the U.S. National Institutes of Health (NIH). PubMed provides free access to over 34 million citations from MEDLINE, PubMed Central (PMC) and the National Center for Biotechnology Information databases.

Started back in the 1960s, MEDLINE is a large bibliographic citation and abstract database for life science articles in journals and other scientific publications. MEDLINE now contains more than 29 million references to articles in over 5,200 journals. In 2000, PMC was launched as a free, full-text archive of biomedical and life sciences journal literature.

Both MEDLINE and PMC are operated by the NIH’s National Library of Medicine. Importantly, PubMed and MEDLINE use the same controlled vocabulary thesaurus, called Medical Subject Headings, or MeSH, to ensure that content is easily searchable and properly indexed. The vast scope of scholarly publications in MEDLINE is why Oncotarget is proud to have its papers indexed by this database.

Oncotarget, launched in 2010, is a peer-reviewed, open-access and primarily oncology-focused biomedical journal. This journal has international reach—publishing research from world-renowned institutions. The cornerstones of Oncotarget’s publishing practices are insightful peer review, scientific integrity, rigorous ethical standards, up-to-date tools and resources, and a commitment to local and scientific communities. Oncotarget aims to maximize research impact, eliminate borders between specialties and foster the application of basic and clinical science.

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A new research paper was published in Oncotarget's Volume 13 on October 19, 2022, entitled, “Therapeutic efficacy of the humanized JAA-F11 anti-Thomsen-Friedenreich antibody constructs H2aL2a and H3L3 in human breast and lung cancer xenograft models.”

The Thomsen-Friedenreich antigen (TF-Ag-α) is found on ~85% of human carcinomas but is cryptic on normal tissue. The humanized, highly specific hJAA-F11-H2aL2a and -H3L3 antibodies target TF-Ag-α without binding to TF-Ag-beta (found on surface glycolipids of some normal cells).

“The relative affinity of H3L3 is 17 times that of H2aL2a, which would seem to favor superior efficacy, however, increased affinity can result in less tumor penetration.”

In a new study, researchers Diala Ghazal, Fatma Zalzala, John C. Fisk, Swetha Tati, Loukia G. Karacosta, Susan Morey, James R. Olson, Sally Quataert, Grace K. Dy, and Kate Rittenhouse-Olson from For-Robin, Inc, University at Buffalo, University of Rochester, and Roswell Park Comprehensive Cancer Center Buffalo aimed to assess the potential therapeutic efficacy of these antibodies by treating four human cancer- mouse xenograft models with H2aL2a and H3L3. The tumor xenograft models used were human non-small cell lung cancer, H520, and small cell lung cancer, HTB171 in nude mice and human triple negative breast cancer, MDA-MB-231 and HCC1806 in SCID mice.

H2aL2a significantly decreased tumor growth in both breast and both lung cancer models. H2aL2a showed statistically equal or better efficacy than H3L3 and has superior production capabilities. These results suggest that H2aL2a may be superior as a naked antibody, as an antibody drug conjugate or as a radiolabeled antibody, however the higher affinity of H3L3 may lead to better efficacy in bi-specific therapies in which the binding is decreased due to the presence of only one TF-Ag-α binding site.

“In conclusion, both H2aL2a and H3L3 humanized antibodies to TF-Ag-α show efficacy in in vivo xenograft models of human tumors in SCID and nude mice and thus hold promise as therapeutics for breast and lung cancer. H2aL2a significantly decreased tumor growth rate in both breast cancer and both lung cancer models tested. H2aL2a is equal to or better than H3L3 in four of the four models and H2aL2a cell lines have far superior antibody production capabilities under the conditions tested.”

DOI: https://doi.org/10.18632/oncotarget.28282

Correspondence to: Kate Rittenhouse-Olson - [email protected]

Keywords: hJAA-F11, TF-Ag, Thomsen-Friedenreich antigen, tumor immunotherapy, translational oncology

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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A new research paper was published in Oncotarget's Volume 13 on October 19, 2022, entitled, “Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer.”

Platelet-derived growth factor (PDGF) signaling, besides other growth factor-mediated signaling pathways like vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), seems to play a crucial role in tumor development and progression.

Previously, researchers Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Amrendra K. Ajay, Larissa Camila Ribeiro de Souza, Minghua Cao, Yueming Luo, Petra Hoegger, Carmen M. Ribas, Jurandir M. Ribas-Filho, Osvaldo Malafaia, Reinhard Lissner, Li-Li Hsiao, and Ana Maria Waaga-Gasser, from Harvard Medical School, Shenzhen Traditional Chinese Medicine Hospital, University of Wuerzburg, and Mackenzie Evangelical Faculty of Paraná, recently provided evidence for upregulation of PDGF expression in UICC stage I–IV primary colorectal cancer (CRC) and demonstrated PDGF-mediated induction of PI3K/Akt/mTOR signaling in CRC cell lines. In their new study, the researchers sought to follow up on our previous findings and explore the alternative receptor cross-binding potential of PDGF in CRC.

“Our analysis of primary human colon tumor samples demonstrated upregulation of the PDGFRβ, VEGFR1, and VEGFR2 genes in UICC stage I-III tumors.”

Immunohistological analysis revealed co-expression of PDGF and its putative cross-binding partners, VEGFR2 and EGFR. The team then analyzed several CRC cell lines for PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 protein expression. They found these receptors to be variably expressed amongst the investigated cell lines.

Interestingly, whereas Caco-2 and SW480 cells showed expression of all analyzed receptors, HT29 cells expressed only VEGFR1 and VEGFR2. However, stimulation of HT29 cells with PDGF resulted in upregulation of VEGFR1 and VEGFR2 expression despite the absence of PDGFR expression and mimicked the effect of VEGF stimulation. Moreover, PDGF recovered HT29 cell proliferation under simultaneous treatment with a VEGFR or EGFR inhibitor.

“Our results provide some of the first evidence for PDGF cross-signaling through alternative receptors in colorectal cancer and support anti-PDGF therapy as a combination strategy alongside VEGF and EGF targeting even in tumors lacking PDGFR expression.”

DOI: https://doi.org/10.18632/oncotarget.28281

Correspondence to: Ana Maria Waaga-Gasser - [email protected]

Keywords: PDGF, VEGFR, EGFR, bypassed signaling, colorectal cancer

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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Listen to a blog summary of a recently published research paper in Volume 13 of Oncotarget, entitled, "HDAC inhibitors suppress protein poly(ADP-ribosyl)ation and DNA repair protein levels and phosphorylation status in hematologic cancer cells: implications for their use in combination with PARP inhibitors and chemotherapeutic drugs."

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Chromatin constitutes chromosomes in eukaryotic cells and comprises DNA and proteins. Chromosomes produce proteins and enzymes that are essential for cellular function and maintenance, including DNA repair. A critical process for DNA repair is poly(ADP-ribosyl)ation, or PARylation.

PARylation is triggered by poly(ADP ribose) polymerase (PARP) enzymes. When DNA becomes damaged, PARP enzymes bind to the damaged location in the cell. In cancer cells, however, this natural process can be counterproductive in respect to cancer treatment. PARylation can produce DNA repair mechanisms in cancer cells that can lead to the evasion of cell death, and even drug resistance. Inhibiting PARylation may be a viable therapeutic strategy for cancer treatment.

Histones, the main proteins that constitute chromatin, undergo post-translational modifications that regulate gene expression. Histone acetylation is an important epigenetic process that affects gene expression by relaxing the chromatin structure, making chromatin remodeling more feasible. Histone deacetylases (HDACs) are enzymes that can have the opposite effect. Histone deacetylation makes the chromatin more compact and difficult to remodel. The overexpression of HDAC has also been associated with tumorigenesis. Histone deacetylase inhibitors (HDACi) are a class of therapeutics that have shown promise in the treatment of hematologic malignancies (blood cancer) and solid tumors.

In a new study, researchers Benigno C. Valdez, Yago Nieto, Bin Yuan, David Murray, and Borje S. Andersson from the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center and the Cross Cancer Institute’s Department of Experimental Oncology at the University of Alberta investigate the efficacy of HDACi in combination with PARP inhibitors (PARPi) and chemotherapeutic drugs to treat hematologic cancer. On October 14, 2022, their research paper was published in Volume 13 of Oncotarget, entitled, “HDAC inhibitors suppress protein poly(ADP-ribosyl)ation and DNA repair protein levels and phosphorylation status in hematologic cancer cells: implications for their use in combination with PARP inhibitors and chemotherapeutic drugs.”

Full blog - https://www.oncotarget.org/2022/10/19/synergy-of-hdaci-parpi-and-chemotherapeutics-against-blood-cancer/

DOI - https://doi.org/10.18632/oncotarget.28278

Correspondence to - Benigno C. Valdez - [email protected]

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Keywords - poly(ADP-ribosyl)ation, HDAC inhibitors, PARP inhibitors, chemotherapy, hematologic malignancy

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 13 on October 8, 2022, entitled, “Effectiveness of radiotherapy for local control in T3N0 rectal cancer managed with total mesorectal excision: a meta-analysis.”

The total mesorectal excision (TME) significantly improves rectal cancer outcomes. Radiotherapy’s benefit in T3N0 rectal cancer patients managed with TME has not been clearly demonstrated.

In a new study, researchers Michael Jonathan Kucharczyk, Andrew Bang, Michael C. Tjong, Stefania Papatheodoru, and Jesus C. Fabregas from Nova Scotia Cancer Centre, Dalhousie University, BC Cancer – Vancouver, Princess Margaret Cancer Centre, Harvard T.H. Chan School of Public Health, and University of Florida Health Cancer Center conducted a systematic review and meta-analysis to determine whether radiotherapy alteres the risk of locoregional recurrence (LR) in T3N0 rectal cancer patients managed with a TME.

“This systematic review identified unique 7 retrospective cohort studies which evaluated whether radiotherapy reduces LR in T3N0 rectal cancer patients managed with TME.”

The studies indexed on PubMed or Embase were systematically searched from inception to October 18, 2020. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were observed for the literature search, study screening and data extraction; the Newcastle Ottawa Scale evaluated bias; Grades of Recommendation, Assessment, Development, and Evaluation Working Group system evaluated certainty. All were performed independently by at least two investigators.

Studies that reported LR data specific to T3N0 rectal cancer patients managed with TME, treated with and without radiotherapy, were included. Data was pooled using a random-effects model. Meta-analyses of the relative risk of local recurrence were conducted.

Five retrospective cohort studies involving 932 unique patients reported LR outcomes; no prospective studies met eligibility criteria. Median follow-up ranged from 38.4–78 months. Adjuvant radiotherapy was provided in 3 studies. Chemotherapy was delivered and reported in 4 studies, providing both concurrent and adjuvant chemotherapy.

A non-significant LR benefit with radiotherapy’s addition was estimated. Meta-analysis of exclusively retrospective cohort studies was concerning for biased results. Adequately powered randomized trials are warranted.

“With low certainty, this meta-analysis observed a non-significant benefit with radiotherapy to 5-year LR rates among T3N0 rectal cancer patients that received a TME. Until a pragmatically sized randomized control trial is completed, our research adds a layer of data to facilitate informed and personalized treatment decisions for T3N0 rectal cancer patients, albeit with potential significant bias from solely relying on retrospective cohort studies.”

DOI: https://doi.org/10.18632/oncotarget.28280

Correspondence to: Michael Jonathan Kucharczyk - [email protected]

Keywords: radiotherapy, meta-analysis, systematic review, rectal cancer, total mesorectal excision

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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A new research paper was published in Oncotarget’s Volume 13 on October 8, 2022, entitled, “In vitro chemotherapy-associated muscle toxicity is attenuated with nutritional support, while treatment efficacy is retained.”

Muscle-wasting and treatment-related toxicities negatively impact prognosis of colorectal cancer (CRC) patients. Specific nutritional composition might support skeletal muscle and enhance treatment support.

In this new in vitro study, researchers Liza A. Wijler, Francina J. Dijk, Hanil Quirindongo, Danielle A.E. Raats, Bram Dorresteijn, Matthew J.W. Furber, Anne M. May, Onno Kranenburg, and Miriam van Dijk, from University Medical Centre Utrecht, Danone Nutricia Research and Utrecht University, assessed the effect of nutrients eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), L-leucine, and vitamin D3 as single nutrients or in combination on chemotherapy-treated C2C12-myotubes and specific CRC-tumor cells.

Using C2C12-myotubes, the effects of chemotherapy (oxaliplatin, 5-fluorouracil, oxaliplatin+5-fluorouracil and irinotecan) on protein synthesis, cell-viability, caspase-3/7-activity and lactic acid dehydrogenase (LDH)-activity were assessed. Addition of EPA, DHA, L-leucine and vitamin D3 and their combination (SNCi) were studied in presence of above chemotherapies. Tumor cell-viability was assessed in oxaliplatin-treated C26 and MC38 CRC cells, and in murine and patient-derived CRC-organoids.

While chemotherapy treatment of C2C12-myotubes decreased protein synthesis, cell-viability and increased caspase-3/7 and LDH-activity, SNCi showed improved protein synthesis and cell viability and lowered LDH activity. The nutrient combination SNCi showed a better overall performance compared to the single nutrients. Treatment response of tumor models was not significantly affected by addition of nutrients.

“This in vitro study shows protective effect with specific nutrition composition of C2C12-myotubes against chemotherapy toxicity, which is superior to the single nutrients, while treatment response of tumor cells remained.”

DOI: https://doi.org/10.18632/oncotarget.28279

Correspondence to: Miriam van Dijk – Email: [email protected]

Keywords: C2C12 myotubes, chemotherapy, chemotherapy-associated toxicity, colorectal cancer, nutrients, tumor (organoid) cells

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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Blog summary of a trending research paper published by Oncotarget, entitled, "Complementary CRISPR genome-wide genetic screens in PARP10-knockout and overexpressing cells identify synthetic interactions for PARP10-mediated cellular survival."

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Genetic interactions involved in the survival of cancer cells are potential therapeutic targets in personalized cancer therapy. “Synthetic lethal” is a type of genetic interaction where the knockout of one gene can cause cell death but only in the presence of another dependent gene. Cancer researchers view synthetic lethality screening as a powerful tool in precision medicine.

“Identifying genetic susceptibilities based on PARP10 expression levels is thus potentially relevant for finding new targets for precision oncology.”

Poly-ADP-ribose polymerase 10, or PARP10, is a nuclear protein that is overexpressed in multiple cancers. Genetic susceptibilities based on PARP10 expression levels in an individual may be potential targets for personalized cancer therapy. In a new study, researchers Jude B. Khatib, Emily M. Schleicher, Lindsey M. Jackson, Ashna Dhoonmoon, George-Lucian Moldovan, and Claudia M. Nicolae, from the Department of Biochemistry and Molecular Biology at Penn State College of Medicine, used CRISPR-based, genome-wide genetic screens to identify potential synthetic lethality interactions with PARP10-overexpressing and -knockout cancer cells. On September 28, 2022, their research paper was published in Oncotarget and entitled, “Complementary CRISPR genome-wide genetic screens in PARP10-knockout and overexpressing cells identify synthetic interactions for PARP10-mediated cellular survival.”

“Here, we employed complementary CRISPR loss-of-function genome-wide screening to identify genes required for proliferation of PARP10-overexpressing and PARP10-knockout cells.”

Full blog - https://www.oncotarget.org/2022/10/07/crispr-screens-identify-novel-targets-for-personalized-cancer-therapy/

DOI - https://doi.org/10.18632/oncotarget.28277

Correspondence to - Claudia M. Nicolae - [email protected]

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Keywords - PARP10, ATM, CRISPR screens, genome stability, cancer cell proliferation

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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