ATR inhibition reverses the resistance of homologous recombination deficient MGMT < sup > low < /sup > /MMR < sup > proficient < /sup > cancer cells to temozolomide
Oncotarget. 2021 Oct 12;12(21):2114-2130. doi: 10.18632/oncotarget.28090. eCollection 2021 Oct 12.ABSTRACTThe therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all MGMTlow/-ve/MMRproficient patients benefit from TMZ treatment, indicating a need for additional patient selection criteria. We explored the role of ATR in mediating TMZ resistance and whether ATR inhibitors (ATRi) could reverse this resistance in multiple cancer lines. We observed that only 31% of MGMTlow/-ve/MMRprofic...
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Lara H El Touny Curtis Hose John Connelly Erik Harris Anne Monks Angie B Dull Deborah F Wilsker Melinda G Hollingshead Michelle Gottholm-Ahalt Sergio Y Alcoser Michael E Mullendore Ralph E Parchment James H Doroshow Beverly A Teicher Annamaria Rapisarda Source Type: research

Hyperprogression of a mismatch repair-deficient colon cancer in a humanized mouse model following administration of immune checkpoint inhibitor pembrolizumab
Oncotarget. 2021 Oct 12;12(21):2131-2146. doi: 10.18632/oncotarget.28086. eCollection 2021 Oct 12.ABSTRACTImmunotherapy is an established treatment modality in oncology. However, in addition to primary or acquired therapy resistance with immune checkpoint blockade (ICB), hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. A validated and predictive animal model would help investigate HPD/HP to develop new approaches for this challenging clinical entity. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immun...
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Ilyas Sahin Andrew George Shengliang Zhang Kelsey E Huntington Zehra Ordulu Lanlan Zhou Wafik S El-Deiry Source Type: research

Luminescence complementation technology for the identification of MYC:TRRAP inhibitors
Oncotarget. 2021 Oct 12;12(21):2147-2157. doi: 10.18632/oncotarget.28078. eCollection 2021 Oct 12.ABSTRACTMechanism-based targeted therapies have exhibited remarkable success in treating otherwise untreatable or unresectable cancers. Novel targeted therapies that correct dysregulated transcriptional programs in cancer are an unmet medical need. The transcription factor MYC is the most frequently amplified gene in human cancer and is overexpressed because of mutations in an array of oncogenic signaling pathways. The fact that many cancer cells cannot survive without MYC - a phenomenon termed "MYC addiction" - prov...
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Edmond J Feris John W Hinds Michael D Cole Source Type: research

TAK1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan
Oncotarget. 2021 Oct 12;12(21):2158-2168. doi: 10.18632/oncotarget.28073. eCollection 2021 Oct 12.ABSTRACTMultiple myeloma (MM) is an incurable cancer caused by malignant transformation of plasma cells. Transforming growth factor-β activated kinase 1 (MAP3K7, TAK1) is a major regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. Both NF-κB and MAPK control expression of genes with vital roles for drug resistance in MM. TAK1 is an attractive drug target as it switches these survival pathways to cell death. Our analysis show...
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Erling H åland Ingrid Nyhus Moen Elias Veidal Hanne Hella Kristine Misund Tobias S Sl ørdahl Kristian K Starheim Source Type: research

The experiences and needs of Australian medical oncologists in integrating comprehensive genomic profiling into clinical care: a nation-wide survey
This study aimed to characterise oncologists' experiences and needs when utilising genomic results.MATERIALS AND METHODS: An electronic survey distributed nation-wide to practising medical oncologists in Australia explored oncologists' experiences with consenting, interpreting and communicating CGP results to patients.RESULTS: The survey was completed by 108 of 333 oncologists (32%) and most respondents (n = 97, 90%) had referred patients for CGP. Using a 100-point visual analogue scale score [VAS], where higher values indicate greater confidence, most oncologists were confident consenting patients for referral [median 75 ...
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Subotheni Thavaneswaran Mandy Ballinger Phyllis Butow Bettina Meiser David Goldstein Frank Lin Christine Napier David Thomas Megan Best Source Type: research

Low tumour-infiltrating lymphocyte density in primary and recurrent glioblastoma
This study shows that TILs are present at low densities in both primary and recurrent glioblastoma. Furthermore, PD-1+ TILs were frequently absent, which may provide evidence as to why anti-PD-1 immunotherapy trials have been largely unsuccessful in glioblastoma.PMID:34676050 | PMC:PMC8522837 | DOI:10.18632/oncotarget.28069 (Source: Oncotarget)
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Kelsey Maddison Moira C Graves Nikola A Bowden Michael Fay Ricardo E Vilain Sam Faulkner Paul A Tooney Source Type: research

Trends in oligomannosylation and α1,2-mannosidase expression in human cancers
Oncotarget. 2021 Oct 12;12(21):2188-2205. doi: 10.18632/oncotarget.28064. eCollection 2021 Oct 12.ABSTRACTAberrant protein glycosylation is a prominent cancer feature. While many tumour-associated glycoepitopes have been reported, advances in glycoanalytics continue to uncover new associations between glycosylation and cancer. Guided by a comprehensive literature survey suggesting that oligomannosylation (Man5-9 GlcNAc2) is a widespread and often regulated glycosignature in human cancers, we here revisit a valuable compilation of nearly 500 porous graphitized carbon LC-MS/MS N-glycomics datasets acquired across 11 human ca...
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Sayantani Chatterjee Julian Ugonotti Ling Y Lee Arun Everest-Dass Rebeca Kawahara Morten Thaysen-Andersen Source Type: research

TP53 mutations determined by targeted NGS in breast cancer: a case-control study
CONCLUSIONS: Our case-control study suggests that TP53 somatic mutations detected by next-generation sequencing (NGS) are associated with an adverse prognosis in breast cancer.PMID:34676052 | PMC:PMC8522843 | DOI:10.18632/oncotarget.28071 (Source: Oncotarget)
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Angeliki Andrikopoulou Evangelos Terpos Spyridoula Chatzinikolaou Kleoniki Apostolidou Ioannis Ntanasis-Stathopoulos Maria Gavriatopoulou Meletios-Athanasios Dimopoulos Flora Zagouri Source Type: research

Association of four genetic variants with colorectal cancer in Kazakhstan population
Oncotarget. 2021 Oct 12;12(21):2215-2222. doi: 10.18632/oncotarget.28070. eCollection 2021 Oct 12.ABSTRACTThe study was conducted to search for polymorphisms located in the 10th chromosome associated with colorectal adenocarcinoma in representatives of the Kazakhstan population. Study was performed with 282 colorectal cancer (CRC) patients and 159 controls. Genotyping of SNPs was performed by QuantStudio 12K Flex PCR. For four significant SNPs inheritance model analysis was performed. Increasing risk of CRC was noted for rs10795668 in log-additive model (OR = 1.45, 95% CI: 1.05-1.99, p = 0.023); for rs1035209 in log-additi...
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Yevgeniya Kolesnikova Dmitriy Babenko Irina Kadyrova Svetlana Kolesnichenko Lyudmila Akhmaltdinova Ilya Korshukov Naylya Kabildina Valentina Sirota Vera Zhumaliyeva Dana Taizhanova Dmitriy Vazenmiller Anar Turmukhambetova Source Type: research

Javelin Head Neck 100: Should we combine immunotherapy with radiation therapy?
Oncotarget. 2021 Oct 12;12(21):2223-2226. doi: 10.18632/oncotarget.27987. eCollection 2021 Oct 12.NO ABSTRACTPMID:34676054 | PMC:PMC8522846 | DOI:10.18632/oncotarget.27987 (Source: Oncotarget)
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Yao Yu Kaveh Zakeri Nancy Lee Source Type: research

Neddylation and anti-tumor immunity
Oncotarget. 2021 Oct 12;12(21):2227-2230. doi: 10.18632/oncotarget.28019. eCollection 2021 Oct 12.ABSTRACTContrary to chemotherapy, novel targeted therapies are associated with diverse immunomodulatory effects. Nedd8 is a small ubiquitin-like modifier that is involved in regulation of protein degradation. Neddylation is a promising target in cancer. Pevonedistat, a small molecule inhibitor of the Nedd8-activating enzyme, demonstrates pre-clinical activity in multiple tumor types. Recent studies have revealed that neddylation is important in immunity. We and others have shown that interfering with neddylation causes downstr...
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Xiaoguang Wang Scott Best Alexey V Danilov Source Type: research

Correction: Discovery and clinical introduction of first-in-class imipridone ONC201
Oncotarget. 2021 Oct 12;12(21):2231. doi: 10.18632/oncotarget.28012. eCollection 2021 Oct 12.ABSTRACT[This corrects the article DOI: 10.18632/oncotarget.11814.].PMID:34676056 | PMC:PMC8522842 | DOI:10.18632/oncotarget.28012 (Source: Oncotarget)
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Joshua E Allen C Leah B Kline Varun V Prabhu Jessica Wagner Jo Ishizawa Neel Madhukar Avital Lev Marie Baumeister Lanlan Zhou Amriti Lulla Martin Stogniew Lee Schalop Cyril Benes Howard L Kaufman Richard S Pottorf B Rao Nallaganchu Gary L Olson Fahd Al-Mu Source Type: research

Correction: Lipolysis-stimulated lipoprotein receptor overexpression is a novel predictor of poor clinical prognosis and a potential therapeutic target in gastric cancer
Oncotarget. 2021 Oct 12;12(21):2232-2233. doi: 10.18632/oncotarget.28096. eCollection 2021 Oct 12.ABSTRACT[This corrects the article DOI: 10.18632/oncotarget.25952.].PMID:34676057 | PMC:PMC8522840 | DOI:10.18632/oncotarget.28096 (Source: Oncotarget)
Source: Oncotarget - October 22, 2021 Category: Cancer & Oncology Authors: Takahito Sugase Tsuyoshi Takahashi Satoshi Serada Minoru Fujimoto Tomoharu Ohkawara Kosuke Hiramatsu Masahiro Koh Yurina Saito Koji Tanaka Yasuhiro Miyazaki Tomoki Makino Yukinori Kurokawa Makoto Yamasaki Kiyokazu Nakajima Kazuhiro Hanazaki Masaki Mori Yu Source Type: research

Identification of Smurf2 as a HIF-1 α degrading E3 ubiquitin ligase
Oncotarget. 2021 Sep 28;12(20):1970-1979. doi: 10.18632/oncotarget.28081. eCollection 2021 Sep 28.ABSTRACTThe major adaptive response to hypoxia involves hypoxia-inducible factor HIF-1α which is regulated by von Hippel Lindau (VHL) E3 ligase. We previously observed a stabilization of HIF-1α by cyclin-dependent kinases CDK1 and CDK4/6 that is independent of VHL, hypoxia or p53, and found that CDK4/6 inhibitors destabilize HIF-1α under normoxia and hypoxia. To further investigate the molecular mechanism of HIF-1α destabilization by CDK1 or CDK4/6 inhibitors, we performed a proteomic screen on immunopr...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Shuai Zhao Wafik S El-Deiry Source Type: research

A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs
Oncotarget. 2021 Sep 28;12(20):1980-1991. doi: 10.18632/oncotarget.28079. eCollection 2021 Sep 28.ABSTRACTInflammatory cytokines, chemokines, and growth factors are molecular messengers that circulate and have the capability to modify the tumor microenvironment and impact therapeutic response. The characterization of soluble mediators as biomarkers for diagnosis and prognosis is of interest in oncology. We utilize the cytokinome to characterize the response of colorectal tumor cell lines to selected small-molecules in oncology as a proof-of-concept dataset with immunomodulatory analyte heat map rankings for drug and cell l...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Kelsey E Huntington Anna Louie Lanlan Zhou Wafik S El-Deiry Source Type: research

Opposing effects of BRCA1 mRNA expression on patient survival in breast and colorectal cancer and variations among African American, Asian, and younger patients
Oncotarget. 2021 Sep 28;12(20):1992-2005. doi: 10.18632/oncotarget.28082. eCollection 2021 Sep 28.ABSTRACTBreast cancer (BC) and colorectal cancer (CRC) are common and show poor survival in advanced stages. Using The Cancer Genome Atlas (TCGA) computational tool cBioPortal, we evaluated overall patient survival in BRCA1 mRNA-low versus -high cohorts (1.05 SD from mean BRCA1 expression, respectively). Analysis included 1082 BC patients with mRNA data (PanCancer Atlas), 382 CRCs (Firehose Legacy) and 592 CRCs (PanCancer Atlas). As previously reported, BRCA1 mRNA-low tumor expression positively correlated with BC patient surv...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Sofia Leaf Lindsey Carlsen Wafik S El-Deiry Source Type: research

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells
Oncotarget. 2021 Sep 28;12(20):2006-2021. doi: 10.18632/oncotarget.28075. eCollection 2021 Sep 28.ABSTRACTColorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53-/- colorectal cancer ...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Lindsey Carlsen Christoph Schorl Kelsey Huntington Liz Hernandez-Borrero Aakash Jhaveri Shengliang Zhang Lanlan Zhou Wafik S El-Deiry Source Type: research

Comparative microsomal proteomics of a model lung cancer cell line NCI-H23 reveals distinct differences between molecular profiles of 3D and 2D cultured cells
Oncotarget. 2021 Sep 28;12(20):2022-2038. doi: 10.18632/oncotarget.28072. eCollection 2021 Sep 28.ABSTRACTLung cancer is the leading cause of cancer-related deaths in the USA and worldwide. Yet, about 95% of new drug candidates validated in preclinical phase eventually fail in clinical trials. Such a high attrition rate is attributed mostly to the inability of conventional two-dimensionally (2D) cultured cancer cells to mimic native three-dimensional (3D) growth of malignant cells in human tumors. To ascertain phenotypical differences between these two distinct culture conditions, we carried out a comparative proteomic ana...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Jan A Kaczmarczyk Rhonda R Roberts Brian T Luke King C Chan Carly M Van Wagoner Robin A Felder Richard G Saul Colantonio Simona Josip Blonder Source Type: research

Tissue biodistribution and tumor targeting of near-infrared labelled anti-CD38 antibody-drug conjugate in preclinical multiple myeloma
In this study, we evaluated the anti-tumor efficacy of DARA conjugated to the maytansine derivative, mertansine (DM1), linked via a non-cleavable bifunctional linker. The ADC was labelled with the near-infrared (NIR) fluorophore IRDye800 (DARA-DM1-IR) to evaluate its stability, biodistribution and pharmacokinetics in vitro and in vivo. We demonstrated the conjugation of: 1) DM1 enhanced tumor-killing efficacy of the native DARA and 2) IRDye800 allowed for visualization of uptake and tumor targeting ability of the ADC. With the advent of other classes of immunoconjugates for use in MM, we reasoned that such imaging techniqu...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Nicholas Cho Sooah Ko Monica Shokeen Source Type: research

Multipeptide stimulated PBMCs generate T < sub > EM < /sub > /T < sub > CM < /sub > for adoptive cell therapy in multiple myeloma
Oncotarget. 2021 Sep 28;12(20):2051-2067. doi: 10.18632/oncotarget.28067. eCollection 2021 Sep 28.ABSTRACTMultiple Myeloma (MM) patients suffer disease relapse due to the development of therapeutic resistance. Increasing evidence suggests that immunotherapeutic strategies can provide durable responses. Here we evaluate the possibility of adoptive cell transfer (ACT) by generating ex vivo T cells from peripheral blood mononuclear cells (PBMCs) isolated from MM patients by employing our previously devised protocols. We designed peptides from antigens (Ags) including cancer testis antigens (CTAs) that are over expressed in MM...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Trupti Vardam-Kaur Latha B Pathangey Daniel J McCormick P Leif Bergsagel Peter A Cohen Sandra J Gendler Source Type: research

NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells
Oncotarget. 2021 Sep 28;12(20):2068-2074. doi: 10.18632/oncotarget.28063. eCollection 2021 Sep 28.ABSTRACTPeripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated ...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Adam S Kittai Olga V Danilova Vi Lam Tingting Liu Nur Bruss Scott Best Guang Fan Alexey V Danilov Source Type: research

Safety and initial efficacy of ablative radioembolization for the treatment of unresectable intrahepatic cholangiocarcinoma
CONCLUSIONS: Radioembolization of unresectable intrahepatic cholangiocarcinoma with ablative intent has a high response rate, promising survival, and is well tolerated.PMID:34611481 | PMC:PMC8487720 | DOI:10.18632/oncotarget.28060 (Source: Oncotarget)
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Ricardo Paz-Fumagalli Jacob Core Carlos Padula Seyed Montazeri John McKinney Gregory Frey Zlatko Devcic Andrew Lewis Charles Ritchie Kabir Mody Sunil Krishnan Beau Toskich Source Type: research

Switching Hedgehog inhibitors and other strategies to address resistance when treating advanced basal cell carcinoma
Oncotarget. 2021 Sep 28;12(20):2089-2100. doi: 10.18632/oncotarget.28080. eCollection 2021 Sep 28.ABSTRACTAlthough basal cell carcinoma (BCC) is often managed successfully with surgery, patients with locally advanced BCC (laBCC) or metastatic BCC (mBCC) who are not candidates for surgery or radiotherapy have limited treatment options. Most BCCs result from aberrant Hedgehog pathway activation in keratinocyte tumor cells, caused by sporadic or inherited mutations. Mutations in the patched homologue 1 gene that remove its inhibitory regulation of Smoothened homologue (SMO) or mutations in SMO that make it constitutively acti...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Hung Q Doan Leon Chen Zeena Nawas Heng-Huan Lee Sirunya Silapunt Michael Migden Source Type: research

Fibrocytes in primary myelofibrosis
Oncotarget. 2021 Sep 28;12(20):2101-2103. doi: 10.18632/oncotarget.27971. eCollection 2021 Sep 28.NO ABSTRACTPMID:34611483 | PMC:PMC8487717 | DOI:10.18632/oncotarget.27971 (Source: Oncotarget)
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Kazuya Shimoda Yoshinori Ozono Kotaro Shide Source Type: research

Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers
Oncotarget. 2021 Sep 28;12(20):2104-2110. doi: 10.18632/oncotarget.27983. eCollection 2021 Sep 28.ABSTRACTDespite increasingly thorough mechanistic understanding of the dominant genetic drivers of gastrointestinal (GI) tumorigenesis (e.g., Ras/Raf, TP53, etc.), only a small proportion of these molecular alterations are therapeutically actionable. In an attempt to address this therapeutic impasse, our group has proposed an innovative extreme outlier model to identify novel cooperative molecular vulnerabilities in high-risk GI cancers which dictate prognosis, correlate with distinct patterns of metastasis, and define therape...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Austin R Dosch Walid K Chatila Yuguang Ban Anna Bianchi Nilesh U Deshpande Iago De Castro Silva Nipun B Merchant Jashodeep Datta Source Type: research

Correction: PSC-derived Galectin-1 inducing epithelial-mesenchymal transition of pancreatic ductal adenocarcinoma cells by activating the NF- κB pathway
Oncotarget. 2021 Sep 28;12(20):2111-2113. doi: 10.18632/oncotarget.28087. eCollection 2021 Sep 28.ABSTRACT[This corrects the article DOI: 10.18632/oncotarget.21212.].PMID:34611485 | PMC:PMC8487725 | DOI:10.18632/oncotarget.28087 (Source: Oncotarget)
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Dong Tang Jingqiu Zhang Zhongxu Yuan Hongpeng Zhang Yang Chong Yuqin Huang Jie Wang Qingquan Xiong Sen Wang Qi Wu Ying Tian Yongdie Lu Xiao Ge Wenjing Shen Daorong Wang Source Type: research

Identification of Smurf2 as a HIF-1 α degrading E3 ubiquitin ligase
Oncotarget. 2021 Sep 28;12(20):1970-1979. doi: 10.18632/oncotarget.28081. eCollection 2021 Sep 28.ABSTRACTThe major adaptive response to hypoxia involves hypoxia-inducible factor HIF-1α which is regulated by von Hippel Lindau (VHL) E3 ligase. We previously observed a stabilization of HIF-1α by cyclin-dependent kinases CDK1 and CDK4/6 that is independent of VHL, hypoxia or p53, and found that CDK4/6 inhibitors destabilize HIF-1α under normoxia and hypoxia. To further investigate the molecular mechanism of HIF-1α destabilization by CDK1 or CDK4/6 inhibitors, we performed a proteomic screen on immunopr...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Shuai Zhao Wafik S El-Deiry Source Type: research

A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs
Oncotarget. 2021 Sep 28;12(20):1980-1991. doi: 10.18632/oncotarget.28079. eCollection 2021 Sep 28.ABSTRACTInflammatory cytokines, chemokines, and growth factors are molecular messengers that circulate and have the capability to modify the tumor microenvironment and impact therapeutic response. The characterization of soluble mediators as biomarkers for diagnosis and prognosis is of interest in oncology. We utilize the cytokinome to characterize the response of colorectal tumor cell lines to selected small-molecules in oncology as a proof-of-concept dataset with immunomodulatory analyte heat map rankings for drug and cell l...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Kelsey E Huntington Anna Louie Lanlan Zhou Wafik S El-Deiry Source Type: research

Opposing effects of BRCA1 mRNA expression on patient survival in breast and colorectal cancer and variations among African American, Asian, and younger patients
Oncotarget. 2021 Sep 28;12(20):1992-2005. doi: 10.18632/oncotarget.28082. eCollection 2021 Sep 28.ABSTRACTBreast cancer (BC) and colorectal cancer (CRC) are common and show poor survival in advanced stages. Using The Cancer Genome Atlas (TCGA) computational tool cBioPortal, we evaluated overall patient survival in BRCA1 mRNA-low versus -high cohorts (1.05 SD from mean BRCA1 expression, respectively). Analysis included 1082 BC patients with mRNA data (PanCancer Atlas), 382 CRCs (Firehose Legacy) and 592 CRCs (PanCancer Atlas). As previously reported, BRCA1 mRNA-low tumor expression positively correlated with BC patient surv...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Sofia Leaf Lindsey Carlsen Wafik S El-Deiry Source Type: research

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells
Oncotarget. 2021 Sep 28;12(20):2006-2021. doi: 10.18632/oncotarget.28075. eCollection 2021 Sep 28.ABSTRACTColorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53-/- colorectal cancer ...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Lindsey Carlsen Christoph Schorl Kelsey Huntington Liz Hernandez-Borrero Aakash Jhaveri Shengliang Zhang Lanlan Zhou Wafik S El-Deiry Source Type: research

Comparative microsomal proteomics of a model lung cancer cell line NCI-H23 reveals distinct differences between molecular profiles of 3D and 2D cultured cells
Oncotarget. 2021 Sep 28;12(20):2022-2038. doi: 10.18632/oncotarget.28072. eCollection 2021 Sep 28.ABSTRACTLung cancer is the leading cause of cancer-related deaths in the USA and worldwide. Yet, about 95% of new drug candidates validated in preclinical phase eventually fail in clinical trials. Such a high attrition rate is attributed mostly to the inability of conventional two-dimensionally (2D) cultured cancer cells to mimic native three-dimensional (3D) growth of malignant cells in human tumors. To ascertain phenotypical differences between these two distinct culture conditions, we carried out a comparative proteomic ana...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Jan A Kaczmarczyk Rhonda R Roberts Brian T Luke King C Chan Carly M Van Wagoner Robin A Felder Richard G Saul Colantonio Simona Josip Blonder Source Type: research

Tissue biodistribution and tumor targeting of near-infrared labelled anti-CD38 antibody-drug conjugate in preclinical multiple myeloma
In this study, we evaluated the anti-tumor efficacy of DARA conjugated to the maytansine derivative, mertansine (DM1), linked via a non-cleavable bifunctional linker. The ADC was labelled with the near-infrared (NIR) fluorophore IRDye800 (DARA-DM1-IR) to evaluate its stability, biodistribution and pharmacokinetics in vitro and in vivo. We demonstrated the conjugation of: 1) DM1 enhanced tumor-killing efficacy of the native DARA and 2) IRDye800 allowed for visualization of uptake and tumor targeting ability of the ADC. With the advent of other classes of immunoconjugates for use in MM, we reasoned that such imaging techniqu...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Nicholas Cho Sooah Ko Monica Shokeen Source Type: research

Multipeptide stimulated PBMCs generate T < sub > EM < /sub > /T < sub > CM < /sub > for adoptive cell therapy in multiple myeloma
Oncotarget. 2021 Sep 28;12(20):2051-2067. doi: 10.18632/oncotarget.28067. eCollection 2021 Sep 28.ABSTRACTMultiple Myeloma (MM) patients suffer disease relapse due to the development of therapeutic resistance. Increasing evidence suggests that immunotherapeutic strategies can provide durable responses. Here we evaluate the possibility of adoptive cell transfer (ACT) by generating ex vivo T cells from peripheral blood mononuclear cells (PBMCs) isolated from MM patients by employing our previously devised protocols. We designed peptides from antigens (Ags) including cancer testis antigens (CTAs) that are over expressed in MM...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Trupti Vardam-Kaur Latha B Pathangey Daniel J McCormick P Leif Bergsagel Peter A Cohen Sandra J Gendler Source Type: research

NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells
Oncotarget. 2021 Sep 28;12(20):2068-2074. doi: 10.18632/oncotarget.28063. eCollection 2021 Sep 28.ABSTRACTPeripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated ...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Adam S Kittai Olga V Danilova Vi Lam Tingting Liu Nur Bruss Scott Best Guang Fan Alexey V Danilov Source Type: research

Safety and initial efficacy of ablative radioembolization for the treatment of unresectable intrahepatic cholangiocarcinoma
CONCLUSIONS: Radioembolization of unresectable intrahepatic cholangiocarcinoma with ablative intent has a high response rate, promising survival, and is well tolerated.PMID:34611481 | PMC:PMC8487720 | DOI:10.18632/oncotarget.28060 (Source: Oncotarget)
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Ricardo Paz-Fumagalli Jacob Core Carlos Padula Seyed Montazeri John McKinney Gregory Frey Zlatko Devcic Andrew Lewis Charles Ritchie Kabir Mody Sunil Krishnan Beau Toskich Source Type: research

Switching Hedgehog inhibitors and other strategies to address resistance when treating advanced basal cell carcinoma
Oncotarget. 2021 Sep 28;12(20):2089-2100. doi: 10.18632/oncotarget.28080. eCollection 2021 Sep 28.ABSTRACTAlthough basal cell carcinoma (BCC) is often managed successfully with surgery, patients with locally advanced BCC (laBCC) or metastatic BCC (mBCC) who are not candidates for surgery or radiotherapy have limited treatment options. Most BCCs result from aberrant Hedgehog pathway activation in keratinocyte tumor cells, caused by sporadic or inherited mutations. Mutations in the patched homologue 1 gene that remove its inhibitory regulation of Smoothened homologue (SMO) or mutations in SMO that make it constitutively acti...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Hung Q Doan Leon Chen Zeena Nawas Heng-Huan Lee Sirunya Silapunt Michael Migden Source Type: research

Fibrocytes in primary myelofibrosis
Oncotarget. 2021 Sep 28;12(20):2101-2103. doi: 10.18632/oncotarget.27971. eCollection 2021 Sep 28.NO ABSTRACTPMID:34611483 | PMC:PMC8487717 | DOI:10.18632/oncotarget.27971 (Source: Oncotarget)
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Kazuya Shimoda Yoshinori Ozono Kotaro Shide Source Type: research

Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers
Oncotarget. 2021 Sep 28;12(20):2104-2110. doi: 10.18632/oncotarget.27983. eCollection 2021 Sep 28.ABSTRACTDespite increasingly thorough mechanistic understanding of the dominant genetic drivers of gastrointestinal (GI) tumorigenesis (e.g., Ras/Raf, TP53, etc.), only a small proportion of these molecular alterations are therapeutically actionable. In an attempt to address this therapeutic impasse, our group has proposed an innovative extreme outlier model to identify novel cooperative molecular vulnerabilities in high-risk GI cancers which dictate prognosis, correlate with distinct patterns of metastasis, and define therape...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Austin R Dosch Walid K Chatila Yuguang Ban Anna Bianchi Nilesh U Deshpande Iago De Castro Silva Nipun B Merchant Jashodeep Datta Source Type: research

Correction: PSC-derived Galectin-1 inducing epithelial-mesenchymal transition of pancreatic ductal adenocarcinoma cells by activating the NF- κB pathway
Oncotarget. 2021 Sep 28;12(20):2111-2113. doi: 10.18632/oncotarget.28087. eCollection 2021 Sep 28.ABSTRACT[This corrects the article DOI: 10.18632/oncotarget.21212.].PMID:34611485 | PMC:PMC8487725 | DOI:10.18632/oncotarget.28087 (Source: Oncotarget)
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Dong Tang Jingqiu Zhang Zhongxu Yuan Hongpeng Zhang Yang Chong Yuqin Huang Jie Wang Qingquan Xiong Sen Wang Qi Wu Ying Tian Yongdie Lu Xiao Ge Wenjing Shen Daorong Wang Source Type: research

Identification of Smurf2 as a HIF-1 α degrading E3 ubiquitin ligase
Oncotarget. 2021 Sep 28;12(20):1970-1979. doi: 10.18632/oncotarget.28081. eCollection 2021 Sep 28.ABSTRACTThe major adaptive response to hypoxia involves hypoxia-inducible factor HIF-1α which is regulated by von Hippel Lindau (VHL) E3 ligase. We previously observed a stabilization of HIF-1α by cyclin-dependent kinases CDK1 and CDK4/6 that is independent of VHL, hypoxia or p53, and found that CDK4/6 inhibitors destabilize HIF-1α under normoxia and hypoxia. To further investigate the molecular mechanism of HIF-1α destabilization by CDK1 or CDK4/6 inhibitors, we performed a proteomic screen on immunopr...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Shuai Zhao Wafik S El-Deiry Source Type: research

A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs
Oncotarget. 2021 Sep 28;12(20):1980-1991. doi: 10.18632/oncotarget.28079. eCollection 2021 Sep 28.ABSTRACTInflammatory cytokines, chemokines, and growth factors are molecular messengers that circulate and have the capability to modify the tumor microenvironment and impact therapeutic response. The characterization of soluble mediators as biomarkers for diagnosis and prognosis is of interest in oncology. We utilize the cytokinome to characterize the response of colorectal tumor cell lines to selected small-molecules in oncology as a proof-of-concept dataset with immunomodulatory analyte heat map rankings for drug and cell l...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Kelsey E Huntington Anna Louie Lanlan Zhou Wafik S El-Deiry Source Type: research

Opposing effects of BRCA1 mRNA expression on patient survival in breast and colorectal cancer and variations among African American, Asian, and younger patients
Oncotarget. 2021 Sep 28;12(20):1992-2005. doi: 10.18632/oncotarget.28082. eCollection 2021 Sep 28.ABSTRACTBreast cancer (BC) and colorectal cancer (CRC) are common and show poor survival in advanced stages. Using The Cancer Genome Atlas (TCGA) computational tool cBioPortal, we evaluated overall patient survival in BRCA1 mRNA-low versus -high cohorts (1.05 SD from mean BRCA1 expression, respectively). Analysis included 1082 BC patients with mRNA data (PanCancer Atlas), 382 CRCs (Firehose Legacy) and 592 CRCs (PanCancer Atlas). As previously reported, BRCA1 mRNA-low tumor expression positively correlated with BC patient surv...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Sofia Leaf Lindsey Carlsen Wafik S El-Deiry Source Type: research

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells
Oncotarget. 2021 Sep 28;12(20):2006-2021. doi: 10.18632/oncotarget.28075. eCollection 2021 Sep 28.ABSTRACTColorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53-/- colorectal cancer ...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Lindsey Carlsen Christoph Schorl Kelsey Huntington Liz Hernandez-Borrero Aakash Jhaveri Shengliang Zhang Lanlan Zhou Wafik S El-Deiry Source Type: research

Comparative microsomal proteomics of a model lung cancer cell line NCI-H23 reveals distinct differences between molecular profiles of 3D and 2D cultured cells
Oncotarget. 2021 Sep 28;12(20):2022-2038. doi: 10.18632/oncotarget.28072. eCollection 2021 Sep 28.ABSTRACTLung cancer is the leading cause of cancer-related deaths in the USA and worldwide. Yet, about 95% of new drug candidates validated in preclinical phase eventually fail in clinical trials. Such a high attrition rate is attributed mostly to the inability of conventional two-dimensionally (2D) cultured cancer cells to mimic native three-dimensional (3D) growth of malignant cells in human tumors. To ascertain phenotypical differences between these two distinct culture conditions, we carried out a comparative proteomic ana...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Jan A Kaczmarczyk Rhonda R Roberts Brian T Luke King C Chan Carly M Van Wagoner Robin A Felder Richard G Saul Colantonio Simona Josip Blonder Source Type: research

Tissue biodistribution and tumor targeting of near-infrared labelled anti-CD38 antibody-drug conjugate in preclinical multiple myeloma
In this study, we evaluated the anti-tumor efficacy of DARA conjugated to the maytansine derivative, mertansine (DM1), linked via a non-cleavable bifunctional linker. The ADC was labelled with the near-infrared (NIR) fluorophore IRDye800 (DARA-DM1-IR) to evaluate its stability, biodistribution and pharmacokinetics in vitro and in vivo. We demonstrated the conjugation of: 1) DM1 enhanced tumor-killing efficacy of the native DARA and 2) IRDye800 allowed for visualization of uptake and tumor targeting ability of the ADC. With the advent of other classes of immunoconjugates for use in MM, we reasoned that such imaging techniqu...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Nicholas Cho Sooah Ko Monica Shokeen Source Type: research

Multipeptide stimulated PBMCs generate T < sub > EM < /sub > /T < sub > CM < /sub > for adoptive cell therapy in multiple myeloma
Oncotarget. 2021 Sep 28;12(20):2051-2067. doi: 10.18632/oncotarget.28067. eCollection 2021 Sep 28.ABSTRACTMultiple Myeloma (MM) patients suffer disease relapse due to the development of therapeutic resistance. Increasing evidence suggests that immunotherapeutic strategies can provide durable responses. Here we evaluate the possibility of adoptive cell transfer (ACT) by generating ex vivo T cells from peripheral blood mononuclear cells (PBMCs) isolated from MM patients by employing our previously devised protocols. We designed peptides from antigens (Ags) including cancer testis antigens (CTAs) that are over expressed in MM...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Trupti Vardam-Kaur Latha B Pathangey Daniel J McCormick P Leif Bergsagel Peter A Cohen Sandra J Gendler Source Type: research

NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells
Oncotarget. 2021 Sep 28;12(20):2068-2074. doi: 10.18632/oncotarget.28063. eCollection 2021 Sep 28.ABSTRACTPeripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated ...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Adam S Kittai Olga V Danilova Vi Lam Tingting Liu Nur Bruss Scott Best Guang Fan Alexey V Danilov Source Type: research

Safety and initial efficacy of ablative radioembolization for the treatment of unresectable intrahepatic cholangiocarcinoma
CONCLUSIONS: Radioembolization of unresectable intrahepatic cholangiocarcinoma with ablative intent has a high response rate, promising survival, and is well tolerated.PMID:34611481 | PMC:PMC8487720 | DOI:10.18632/oncotarget.28060 (Source: Oncotarget)
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Ricardo Paz-Fumagalli Jacob Core Carlos Padula Seyed Montazeri John McKinney Gregory Frey Zlatko Devcic Andrew Lewis Charles Ritchie Kabir Mody Sunil Krishnan Beau Toskich Source Type: research

Switching Hedgehog inhibitors and other strategies to address resistance when treating advanced basal cell carcinoma
Oncotarget. 2021 Sep 28;12(20):2089-2100. doi: 10.18632/oncotarget.28080. eCollection 2021 Sep 28.ABSTRACTAlthough basal cell carcinoma (BCC) is often managed successfully with surgery, patients with locally advanced BCC (laBCC) or metastatic BCC (mBCC) who are not candidates for surgery or radiotherapy have limited treatment options. Most BCCs result from aberrant Hedgehog pathway activation in keratinocyte tumor cells, caused by sporadic or inherited mutations. Mutations in the patched homologue 1 gene that remove its inhibitory regulation of Smoothened homologue (SMO) or mutations in SMO that make it constitutively acti...
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Hung Q Doan Leon Chen Zeena Nawas Heng-Huan Lee Sirunya Silapunt Michael Migden Source Type: research

Fibrocytes in primary myelofibrosis
Oncotarget. 2021 Sep 28;12(20):2101-2103. doi: 10.18632/oncotarget.27971. eCollection 2021 Sep 28.NO ABSTRACTPMID:34611483 | PMC:PMC8487717 | DOI:10.18632/oncotarget.27971 (Source: Oncotarget)
Source: Oncotarget - October 6, 2021 Category: Cancer & Oncology Authors: Kazuya Shimoda Yoshinori Ozono Kotaro Shide Source Type: research