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Article ; Online: Erratum: "Toward improved models of human cancer" [APL Bioeng.

Welm, Bryan E / Vaklavas, Christos / Welm, Alana L

APL bioengineering

2021 Volume 5, Issue 2, Page(s) 29901

Abstract: This corrects the article DOI: 10.1063/5.0030534.]. ...

Abstract	[This corrects the article DOI: 10.1063/5.0030534.].
Language	English
Publishing date	2021-06-02
Publishing country	United States
Document type	Published Erratum
ISSN	2473-2877
ISSN (online)	2473-2877
DOI	10.1063/5.0057199
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Article ; Online: Toward improved models of human cancer.

Welm, Bryan E / Vaklavas, Christos / Welm, Alana L

APL bioengineering

2021 Volume 5, Issue 1, Page(s) 10901

Abstract: Human cancer is a complex and heterogeneous collection of diseases that kills more than 18 million people every year worldwide. Despite advances in detection, diagnosis, and treatments for cancers, new strategies are needed to combat deadly cancers. ... ...

Abstract	Human cancer is a complex and heterogeneous collection of diseases that kills more than 18 million people every year worldwide. Despite advances in detection, diagnosis, and treatments for cancers, new strategies are needed to combat deadly cancers. Models of human cancer continue to evolve for preclinical research and have culminated in patient-derived systems that better represent the diversity and complexity of cancer. Still, no model is perfect. This Perspective attempts to address ways that we can improve the clinical translatability of models used for cancer research, from the point of view of researchers who mainly conduct cancer studies
Language	English
Publishing date	2021-01-04
Publishing country	United States
Document type	Journal Article
ISSN	2473-2877
ISSN (online)	2473-2877
DOI	10.1063/5.0030534
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Article: Hallmarks and Determinants of Oncogenic Translation Revealed by Ribosome Profiling in Models of Breast Cancer.

Vaklavas, Christos / Blume, Scott W / Grizzle, William E

Translational oncology

2020 Volume 13, Issue 2, Page(s) 452–470

Abstract: Gene expression is extensively and dynamically modulated at the level of translation. How cancer cells prioritize the translation of certain mRNAs over others from a pool of competing mRNAs remains an open question. Here, we analyze translation in cell ... ...

Abstract	Gene expression is extensively and dynamically modulated at the level of translation. How cancer cells prioritize the translation of certain mRNAs over others from a pool of competing mRNAs remains an open question. Here, we analyze translation in cell line models of breast cancer and normal mammary tissue by ribosome profiling. We identify key recurrent themes of oncogenic translation: higher ribosome occupancy, greater variance of translational efficiencies, and preferential translation of transcriptional regulators and signaling proteins in malignant cells as compared with their nonmalignant counterpart. We survey for candidate RNA interacting proteins that could associate with the 5'untranslated regions of the transcripts preferentially translated in breast tumour cells. We identify SRSF1, a prototypic splicing factor, to have a pervasive direct and indirect impact on translation. In a representative estrogen receptor-positive and estrogen receptor-negative cell line, we find that protein synthesis relies heavily on SRSF1. SRSF1 is predominantly intranuclear. Under certain conditions, SRSF1 translocates from the nucleus to the cytoplasm where it associates with MYC and CDK1 mRNAs and upregulates their internal ribosome entry site-mediated translation. Our results point to a synergy between splicing and translation and unveil how certain RNA-binding proteins modulate the translational landscape in breast cancer.
Language	English
Publishing date	2020-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2443840-6
ISSN	1936-5233 ; 1936-5233 ; 1944-7124
ISSN (online)	1936-5233
ISSN	1936-5233 ; 1944-7124
DOI	10.1016/j.tranon.2019.12.002
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Article ; Online: A phase I/II study of preoperative letrozole, everolimus, and carotuximab in stage 2 and 3 hormone receptor-positive and Her2-negative breast cancer.

Vaklavas, Christos / Stringer-Reasor, Erica M / Elkhanany, Ahmed M / Ryan, Kevin J / Li, Yufeng / Theuer, Charles P / Acosta, Edward P / Wei, Shi / Yang, Eddy S / Grizzle, William E / Forero-Torres, Andres

Breast cancer research and treatment

2023 Volume 198, Issue 2, Page(s) 217–229

Abstract: Purpose: In nonmetastatic hormone receptor-positive and Her2-negative breast cancer, preoperative endocrine therapies can yield outcomes similar with chemotherapy. We evaluated the tolerability and preliminary antitumor activity of preoperative ... ...

Abstract	Purpose: In nonmetastatic hormone receptor-positive and Her2-negative breast cancer, preoperative endocrine therapies can yield outcomes similar with chemotherapy. We evaluated the tolerability and preliminary antitumor activity of preoperative letrozole, everolimus, and carotuximab, a monoclonal antibody targeting endoglin, in nonmetastatic breast cancer. Methods: Eligible patients had newly diagnosed, stage 2 or 3, hormone receptor-positive and Her2/neu-negative breast cancer. Patients received escalating doses of everolimus; the dose of letrozole and carotuximab were fixed at 2.5 mg PO daily and 15 mg/kg intravenously every 2 weeks, respectively. The primary objective was to determine the safety and tolerability of the combination. Secondary objectives included pharmacokinetic and pharmacodynamic studies and assessments of antitumor activity. Results: Fifteen patients enrolled. The recommended phase 2 dose of everolimus in combination with letrozole and carotuximab was 10 mg PO daily. The most frequent adverse events were headache (67%), fatigue (47%), facial flushing and swelling (47%), gingival hemorrhage (40%), epistaxis (33%), nausea and vomiting (27%). Headache constituted a dose-limiting toxicity. At least two signs of mucocutaneous telangiectasia developed in 92% of patients. Carotuximab accumulated in the extravascular space and accelerated the biodistribution and clearance of everolimus. All patients had residual disease. Gene expression analyses were consistent with downregulation of genes involved in proliferation and DNA repair. Among 6 patients with luminal B breast cancer, 5 converted to luminal A after one cycle of therapy. Conclusion: Letrozole, everolimus, and carotuximab were tolerated in combination at their single-agent doses. Pharmacokinetic studies revealed an interaction between everolimus and carotuximab. Trial registration: This trial is registered with ClinicalTrials.gov (Identifier: NCT02520063), first posted on August 11, 2015, and is active, not recruiting.
MeSH term(s)	Humans ; Female ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Letrozole ; Everolimus ; Tissue Distribution ; Receptor, ErbB-2/metabolism ; Biomarkers, Tumor/genetics ; Antibodies, Monoclonal/metabolism ; Antineoplastic Combined Chemotherapy Protocols/adverse effects
Chemical Substances	Letrozole (7LKK855W8I) ; Everolimus (9HW64Q8G6G) ; carotuximab (YB2EWE6139) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Biomarkers, Tumor ; Antibodies, Monoclonal
Language	English
Publishing date	2023-02-03
Publishing country	Netherlands
Document type	Clinical Trial, Phase II ; Clinical Trial, Phase I ; Journal Article
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-023-06864-9
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Article: Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development.

Vaklavas, Christos / Blume, Scott W / Grizzle, William E

Frontiers in oncology

2017 Volume 7, Page(s) 158

Abstract: Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level of translation (messenger RNA to protein). Over the ... ...

Abstract	Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level of translation (messenger RNA to protein). Over the recent years, significant progress has been made in dissecting the complex posttranscriptional mechanisms that regulate gene expression. This advancement in knowledge came hand in hand with the progress made in the methodologies to study translation both at gene-specific as well as global genomic level. The majority of translational control is exerted at the level of initiation; nonetheless, protein synthesis can be modulated at the level of translation elongation, termination, and recycling. Sequence and structural elements and epitranscriptomic modifications of individual transcripts allow for dynamic gene-specific modulation of translation. Cancer cells usurp the regulatory mechanisms that govern translation to carry out translational programs that lead to the phenotypic hallmarks of cancer. Translation is a critical nexus in neoplastic transformation. Multiple oncogenes and signaling pathways that are activated, upregulated, or mutated in cancer converge on translation and their transformative impact "bottlenecks" at the level of translation. Moreover, this translational dysregulation allows cancer cells to adapt to a diverse array of stresses associated with a hostile microenviroment and antitumor therapies. All elements involved in the process of translation, from the transcriptional template, the components of the translational machinery, to the proteins that interact with the transcriptome, have been found to be qualitatively and/or quantitatively perturbed in cancer. This review discusses the regulatory mechanisms that govern translation in normal cells and how translation becomes dysregulated in cancer leading to the phenotypic hallmarks of malignancy. We also discuss how dysregulated mediators or components of translation can be utilized as biomarkers with potential diagnostic, prognostic, or predictive significance. Such biomarkers have the potential advantage of uniform applicability in the face of inherent tumor heterogeneity and deoxyribonucleic acid instability. As translation becomes increasingly recognized as a process gone awry in cancer and agents are developed to target it, the utility and significance of these potential biomarkers is expected to increase.
Language	English
Publishing date	2017-07-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2017.00158
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Article ; Online: Management of metastatic breast cancer with second-generation antibody-drug conjugates: focus on glembatumumab vedotin (CDX-011, CR011-vcMMAE).

Vaklavas, Christos / Forero, Andres

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy

2014 Volume 28, Issue 3, Page(s) 253–263

Abstract: Exploiting the highly targeted nature of monoclonal antibodies to deliver selectively to tumor cells a cytotoxic payload is an attractive concept and the successful precedents of the recent past set the stage for broader applications in the future. ... ...

Abstract	Exploiting the highly targeted nature of monoclonal antibodies to deliver selectively to tumor cells a cytotoxic payload is an attractive concept and the successful precedents of the recent past set the stage for broader applications in the future. Antibody-drug conjugates may currently hold an unprecedented potential; however, there are multiple unique challenges in their development, and the recent successes have come hand in hand with significant technologic advances in their chemistry and manufacturing. Over the years, multiple factors have been identified to affect the pharmacokinetic and pharmacodynamic properties of an antibody-drug conjugate, but many important details remain to be further investigated. These factors pertain to the target antigen, antibody, conjugate, linker, as well as the nature of the malignancy under treatment. Glembatumumab vedotin is an antibody-drug conjugate targeting glycoprotein non-metastatic B (GPNMB) expressed in multiple malignancies, including breast cancer. The expression of this protein has been associated with an aggressive malignant phenotype, invasive growth, angiogenesis, and generation of skeletal metastases. Glembatumumab vedotin is currently in early stages of clinical development in melanoma and breast cancer. Although in unselected patients with metastatic breast cancer glembatumumab vedotin was not superior to other agents, by virtue of its target being frequently and highly expressed in triple-negative breast cancer, its activity was particularly promising in this subset of patients. Results from the clinical studies in breast cancer as well as companion studies in melanoma indicate that a biomarker-informed approach is the optimal pathway for the future development of this drug.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Breast Neoplasms/drug therapy ; Female ; Humans ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use
Chemical Substances	Antibodies, Monoclonal ; CR011-vcMMAE ; Immunoconjugates ; glembatumumab vedotin (1568H6A58U)
Language	English
Publishing date	2014-06
Publishing country	New Zealand
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1364202-9
ISSN	1179-190X ; 1173-8804
ISSN (online)	1179-190X
ISSN	1173-8804
DOI	10.1007/s40259-014-0085-2
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Article: Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma.

Vaklavas, Christos / Forero-Torres, Andres

Therapeutic advances in hematology

2013 Volume 3, Issue 4, Page(s) 209–225

Abstract: Antibody-based immunotherapy has become an integral part of cancer therapeutics. However, monoclonal antibodies have their limitations as identifying an antigen selectively expressed on malignant cells and developing a high-affinity antibody may not by ... ...

Abstract	Antibody-based immunotherapy has become an integral part of cancer therapeutics. However, monoclonal antibodies have their limitations as identifying an antigen selectively expressed on malignant cells and developing a high-affinity antibody may not by itself alter tumor growth. This is illustrated in the case of CD30; CD30 epitomizes many properties of an ideal pharmacologic target such as high expression on malignant cells and limited expression on normal tissues. However, until the advent of brentuximab vedotin, CD30 remained an elusive target as antibody-based anti-CD30 immunotherapy had been largely clinically unsuccessful. Brentuximab vedotin (cAC10-vcMMAE, SGN-35) is an antibody-drug conjugate consisting of a chimeric anti-CD30 monoclonal antibody whereupon the potent microtubule inhibitor monomethyl auristatin E (MMAE) is attached via a valine-citrulline linker. Once bound to CD30, brentuximab vedotin is internalized and MMAE is released with the action of lysosomal enzymes on the linker. In phase I studies in relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma, brentuximab vedotin induced unprecedented responses with manageable toxicity. In phase II studies, brentuximab vedotin induced overall response rates of 75% and 86% in relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma, respectively. The results of these trials led to the accelerated approval of the drug by the US Food and Drug Administration in a patient population with few other alternative options. Brentuximab vedotin has overall manageable toxicity profile; however, cumulative peripheral neuropathy constitutes an important clinical consideration as it may limit prolonged administration of the drug. The mechanism by which brentuximab vedotin exerts its antitumor activity is not entirely clear. Diffusion of MMAE in the tumor microenvironment and cytotoxicity on bystander cells may in part explain its activity, especially in Hodgkin lymphoma. Herein, we review the biology of CD30 and brentuximab vedotin, and the clinical data that has accumulated thus far with SGN-35.
Language	English
Publishing date	2013-04-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2585183-4
ISSN	2040-6215 ; 2040-6207
ISSN (online)	2040-6215
ISSN	2040-6207
DOI	10.1177/2040620712443076
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Article ; Online: A single center case series of immune checkpoint inhibitor-induced type 1 diabetes mellitus, patterns of disease onset and long-term clinical outcome.

Marsiglio, John / McPherson, Jordan P / Kovacsovics-Bankowski, Magdalena / Jeter, Joanne / Vaklavas, Christos / Swami, Umang / Grossmann, Douglas / Erickson-Wayman, Alyssa / Soares, Heloisa P / Kerrigan, Katie / Gibson, Berit / Doherty, Jennifer Anne / Hyngstrom, John / Hardikar, Sheetal / Hu-Lieskovan, Siwen

Frontiers in immunology

2023 Volume 14, Page(s) 1229823

Abstract: Background: Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ICI-induced T1DM through analysis of clinical, ...

Abstract	Background: Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ICI-induced T1DM through analysis of clinical, immunological and proteomic data. Methods: This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes. Results: Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort. Conclusions: Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.
MeSH term(s)	Humans ; Immune Checkpoint Inhibitors ; Diabetes Mellitus, Type 1 ; Blood Glucose ; Proteomics ; Neoplasm Recurrence, Local ; Melanoma
Chemical Substances	Immune Checkpoint Inhibitors ; Blood Glucose
Language	English
Publishing date	2023-08-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1229823
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Article: Automated lesion detection of breast cancer in [

Leal, Jeffrey P / Rowe, Steven P / Stearns, Vered / Connolly, Roisin M / Vaklavas, Christos / Liu, Minetta C / Storniolo, Anna Maria / Wahl, Richard L / Pomper, Martin G / Solnes, Lilja B

Frontiers in oncology

2022 Volume 12, Page(s) 1007874

Abstract: Applications based on artificial intelligence (AI) and deep learning (DL) are rapidly being developed to assist in the detection and characterization of lesions on medical images. In this study, we developed and examined an image-processing workflow that ...

Abstract	Applications based on artificial intelligence (AI) and deep learning (DL) are rapidly being developed to assist in the detection and characterization of lesions on medical images. In this study, we developed and examined an image-processing workflow that incorporates both traditional image processing with AI technology and utilizes a standards-based approach for disease identification and quantitation to segment and classify tissue within a whole-body [ Methods: One hundred thirty baseline PET/CT studies from two multi-institutional preoperative clinical trials in early-stage breast cancer were semi-automatically segmented using techniques based on PERCIST v1.0 thresholds and the individual segmentations classified as to tissue type by an experienced nuclear medicine physician. These classifications were then used to train a convolutional neural network (CNN) to automatically accomplish the same tasks. Results: Our CNN-based workflow demonstrated Sensitivity at detecting disease (either primary lesion or lymphadenopathy) of 0.96 (95% CI [0.9, 1.0], 99% CI [0.87,1.00]), Specificity of 1.00 (95% CI [1.0,1.0], 99% CI [1.0,1.0]), DICE score of 0.94 (95% CI [0.89, 0.99], 99% CI [0.86, 1.00]), and Jaccard score of 0.89 (95% CI [0.80, 0.98], 99% CI [0.74, 1.00]). Conclusion: This pilot work has demonstrated the ability of AI-based workflow using DL-CNNs to specifically identify breast cancer tissue as determined by [
Language	English
Publishing date	2022-11-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.1007874
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Article ; Online: Prospective Pilot Study of

Covington, Matthew F / Hoffman, John M / Morton, Kathryn A / Buckway, Brandon / Boucher, Kenneth M / Rosenthal, Regina E / Porretta, Jane M / Brownson, Kirstyn E / Matsen, Cindy B / Vaklavas, Christos / Ward, John H / Wei, Mei / Buys, Saundra S / Chittoria, Namita / Yakish, Ellen D / Archibald, Zane G / Burrell, Lance D / Butterfield, Regan I / Yap, Jeffrey T

AJR. American journal of roentgenology

2023 Volume 221, Issue 2, Page(s) 228–239

Abstract: BACKGROUND. ...

Abstract	BACKGROUND.
MeSH term(s)	Humans ; Middle Aged ; Aged ; Female ; Positron Emission Tomography Computed Tomography/methods ; Carcinoma, Lobular/diagnostic imaging ; Carcinoma, Lobular/pathology ; Pilot Projects ; Fluorodeoxyglucose F18 ; Prospective Studies ; Breast Neoplasms/diagnostic imaging ; Breast Neoplasms/pathology ; Positron-Emission Tomography/methods ; Estradiol
Chemical Substances	Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2023-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	82076-3
ISSN	1546-3141 ; 0361-803X ; 0092-5381
ISSN (online)	1546-3141
ISSN	0361-803X ; 0092-5381
DOI	10.2214/AJR.22.28809
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