Oncotarget

The cover for issue 49 of Oncotarget features Figure 4, "CART-Tree analysis for overall survival in IMDC intermediate risk group," by Guida, et al.recently published in "Identification of international metastatic renal cell carcinoma database consortium (IMDC) intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma" which reported that as these patients have different prognosis, the aim of this study is to better characterize IR patients in order to better tailor the treatment.

A multivariable Cox model with backward selection procedure and a Classification and Regression Tree analysis were performed to identify which prognostic factors were associated to OS in IR patients.

Median OS for patients with PLT > UNL was 18 months versus 29 months for patients with normal PLT count.

The selection of PLT count was confirmed on bootstrap samples and was also selected for the first split of the CART-tree analysis.

Elevated PLT count seems to identify a subgroup of patients with poor outcome in the IMDC intermediate-risk population with ccRCC.

Dr. Laurence Albiges from The Université Paris-Saclay said, "The risk stratification models for metastatic renal cell carcinoma (mRCC) patients were developed as clinical tool to guide counseling, to predict individual patient prognosis and also to design clinical trial."

Patients lacking these negative factors have a good prognosis and may reach a longer survival; patients presenting 1 or 2 factors have an intermediate risk of death with a median overall survival about 23 months; patients with 3 or more factors have an expected poor risk outcome with median survival about 8 months.

Only in the poor risk group the decision-making algorithm was different: these patients were not candidate for upfront cytoreductive nephrectomy and in selected cases could benefit of mTOR inhibitor temsirolimus in first-line setting.

In the phase III trial Checkmate-214 nivolumab plus ipilimumab immunotherapy combination significantly prolonged OS versus sunitinib in intermediate and poor-risk untreated patients with mRCC.

The Albiges Research Team concluded in their Oncotarget Research Paper that given the rapidly evolving field of systemic treatment in mRCC, one of the most important challenges in mRCC is how prognostic stratification will guide front-line treatment selection.

Additionally characterization of heterogeneous IMDC intermediate-risk groups of patients should be seeked for optimal clinical trials design and stratification.

High platelet count reflecting the cancer-related inflammatory status and seems to segregate patients with the worst prognosis in the intermediate-risk group.

Further analyses are ongoing to validate these findings in patients receiving first line CPI based combination in first line.

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DOI - https://doi.org/10.18632/oncotarget.27762

Full text - https://www.oncotarget.com/article/27762/text/

Correspondence to - Laurence Albiges - [email protected]

Keywords - metastatic clear-cell renal cell carcinoma, IDMC, intermediate-risk, heterogeneous prognostic, platelets

About Oncotarget

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

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The cover for issue 45 of Oncotarget features Figure 3, "Representative images of whole tumor volume segmentation of the co-registered T1 post-contrast sequence and apparent diffusion coefficient (ADC) map, yielding the corresponding ADC histogram distribution utilized for data analysis," recently published in “Diffusion-weighted MR imaging histogram analysis in HIV positive and negative patients with primary central nervous system lymphoma as a predictor of outcome and tumor proliferation” by Khan, et al.

This authors reported that the aim of this study is to investigate the correlation between ADC parameters, Ki-67 expression, overall survival and progression free survival in PCNSL.

Selection criteria yielded 90 patients, 23 patients living with HIV and 67 immunocompetent patients.

In patients with available Ki-67 expression data, nADCmean, nADC15 and nADC75 inversely correlated with Ki-67 expression.

For PLWH, there was no correlation between ADC parameters and Ki-67 expression or clinical outcomes.

ADC histogram analysis can predict tumor proliferation and survival in immunocompetent patients with PCNSL, but with limited utility in PLWH.

Dr. Bilal Khan from The Baylor College of Medicine said, "Primary central nervous system lymphoma (PCNSL) is a rare subgroup of non-Hodgkin lymphoma confined to the central nervous system, with more than 90% of cases classified as Diffuse Large B-cell Lymphoma."

Diffusion weighted imaging and corresponding apparent diffusion coefficient maps can provide a representation of the cellular microenvironment with several studies demonstrating that ADC values can predict tumor cellularity across various neoplasms, including lymphomas.

In a recent similar study of whole tumor histogram analysis in PCNSL performed by the authors of this study, multiple ADC parameters were inversely correlated with Ki-67 expression and associated with poorer OS.

However, tumor segmentation was performed using only the ADC sequence with the potential inclusion of intra-tumoral necrosis, hemorrhage or regions outside of the actual solid tumor that would otherwise have been excluded with contrast co-registration, ultimately providing a suboptimal representation of true tumor parenchyma.

The primary aim of this study is to more comprehensively evaluate the relationship between ADC calculations with tumor Ki-67 expression and clinical outcomes using a larger patient sample with the inclusion of PLWH and whole tumor segmentation with T1 post contrast co-registration.

The Oncotarget author's hypothesis is that ADC values will inversely correlate with Ki-67 expression and that tumors with higher ADC values above the median will have improved OS and PFS.

The Khan Research Team concluded in their Oncotarget Research Paper that the role of MR in PCNSL historically has been the detection and qualitative evaluation of response to treatment.

DWI and derived ADC maps have been a well-established tool in neuroimaging, but the use of ADC histogram profiling has not been widely accepted in daily practice.

This data expands the role of conventional MR imaging by utilizing quantitative ADC histogram analysis to predict clinical outcomes and tumor expression of Ki-67, a biomarker for tumor proliferative activity, in immunocompetent PCNSL patients.

The role of using ADC as an imaging biomarker in PLWH may be limited.

Quantitative ADC histogram analysis should be strongly considered as part of the imaging protocol in the evaluation of immunocompetent patients with PCNSL.

DOI - https://doi.org/10.18632/oncotarget.27800

Full text - https://www.oncotarget.com/article/27800/text/

The cover for issue 44 of Oncotarget features Figure 1, "Schematic diagram of the human IGF2 gene structure," by Radhakrishnan, et al. recently published in "Methylation of a newly identified region of the INS-IGF2 gene determines IGF2 expression in breast cancer tumors and in breast cancer cells" which reported that these authors previously demonstrated that IGF2 protein levels are higher in BC tissues from African American women than in Caucasian women.

They also showed that high IGF2 protein levels are expressed in normal breast tissues of African American women while little or no IGF2 was detected in tissues from Caucasian women.

Thus, they designed this study to determine if differentially methylated regions of the IGF2 gene correspond to IGF2 protein expression in paired breast tissues and in BC cell lines.

The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

Since IGF2 promotes metastasis and chemoresistance, we propose that IGF2 levels contribute to BC aggressiveness.

Dr. Daisy D. De León from The Loma Linda University School of Medicine said, "Insulin-Like Growth factor 2 (IGF2) is a fetal growth factor that plays a critical function in fetal differentiation and metabolism by signaling through the IGF-I receptor and the insulin receptor."

Thus, IGF2 expression is important in normal breast development and increased IGF2 expression in the mammary gland contributes to BC malignancy.

This gene is located on the short arm of chromosome 11 at position 15.5. Methylation of the IGF2 gene regulatory regions occurs during the formation of an egg or sperm cell, and it is distinct and differentially modified depending on the parental origin of the allele.

In particular, dysregulation in the methylation of the IGF2 gene promoters occurs in several cancers including BC and this altered methylation leads to different clinical features in BC disease.

In spite of these advances, there is currently no consensus regarding the methylation status of the IGF2 gene, and its relationship to the levels of IGF2 protein expressed in normal breast or in breast cancer tissues.

DNA methylation patterns of the IGF2 gene were also analyzed in several BC cell lines to determine if there was a correlation between methylation of the IGF2 gene regulatory regions and the cellular expression levels of IGF2 protein.

The De León Research Team concluded in their Oncotarget Research Paper, "the present study shows that IGF2 expression in BC cells and in paired Normal- Malignant breast tissues are determined by the methylation of a novel region in the INS-IGF2 locus. We are currently studying the mechanisms underlying the methylation of the INS-IGF2 and how they control IGF2 expression. Upregulation of IGF2 in terms of the methylation patterns of the DVDMR may have an important function in the tumorigenesis of the breast. In conclusion, we propose that the INS-IGF2 DVDMR may be a useful tool to identify women at risk of developing a more aggressive BC disease."

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DOI - https://doi.org/10.18632/oncotarget.27655

Full text - https://www.oncotarget.com/article/27655/text/

Correspondence to - Daisy D. De León - [email protected]

Keywords - IGF2, INS-IGF2, hypermethylation, DMR, epigenetics

About Oncotarget

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

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Oncotarget recently published "CD44+/EPCAM+ cells detect a subpopulation of ALDHhigh cells in human non-small cell lung cancer: A chance for targeting cancer stem cells?" which reported that a comparison between ALDH high cells and CD44 cells have been previously described with no significant correlation.

This cross-sectional study analyzed the expression of ALDHhigh/low cells and the positivity for CD44 and epithelium cell adhesion molecule antigens in surgical lung cancer tissues.

There was a highly positive correlation between the expressions of ALDHhigh and CD44 /EPCAM cells, with a Pearson’s correlation coefficient equal to 0.69, and Spearman’s correlation coefficient equal to 0.52.

The average paired difference between the expression of ALDHhigh and CD44 /EPCAM cells was very close to 0, being 0.1%; there was no difference between these subpopulations in terms of means.

The Oncotarget author’s study is the first attempt that identifies a high correlation between the ALDHhigh and the CD44 /EPCAM cells, thus suggesting the possibility to use this superficial marker for future target treatments against lung cancer stem cells.

Dr. Beatrice Aramini from The University of Modena and Reggio Emilia said, "The cancer stem cell (CSC) model was proposed over 30 years ago [1] and is a very important field of study in cancer research."

As a cancer stem cell marker in a panel of 11 non-small-cell lung cancer tumor samples, 45 NSCLC lines, and 7 small-cell lung cancer lines.

In 2013 a panel of lung cancer cell lines from primary tumors and characterized a small subpopulation as strongly positive for CD44, with the main population being weakly positive or negative for CD44. The co-expression of CD90 further narrowed down the putative stem cell population.

This showed the putative lung CSC phenotypes of CD166 /CD44 and CD166 /EPCAM with multipotent characteristics of stem cells in lung adenocarcinoma cells.

Hence, a triple-positive marker, EPCAM /CD166 /CD44, has recently been described in the human non-small cell lung cancer cell line.

Nevertheless, although ALDH is considered an intracellular enzyme and is the most used marker to identify CSCs in lung cancer, the scientific community has never correlated this intracellular marker with an epithelial marker, which may be very useful for targeting lung cancer stem cells.

The Aramini Research Team concluded in their Oncotarget Research Paper, “even if we hypothesized that the percentage of CD44 /EPCAM in ALDHhigh cell population would be less than 50% in other patients, the similarity of an intracellular marker highlighting ALDHhigh cell population with a superficial marker CD44 /EPCAM is a very important concept in terms of target treatment.

In summary, our research is an important starting point for further studies that are needed to better define the CD44 /EPCAM superficial marker highlighting lung cancer stem cells.”

Full text - https://www.oncotarget.com/article/27568/text/

The cover for Issue 42 of Oncotarget features Figure 4, "Generation of parametric and texture maps from radiofrequency data," recently published in "Quantitative ultrasound radiomics using texture derivatives in prediction of treatment response to neo-adjuvant chemotherapy for locally advanced breast cancer" by Dasgupta, et al. which reported that to investigate quantitative ultrasound based higher-order texture derivatives in predicting the response to neoadjuvant chemotherapy in patients with locally advanced breast cancer.

Three machine learning algorithms based on linear discriminant, k-nearest-neighbors, and support vector machine were used for developing radiomic models of response prediction.

The most helpful features in separating the two response groups were QUS-Tex1-Tex2 features.

The 5-year recurrence-free survival calculated for KNN predicted responders and non-responders using QUS-Tex1-Tex2 model was comparable to RFS for the actual response groups.

The Oncotarget authors report the first study demonstrating QUS texture-derivative methods in predicting NAC responses in LABC, which leads to better results compared to using texture features alone.

Dr. Gregory J. Czarnota from The Sunnybrook Health Sciences Centre, The University of Toronto, The Sunnybrook Research Institute, as well as York University said, "Breast cancer is the second most common cancer globally in terms of incidence, comprising 11.6% of all new cancers and is the 5th leading cause of mortality attributed to 6.6% of all cancer deaths."

Imaging modalities like ultrasonography, mammography, magnetic resonance imaging, and computed tomography are commonly used in response monitoring of NAC, which primarily considers long-term size related changes of the disease.

Radiofrequency data from QUS provides valuable information compared to conventional B-mode ultrasound imaging, where there is a loss of crucial details involved with instrument-based signal processing. The analysis of the power spectra from ultrasound RF data can be used to determine quantitative parameters, which include average scatterer diameter, average acoustic concentration, mid-band fit, spectral slope, spectral 0-MHz intercept.

The spatial distribution of features within QUS parametric images can be further studied using grey-level co-occurrence matrix analyses, which represent the angular relationship and distance between neighboring pixels.

In the study here, higher-order imaging features in the form of QUS texture-derivatives have been determined from pretreatment QUS data for patients with LABC undergoing NAC to predict treatment response.

The Czarnota Research Team concluded in their Oncotarget Research paper that QUS is a simple, easily accessible imaging modality, with similar scanning techniques akin to the B-mode US, which is widely used in clinical practice.

With appropriate data processing, it is possible to use the information normally processed to generate B-mode images to obtain additional information from tumors. These are related to tumor acoustic properties, which can be linked with biological features and clinical behavior. In this research, we established the role of higher-order imaging analysis (radiomics) of QUS in predicting treatment response to NAC involving 100 patients with LABC.

The work provides a framework for using QUS-radiomics in clinical practice to choose appropriate chemotherapy regimens or other treatment modalities like upfront surgery (in predicted chemo-resistant tumors), leading the way towards personalized oncology.

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DOI - https://doi.org/10.18632/oncotarget.27742

Full text - https://www.oncotarget.com/article/27742/text/

Correspondence to - Gregory J. Czarnota - [email protected]

Keywords - radiomics, breast cancer, texture derivatives, quantitative ultrasound, neoadjuvant chemotherapy

The cover for Issue 41 of Oncotarget features Figure 7, "IPA ATM-signaling pathway in (A) EFV treated MRC-5 and (B) A549 cells," recently published in "Efavirenz induces DNA damage response pathway in lung cancer" by Marima, et al. which reported that the cell-cycle related genes are potential gene targets in understanding the effects of efavirenz in lung cancer.

The present study aimed at investigating the expression changes of cell-cycle related genes in response to EFV drug treatment in human non-small cell lung carcinoma and normal lung fibroblast cells.

The loss in nuclear integrity in response to EFV was detected by 4′, 6-diamidino-2-phenylindole staining. Gene expression profiling was performed using human cell cycle PathwayFinder RT2 Profiler™ PCR Array.

The expression changes of 84 genes key to the cell cycle pathway in humans following EFV treatment was examined.

Interestingly, the p53 signaling pathway was activated irrespective of the repressed ATM pathway in A549 cells as revealed by the Ingenuity Pathway Analysis.

Dr. Rahaba Marima from The University of Pretoria as well as The University of the Witwatersrand said, "The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) is frequently used in human immunodeficiency virus (HIV) treatment, and forms part of the first-line Highly Active Antiretroviral Treatment (HAART) treatment against HIV/AIDS."

Xulu and Hosie showed that ARV drugs including EFV caused apoptosis in the Human Squamous Cell carcinoma from Uterine Cervix cells and observed a change in morphological features such as rounding-up of cells, retraction of filopodia, blebbing and maintenance of plasma membrane integrity- characteristic features of apoptosis.

Due to the fact that the cell cycle is a tightly regulated process, eukaryotic cells respond to external stimuli such as DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair.

A previous study performed by the Marima Research group, involved assessing the effects of EFV on lung cancer cells at the cellular level on the physiological health of treated cells.

To date, several studies including Hecht et al., have revealed the cytotoxic effects of EFV against several cancer cells, but to our knowledge, no study yet has shown the anti-proliferative effects of EFV on lung epithelial cancer cells in relation to primary lung fibroblast cells.

In conjunction with preceding studies on EFV′s cyto-and-genotoxicity, this Oncotarget study is the first to reveal EFV mediated ATM/ATR genotoxicity in lung cells.

The Marima Research Team concluded in their Oncotarget Research Paper that the treatment of MRC-5 and A549 cells with EFV alters the gene expression of important factors that are essential in the maintenance of genomic stability in relation to the cell cycle.

This is particularly observed in the cancerous cells, with the significant down-regulation of AURKB and MAD2L2. Even though the normal p53 expression was shown here, p27, CASP3, Cyclin G1 and G2, NBN, RAD1 and RAD17 were significantly up-regulated.

Interestingly, the S-phase and DNA replication genes were downregulated; MCM4 in particular was –3.65 significantly down-regulated.

Depending on the severity of these effects in the physiological health of normal cells, EFV poses as a promising drug that can be used in synergy with chemo/radiotherapy.

Posttranscriptional gene regulation targeted by EFV in lung cells would also be interesting to pursue.

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DOI - https://doi.org/10.18632/oncotarget.27725

Full text - https://www.oncotarget.com/article/27725/text/

Correspondence to - Rahaba Marima - [email protected]

Keywords - efavirenz, cell cycle, differential gene expression, DNA damage response pathway, lung cancer

About Oncotarget

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

The cover for issue 40 of Oncotarget features Figure 5, "miR-210 silences the proapoptosis member CASP8AP2," by Kling, et al. which reported that hypoxic Ewing's sarcoma cells release exosomes that promote sphere formation, a stem-like phenotype, in EWS cells by enhancing survival.

Analysis of the hypoxic exosomal miRNA cargo identified a HIF-1α regulated miRNA, miR-210, as a potential mediator of sphere formation in cells exposed to hypoxic exosomes.

The knockdown of HIF-1α in hypoxic EWS cells led to decreased exosomal miR-210 levels and reduced the capacity of hypoxic exosomes to form spheres.

Inhibition of miR-210 in hypoxic spheres attenuated sphere formation and overexpression of miR-210 in normoxic spheres significantly enhanced the number of EWS spheres.

Together, the findings in this Oncotarget study suggest that hypoxic exosomes promote stemness in EWS cells by delivering enriched miR-210 that is capable of down-regulating apoptotic pathways, resulting in the survival of cells with increased sphere formation.

Dr. Shantaram S. Joshi from The University of Nebraska Medical Center said, "Ewing's sarcoma (EWS) is an aggressive and highly malignant bone tumor that develops in children and adolescents."

HIF -1α has been demonstrated to regulate tumor formation and stem cell survival in hypoxic cancer cells by inhibiting apoptosis.

Emerging evidence indicates intercellular communication between tumor cells in hypoxic and normoxic regions contributes to functional differences associated with hypoxic tumors.

Other reports demonstrated that shCD99 EWS-derived exosomes could transfer enriched miR-34a to recipient EWS cells and stimulate neural differentiation while in another study, EWS-derived exosomes carrying EZH2 mRNA could be delivered intact to mesenchymal stem cells.

Studies in other cancer models investigating the role of hypoxic exosomes have provided insight into how hypoxic tumors can secrete exosomes that propagate an aggressive phenotype in cells outside the hypoxic niche.

Exosomes released from hypoxic prostate cancer cells enhanced sphere formation in normoxic cells, but the authors were unable to elucidate a mechanism describing how hypoxic exosomes promote stemness in normoxic cells.

The Joshi Research Team concluded in their Oncotarget Research Paper that this study describes a mechanism whereby EWS cells under hypoxic conditions release exosomes that enhance stemness in EWS cells.

The authors identified a hypoxia regulated miRNA significantly expressed in hypoxic cells and HypoxicEXO and characterized a potential target that facilitates an apoptotic pathway critical to sphere formation.

Ongoing studies are investigating the role of HIF-1α on regulating EWS stemness and together, the authors future aim is to investigate how HIF-1α selectively modulates the packaging of miRNAs into HypoxicEXO, and validate additional miRNAs that promote aggressive hypoxic phenotypes.

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DOI - https://doi.org/10.18632/oncotarget.27702

Full text - https://www.oncotarget.com/article/27702/text/

Correspondence to - Shantaram S. Joshi - [email protected]

Keywords - exosomes, hypoxia, Ewing's sarcoma, stemness, miR-210

About Oncotarget

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

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The cover for issue 39 of Oncotarget features Figure 4, "Apoptosis assay of NRXN1-targeted ADC at IC50 dose calculated by growth inhibition curves," by Yotsumoto, et al. which reported that the authors identified transmembrane proteins overexpressed specifically in SCLC with little or no expression in normal tissues and decided to focus on the cell adhesion molecule neurexin-1.

The cell surface overexpression of NRXN1 was confirmed using flow cytometry in SCLC cell lines.

The combination of a primary anti-NRXN1 monoclonal antibody and a secondary ADC exhibited anti-tumor activity in SCLC cell lines.

Moreover, the knockout of NRXN1 in SHP77 cells resulted in a loss of the anti-tumor activity of NRXN1-mediated ADC therapy.

Thus, NRXN1 could be a novel target for ADC therapy for the treatment of SCLC that is worth further research.

Dr. Daiya Takai from The University of Tokyo Hospital and Dr. Takuma Yotsumoto from The University of Tokyo Graduate School of Medicine said, "Small cell lung cancer (SCLC) accounts for 10–15% of lung cancer, and its prognosis has remained relatively dismal for years."

Considering the high sensitivity of SCLC to chemotherapy, the selective delivery of a cytotoxic agent using ADC could be a novel treatment strategy for SCLC.

Five ADCs have been approved by The Food and Drug Administration:

Brentuximab vedotin for Hodgkin lymphoma

Ado-trastuzumab emtansine for HER2-positive metastatic breast cancer

Inotuzumab ozogamicin for acute lymphoblastic leukemia

Gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia, and

Trastuzumab deruxtecan for unresectable or metastatic HER2-positive breast cancer patients who have received two or more prior anti-HER2-based regimens in a metastatic setting.

In SCLC, DLL3, a cell surface Notch ligand that appears to be a direct downstream target of ASCL1, has been identified as a novel target for ADCs.

In this study, the Oncotarget authors aimed to identify novel molecular targets for ADCs in SCLC.

They herein report that NRXN1-mediated ADC exhibited anti-tumor activity in vitro, and thus NRXN1 could be a novel target of ADCs for SCLC.

The Takai/Yotsumoto Research Team concluded in their Oncotarget Research Paper "we identified NRXN1 as a new target for ADCs by screening membrane proteins using a computational-biological approach. The combination of the primary anti-NRXN1 monoclonal antibody and the secondary ADC exhibited anti-tumor activity in an NRXN1-expression dependent manner. NRXN1 could be a novel potential target of ADCs for SCLC that is worth further research."

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DOI - https://doi.org/10.18632/oncotarget.27718

Full text - https://www.oncotarget.com/article/27718/text/

Correspondence to - Daiya Takai - [email protected] and Takuma Yotsumoto - [email protected]

Keywords - antibody-drug conjugates, small cell lung cancer, novel molecular targets, NRXN1, cell adhesion molecule

About Oncotarget

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

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The cover for issue 38 of Oncotarget features Figure 3, "Summary of the time and cost for drug development (modified from DiMasi et al [2016]," by Katayama, et al. which reported that Pancreatic cancer is the most aggressive common cancer and is desperately in need of novel therapies.

In this study, the Oncotarget authors perform the first comprehensive analysis of the current clinical trial landscape in pancreatic cancer to better understand the pipeline of new therapies.

Studies were curated and categorized according to the phase of the study, the clinical stage of the study population, type of intervention under investigation, and biologic mechanism targeted by the therapy under study.

As of May 18, 2019, there were 430 total active therapeutic interventional trials testing 590 interventions.

The vast minority of trials are in phase III testing. 189 interventions are immunotherapies, 69 target cell signaling pathways, 154 target cell cycle or DNA biology, and 35 target metabolic pathways.

Dr. Jordan M. Winter from The Case Western Reserve University School of Medicine as well as The University Hospitals Seidman Cancer Center and Case Comprehensive Cancer Center said, "Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive of the common cancers."

The institute allocates roughly $6 billion annually to cancer research, and just over $100 million is dedicated to studying pancreatic cancer.

Other agencies and organizations like the Pancreatic Cancer Action Network, American Cancer Society, and the Department of Defense contribute significantly to this mission, likely adding more than $20 million per year in totality.

Along these lines, the authors have likely neared a survival ceiling for our patients in the absence of new discoveries that target other aspects of cancer biology, due to the additive toxicities of chemotherapeutic combinations.

Patients, family members, primary care providers, and oncologists battling together against pancreatic cancer often consider the same important questions: what new treatments are coming down the pike, and how soon will they arrive?

This work is necessary to better anticipate the timeframe for novel therapies against pancreatic cancer to reach the market. More importantly, this 20,000-foot view provides a foundation to discuss optimal resource allocation, with a principal goal to accelerate the pace of innovation, with an eye towards improving patient outcomes.

The Winter Research Team concluded in their Oncotarget Research Paper that the majority of PDAC trials are focused on immunotherapy, chemotherapy, and radiation.

Following the herd has not yet worked well for PDAC research; immunotherapy and precision therapy have yet to strongly impact this disease.

Finally, this compendium focuses on therapeutic studies and not early detection.

It is possible that the greatest advance in the future could be the discovery of an effective PDAC biomarker.

If the authors can detect PDAC at the PanIN 3 stage, therapeutic trials of invasive cancer become inconsequential.

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DOI - https://doi.org/10.18632/oncotarget.27727

Full text - https://www.oncotarget.com/article/27727/text/

Correspondence to - Jordan M. Winter - [email protected]

Keywords - pancreatic cancer, pancreatic ductal adenocarcinoma, clinical trial, novel treatment, drug development

About Oncotarget

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

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The cover for issue 37 of Oncotarget features Figure 7, "The combination of romidepsin and KU60019 is synergistic in a xenograft model of MCL," by Scotto, et al. which reported that the antiproliferative effect induced by histone deactylase inhibitors is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug.

HDAC inhibitors appear to activate p21 expression via ataxia telangiectasia mutated activity.

The Oncotarget authors explored the potential synergistic interaction of the ATM inhibitor with romidepsin, given the potential complementary impact around p21. A synergistic cytotoxic effect was observed in all lymphoma cell lines examined when the HDACi was combined with KU60019. The increase in apoptosis correlates with decreased expression of p21 due to the ATM inhibitor.

KU60019 decreased expression of the cyclin-dependent kinase inhibitor at the transcriptional level, compromising the ability of HDACi to induce p21 and cell cycle arrest and ultimately facilitating a shift toward the apoptotic phase.

Central to the increased apoptosis observed when romidepsin is combined with KU60019 is the reduced expression of p21 and the absence of a G2/M cell cycle arrest that would be exploited by the tumor cells to evade the cytotoxic effect of the HDAC inhibitor.

Dr. Owen A. O'Connor from The Columbia University Medical Center said, "HDAC inhibitors (HDACi) have emerged as valuable drugs in the treatment of select lymphomas and synergize with a diverse range of pharmacological and biological agents."

The observation leads to the following hypothesis: if induction of p21 compromises the efficacy of HDAC inhibitors, then strategies to mitigate HDAC inhibitor induced p21 expression could lead to promising synergistic combinations.

Induction of p21 by HDAC inhibitors is compromised in A-T cells given that ATM activity is essential for HDAC inhibitor-induced p21 expression.

Collectively, these observations have led to the following hypothesis: If ATM activity is necessary for HDAC inhibitor mediated p21 induction, then selective ATM inhibitors could mitigate the HDAC induced p21 expression and potentiate its cytotoxic effect.

The ATM inhibitor nullifies HDAC induction of p21 expression resulting in a synergistic interaction.

KU60019 reduces p21 expression at the transcriptional level and antagonizes romidepsin transcriptional induction of p21. In both instances, the result is a markedly down-regulation of p21 expression at the protein level.

The O'Connor Research Team concluded in their Oncotarget Research Paper that it is intuitive that pleotropic drugs like HDACi are likely to have both favorable and unfavorable effects on cell growth and survival.

Strategies directed toward understanding how to mitigate the unfavorable influences of the class can lead to improved efficacy in rational combinations.

Many examples of drug synergy with HDAC inhibitors have been driven by random efforts in mixing and matching in order to identify possible complementary partners.

Obviously, a clear understanding of the molecular pharmacologic features of pleotropic drug classes like HDAC inhibitors can afford unique opportunities to think about logical combinations.

Ultimately, these approaches need to be translated to the clinic in order to establish therapeutic merit in the clinic.

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DOI - https://doi.org/10.18632/oncotarget.27723

Full text - https://www.oncotarget.com/article/27723/text/

Correspondence to - Owen A. O'Connor - [email protected]

Keywords - lymphoma, HDAC inhibitor, ATM inhibitor, p21, cell cycle

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