Oncotarget

PRESS RELEASE https://www.eurekalert.org/pub_releases/2020-05/ijl-aes052720.php#

Volume 11, Number 21 of @Oncotarget reported that eligible patients with stable or responding mPDA after 6 months on chemotherapy were randomized 1:1 to metformin alone or with rapamycin, stratified by prior treatment with FOLFIRINOX. Metformin +/ rapamycin maintenance for mPDA was well-tolerated and several patients achieved stable disease associated with exceptionally long survival.

Dr. Dung T. Le from The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21287 said, "Pancreatic ductal adenocarcinoma (PDA) is aggressive cancer with high mortality at all stages and limited treatment options in the advanced setting."

Metformin is an antidiabetic drug in the biguanide class of agents which inhibits mTOR complex 1 primarily through AMP-kinase activation.

A synergistic effect of the combination of metformin with rapamycin was suggested by preclinical studies demonstrating enhanced inhibition of mTOR in a pancreatic cancer cell line and better growth inhibition of pancreatic cancer cells in a xenograft tumor model with the combination than either agent alone.

Based on this, they conducted an exploratory study of metformin with or without rapamycin in patients with mPDA in the maintenance setting.

The Le Research Team concluded in their Oncotarget Research Article, "the administration of metformin with or without rapamycin in patients with mPDA who achieve a response to chemotherapy is well-tolerated and was associated with better than expected overall survival in this study. Additional studies are needed to prospectively evaluate the role of these agents compared to a maintenance chemotherapy or observation only approach."

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DOI - https://doi.org/10.18632/oncotarget.27539

Full text - https://www.oncotarget.com/article/27586/text/

Correspondence to - Dung T. Le - [email protected]

Keywords - pancreatic cancer, mTOR inhibition, maintenance therapy, metformin

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Human papillomavirus confers radiosensitivity in oropharyngeal cancer cells

The cover for issue 16 of Oncotarget features Figure 6, "Radiation-induced DNA damage measured by γ-H2AX foci formation at a specified time point after 10 Gy irradiation," by Zhang, et al.

HPV-negative UM-SCC4 with and without transfection of HPV E6 oncoprotein, HPV-negative UPCI-SCC-089, and HPV-positive UPCI-SCC-099 cell lines were used in this study.

The survival fraction after 10 Gy was significantly lower for the HPV-positive SCC-099 cells than for the HPV-negative cells.

In contrast, the HPV-positive UPCI-SCC-099 cells displayed persistent -H2AX activity; the expression of -H2AX remained high at 48 hours post-radiation.

HPV-positive SCC-099 cells were more likely to show the classical apoptotic changes of increased cell thickness and increased motility after radiation.

Dr. Angela Hong from The Faculty of Medicine and Health, Central Clinical School at The University of Sydney as well as The Department of Radiation Oncology, Chris O’Brien Lifehouse said, "Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is clinically and biologically distinct from smoking-related (HPV-negative) OPSCC."

The overall better prognosis seen in HPV-positive OPSCC may be related to the disease's response to radiation therapy.

Radiation therapy plays an important role in the management of OPSCC, either as definitive therapy or as adjuvant therapy after surgery.

Cellular response to radiation treatment can be observed with a label-free dynamic Holo Monitor, which allows non-invasive visualization and live-cell analysis of radiation responses and the migration potential of cancer cells.

The Hong Research Team concluded in their Oncotarget Research Paper that the enhanced cell motility is due to disruption of the actin-membrane interactions by radiation, initiating the membrane blubbing and generating force to enhance cell motility.

In contrast, the HPV-negative UPCI-SCC-089 cells exhibited cell flattening and enlargement, which are the common cytological features of cell cycle blockage.

DOI - https://doi.org/10.18632/oncotarget.27535

Full text - https://www.oncotarget.com/article/27535/text/

Correspondence to - Matthew H. Taylor - [email protected]

Keywords - radiosensitivity, oropharyngeal cancer, human papillomavirus, double-strand break, radiobiology

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The cover for issue 6 of Oncotarget features Figure 3, "The effect of NCs treatments on routine lab results during disease and recovery progress," by Ben-Nun-Shaul, et al.

Numerous previous attempts to develop therapeutic treatments, directed at discreet targets of the sepsis cascade, could not cope with the complex pathophysiology of sepsis and failed.

Studies in a severe rat sepsis model showed that pre-treatment by NCs led to a dramatic increase in survival, from zero to 75%.

Further studies are needed to determine whether when applied after sepsis onset, the NCs still improve outcomes.

Dr. Arieh Eden from the Department of Anesthesiology, Critical Care and Pain Medicine at the Lady Davis Carmel Medical Center in Haifa, Israel said in their Oncotarget Research Paper, "Sepsis affects millions of individuals annually worldwide, with a mortality of greater than 25%" and according to the Cancer | Sepsis Alliance "Having cancer and undergoing certain treatments for cancer, such as chemotherapy, can result in a weakened immune system, putting you at higher risk for developing an infection that could lead to sepsis. Sometimes incorrectly called blood poisoning, sepsis is the body's often deadly response to infection." https://www.sepsis.org/sepsisand/cancer/

It accounts for more than 50% of hospital deaths, with mortality rates of 10 20% for sepsis, 20 40% for severe sepsis, and 40 80% for septic shock.

In the present study, the authors tested the hypothesis, based on their earlier unpublished research, that empty SV40 capsids would improve the outcome of sepsis.

Twenty years ago we established a procedure for the production of empty SV40 capsid, in order to develop a safe gene delivery vector, to be assembled in vitro from empty capsids and plasmid DNA of choice.

The underlying mechanism was up-regulation of Hsp/c70 and induction of the PI3K/Akt survival pathway, both seen exclusively in kidney tissue of NCs treated mice.

That study revealed that SV40 and/or its NCs elicit concurrently opposing pathways: cellular stress response, pro-apoptotic host defense, and Akt-1 survival pathway.

The Eden Research Team concluded in their Oncotarget paper, that these findings, and the dynamic adjustment of the therapeutic pathways to the recovery course, lead them to suggest that the effect of the NCs is tailored both to the type and to the temporal course of the injury, implying a general homeostatic activity.

The homeostatic nature of the NC activity is also manifested in their negligible effect on the normal control rats.

Full text - https://doi.org/10.18632/oncotarget.27448

Correspondence to - Ariella Oppenheim - [email protected] and Arieh Eden - [email protected]

Keywords - sepsis, empty SV40 capsids, RNAseq, signaling, cellular functions

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PRESS RELEASE: Overall survival in patients with lung adenocarcinoma harboring “niche” mutations: an observational study

The cover for issue 5 of Oncotarget features Figure 2, "Survival curves in the KRAS, EGFR, and niche mutations cohorts," by Aramini, et al.

Mutations were observed in all genes studied, except c-MET, DDR2, MAP2K1, and RET.

The multivariable analysis showed that:

Niche mutations had higher mortality than EGFR mutations

KRAS mutations had higher mortality than EGFR mutations, and

Niche mutations presented similar mortality to KRAS mutations.

Niche mutations exhibited an increased risk of death when compared with EGFR mutations and a similar risk of death when compared with KRAS mutations.

Dr. Beatrice Aramini from the Division of Thoracic Surgery in Department of Medical and Surgical Sciences at the University of Modena and Reggio Emilia in Modena Italy said in their Oncotarget Research Paper, "In the last century, carcinoma of the lung has progressed from an uncommon and obscure disease to the most common cancer in the world, and the most common cause of death from cancer."

In addition to these somatic mutations, which are the most frequent, other mutations in several genes have been discovered, including BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET mutations.

Moreover, the prevalence of the RET mutation in adenocarcinoma was estimated to be 1.7%, and the prevalence of DDR2 mutation in lung cancer was 2.2%.

With regard to treatment, discoveries of gene mutations have allowed the development of targeted therapies, which are considered more effective for survival than chemotherapy in patients with advanced mutated disease.

Considering the potential aggressiveness of niche mutations in this context, the technological advances of next-generation sequencing, which is currently used in clinical practice, represents a precise approach to identifying a large panel of mutations in oncologic patients.

The Armini Research Team concluded, "The correct selection of mutations will be helpful in terms of the greater efficacy of treatment in association with better prognosis and a higher quality of life for oncologic patients."

Full text - https://doi.org/10.18632/oncotarget.27472

Correspondence to - Beatrice Aramini,[email protected]

Keywords - somatic mutations, non-small cell lung cancer (NSCLC), lung cancer treatment, overall survival, target therapy

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Oncotarget interviews Dr. Beatrice Aramini from the University of Modena and Reggio Emilia in Modena Italy about their Featured Cover Paper for Volume 11 Issue 5 titled "Overall survival in patients with lung adenocarcinoma harboring “niche” mutations: an observational study"

PRESS RELEASE: The cover for issue 5 of Oncotarget features Figure 2, "Survival curves in the KRAS, EGFR, and niche mutations cohorts," by Aramini, et al.

Mutations were observed in all genes studied, except c-MET, DDR2, MAP2K1, and RET.

The multivariable analysis showed that:

Niche mutations had higher mortality than EGFR mutations

KRAS mutations had higher mortality than EGFR mutations, and

Niche mutations presented similar mortality to KRAS mutations.

Niche mutations exhibited an increased risk of death when compared with EGFR mutations and a similar risk of death when compared with KRAS mutations.

Dr. Beatrice Aramini from the Division of Thoracic Surgery in Department of Medical and Surgical Sciences at the University of Modena and Reggio Emilia in Modena Italy said in their Oncotarget Research Paper, "In the last century, carcinoma of the lung has progressed from an uncommon and obscure disease to the most common cancer in the world, and the most common cause of death from cancer."

In addition to these somatic mutations, which are the most frequent, other mutations in several genes have been discovered, including BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET mutations.

Moreover, the prevalence of the RET mutation in adenocarcinoma was estimated to be 1.7%, and the prevalence of DDR2 mutation in lung cancer was 2.2%.

With regard to treatment, discoveries of gene mutations have allowed the development of targeted therapies, which are considered more effective for survival than chemotherapy in patients with advanced mutated disease.

Considering the potential aggressiveness of niche mutations in this context, the technological advances of next-generation sequencing, which is currently used in clinical practice, represents a precise approach to identifying a large panel of mutations in oncologic patients.

The Armini Research Team concluded, "The correct selection of mutations will be helpful in terms of the greater efficacy of treatment in association with better prognosis and a higher quality of life for oncologic patients."

Full text - https://doi.org/10.18632/oncotarget.27472

Correspondence to - Beatrice Aramini,[email protected]

Keywords - somatic mutations, non-small cell lung cancer (NSCLC), lung cancer treatment, overall survival, target therapy

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The cover for issue 68 of Oncotarget features Figure 4, "Gene expression changes to the TME demonstrate sequential development of innate and adaptive immune responses," by Leong, et al.

Intratumoral injection of SD-101 induces significant anti-tumor immunity in preclinical and clinical studies, especially when combined with PD-1 blockade.

Combination therapy generated CD8+ T cell-dependent immunity leading to rejection of both non-injected and injected tumors and long-term survival, even in very large tumors.

Dr. Mary J. Janatpour from Dynavax Technologies, Inc., Emeryville, CA 94608, USA said, "It has long been appreciated by cancer researchers that the phenotypic heterogeneity and progressive evolution of malignant tumors minimize the chance that any agent targeting a single molecular pathway could effectively cure advanced cancer."

The authors have previously demonstrated in mouse tumor models that employing the innate immune system to prime a T cell response, in combination with checkpoint blockade, results in deep and durable anti-tumor efficacy.

These high response rates were observed in both injected and non-injected tumor lesions and patients with PD-L1 negative tumors, indicating low levels of basal immune inflammation, responded as well as patients with PD-L1 positive tumors.

Intratumorally administered SD-101 exerts its priming activity and ultimate orchestration of a systemic anti-tumor T cell response through multiple mechanisms.

The production of interferon stimulates tumor cell killing by natural killer cells, with ensuing tumor antigen release, and induces chemokines that attract T cells back to the tumor bed.

Low-dose cyclophosphamide decreases Tregs. Additional impacted biological activities have been described, such as:

increased interferon production,

induction of immunogenic cell death,

increases in effector T cells, and

increases in functional NK cells,

...likely to be complementary to SD-101 activity by virtue of modulation of the TME. By administering SD-101 locally, rather than systemically, the researchers demonstrate that localized SD-101 injection combined with systemically administered low-dose cyclophosphamide confers an anti-tumor response at non-injected sites.

The Janatpour research Team concluded that taken together, the intratumoral SD-101 plus low-dose CY combination may complement existing checkpoint blockade therapies in patients to improve efficacy in the clinic and extend the benefits of immunotherapy to more patients.

Full text - https://doi.org/10.18632/oncotarget.27322

Correspondence to - Mary J. Janatpour - [email protected]

Keywords - TLR9, SD-101, cyclophosphamide, immune therapy, innate immunity

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open-access biomedical journal covering research on all aspects of oncology.

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Prof. Malka Cohen-Armon and her team at Tel Aviv University's Sackler Faculty of Medicine choose Oncotarget for a third time amongst leading medical journals like The New England Journal of Medicine, Nature or The Lancet to publish groundbreaking preclinical cancer research.

Here's more: Recent reports demonstrate an exclusive eradication of a variety of human cancer cells by the modified phenanthridine PJ34. The efficient eradication of malignant cells in human pancreatic cancer xenografts presents a new model of pancreas cancer treatment.

Prof. Malka Cohen-Armon from the Sackler Faculty of Medicine & the Sagol School of Neuroscience at Tel-Aviv University in Tel-Aviv, Israel said, "Despite a substantial advance in cancer treatment, pancreatic ductal adenocarcinoma (PDAC) have a limited response to current treatments, and a low 5-years survival rate of about 6%."

Furthermore, the authors identified phenanthrenes acting as PARP1 inhibitors that efficiently eradicate a variety of human cancer cells without impairing benign cells.

However, their PARP1 inhibition per-se does not impair nor eradicate human malignant cells, including pancreatic cancer cells, PANC1.

In contrast, at higher concentrations than those causing PARP1 inhibition, PJ34, Tiq-A and Phen eradicate a variety of human cancer cells by mitotic catastrophe cell death.

Here, the efficacy of PJ34 to eradicate human pancreas cancer cells is tested in cell cultures and in xenografts.

In xenografts, eradication of human PANC1 cells deduced from a massive reduction of human proteins in the tumors was measured 30 days after the treatment with PJ34 has been terminated.

The Cohen-Armon Research Team concluded that PJ34, which is permeable in the cell membrane, accessed and eradicated human PDAC cells in xenografts without impairing normal proliferating cells infiltrated into the tumors. The team is 2-3 years away from clinical human trials.

Full text - https://doi.org/10.18632/oncotarget.2...

Correspondence to - Malka Cohen-Armon - [email protected]

Keywords - PJ34, pancreas cancer, stroma, PANC1 cancer xenografts

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The cover for issue 2 of Oncotarget features Figure 5, "MASPIN can prevent the formation of UPA - UPA-receptor complex by a single step, and thus decrease the possibility of the abnormal degradation of the ECM, the development metastasis and angiogenesis," by Fodor, et al.

In the present study, the research team investigated AEZS-108 induced cytotoxicity and the altered mRNA expression profile of regulatory factors related to angiogenesis and metastasis in LHRH receptor-positive OCM3 cells.

Their results show that AEZS-108 upregulates the expression of MASPIN/SERPINB5 tumor suppressor gene, which is downregulated in the normal uvea and UM specimens independently from the LHRH receptor-ligand interaction.

In order to investigate the mechanism of the induction of MASPIN by AEZS-108, OCM3 cells were treated with free DOX, D-Lys6 LHRH analog, or AEZS-108.

Dr. Gabor Halmos from the University of Debrecen, Department of Biopharmacy, in Debrecen, Hungary as well as the Veterans Affairs Medical Center, Endocrine, Polypeptide and Cancer Institute, in Miami, FL, USA said, "Although uveal melanoma (UM) is a rare disease, it is the most prevalent lethal ophthalmological tumor."

The discovery of specific receptors for peptide hormones on cancer cells has led to the development of cytotoxic or radiolabeled hormone analogs that are appropriate for tumor localization and targeted therapy.

AEZS-108 guides the chemotherapeutic agent specifically to those tumors that express LHRH-receptors, which could result in targeted cytotoxicity and less damage to healthy tissues.

The authors reported that previously OCM3 UM cell line expresses the receptor of LHRH localized on the cell membrane and in the cytoplasm, rendering them susceptible to AEZS-108 uptake and the detection of the LHRH receptor in OCM3 cells has led to the use of AEZS-108 for targeted therapy of the tumor.

Moreover, that the OCM3 UM cell line expresses the LHRH receptor and LHRH rendering them susceptible to AEZS-108 uptake.

The Halmos Research Team concluded, "In summary, our data confirmed previous results showing LHRH receptor expression in OCM3 cells, a UM in vitro model. Furthermore, we report for the first time that AEZS-108 causes changes in the expression of genes that are involved in angiogenesis and ECM degradation and which might inhibit cell proliferation and induce apoptosis in OCM3 cells.

These findings suggest that AEZS-108 plays a pivotal role in the regulation of angiogenesis and tumor suppression. Taken together, targeted cytotoxic LHRH analogs, such as AEZS-108, might serve as an effective treatment for patients with LHRH receptor-positive uveal melanoma.”

Keywords - uveal melanoma; luteinizing hormone-releasing hormone (LHRH) receptor; angiogenesis; MASPIN/SERPINB5; AEZS-108 (AN-152/Zoptarelin Doxorubicin Acetate

DOI - https://doi.org/10.18632/oncotarget.27431

Full text - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=27431&path%5B%5D=89358

Correspondence to - Gabor Halmos, email: [email protected]

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PRESS RELEASE https://www.eurekalert.org/pub_releases/2019-10/ijl-oeb101019.php

The 2019 Nobel Prize in Physiology or Medicine has been awarded jointly to Oncotarget Editorial Board Members William G. Kaelin Jr. and Gregg L. Semenza for their discoveries of "how cells sense and adapt to oxygen availability", said the Nobel Committee. The pair was named alongside the UK physician-scientist Sir Peter J. Ratcliffe.

The Nobel Committee made the announcement Monday at the Karolinska Institute in Stockholm, Sweden and the discoveries have implications for how we understand and potentially treat a range of conditions like cancer, heart attack, stroke and anemia. The Nobel Laureates identified molecular machinery that regulates the activity of genes in response to varying levels of oxygen.

Gregg L. Semenza is a professor of Medicine at Johns Hopkins University and Director of the Vascular Research Program at Johns Hopkins Institute for Cell Engineering. Semenza received the Nobel Prize for the discovery of hypoxia-inducible factor 1 (HIF-1), protein, which controls genes in response to changes in oxygen availability.

William G. Kaelin Jr., a Professor of medicine at Harvard Medical School and the Dana-Farber Cancer Institute, earned his share of the Nobel Prize for his work investigating a genetic syndrome called Von Hippel-Lindau's (VHL) disease. Kaelin discovered that the VHL protein prevents the onset of cancer and is involved in the oxygen sensing mechanism through its interaction with HIF-1.

The awarded mechanism has a fundamental importance in physiology, and has far-reaching implications for the treatment of lw-oxygen health conditions such as coronary artery disease and tumor growth.

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Both William G. Kaelin and Gregg L. Semenza are founding members of Oncotarget, launched in 2010. Oncotarget is a weekly peer-reviewed open access bio-medical journal covering research on all aspects of oncology. The editors-in-chief are Mikhail (Misha) Blagosklonny and Andrei V. Gudkov.

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"Genomic characterization of metastatic ultra-hypermutated interdigitating dendritic cell sarcoma through rapid research autopsy"

The research team’s analyses revealed ultra-hypermutation, defined as greater than 100 mutations per megabase, in this patients cancer, which was further characterized by the presence of three distinct mutational signatures including UV radiation and APOBEC signatures.

Truncal alterations, defined as being present in all clonal tumor cell populations, in this patients cancer include point mutations in TP53 and CDKN2A and amplifications of c-KIT and APOBEC3A-H, which are likely driver mutations.

Dr. Sameek Roychowdhury from the Department of Internal Medicine, Division of Medical Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA said, "Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare malignancy of dendritic cell origin with approximately 100 cases reported to date"

Localized IDCS constitutes 47% of cases and manifests as painless lymphadenopathy, most commonly involving the cervical and axillary nodes.

Isolated extra-nodal disease occurs in 25% of cases, involving the liver, lung, spleen, bone marrow and gastrointestinal tract .

Distant metastases occur in 39% of cases and most frequently involved lymph nodes, lung, liver and bone marrow .

Here they performed whole exome sequencing of multiple tumors obtained through rapid research autopsy of a patient with metastatic IDCS. In August 2016, the patient underwent modified radical right neck dissection and partial submandibular gland excision with one level I lymph node demonstrating complete tumor involvement and suspicious for extranodal extension; remaining lymph nodes from levels II, III and IV were negative for tumor infiltration.

In the future, it will be important to study additional patients with this and other rare cancers with hypermutation.

The Roychowdhury research team concluded, “Finally, the broader clinical implication of our results is that although patients with hypermutated cancer, originating from either somatic or germline genomic aberrations, are more likely to benefit from checkpoint inhibition, research is still needed to stratify these patients to maximize therapeutic efficacy and identify the different genetic determinants of primary or acquired resistance to immunotherapy.”

Full text - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=26352&path%5B%5D=82077

Correspondence to - Sameek Roychowdhury email: [email protected]

Keywords - tumor heterogeneity, research autopsy, hypermutation

About Oncotarget

Oncotarget is a twice-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology and publishing sub-sections on topics beyond oncology, including Aging, Immunology and Microbiology, Autophagy, Pathology and Chromosomes among others.

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