bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Materials and Methods S1 from NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer
Authors: Janssens Katleen , Vanhoutte Greetje , Lybaert Willem , Demey Wim , Decaestecker Jochen , Hendrickx Koen , Rezaei Kalantari Hassan , Zwaenepoel Karen , Pauwels Patrick , Fransen Erik , Op de Beeck Ken , Van Camp Guy , Rolfo Christian , Peeters Marc
Published: April 2023

1. Eligibility criteria - Inclusion criteria, Exclusion criteria; 2. ddPCR methodology
Supplementary Table 5 from Phase I Study of Androgen Deprivation Therapy in Combination with Anti–PD-1 in Melanoma Patients Pretreated with Anti–PD-1
Authors: Robert Caroline , Lebbé Céleste , Lesimple Thierry , Lundström Eija , Nicolas Valérie , Gavillet Bruno , Crompton Philippa , Baroudjian Barouyr , Routier Emilie , Lejeune Ferdy J.
Published: April 2023

Representativeness of Study Participants
Supplementary Tables S1-S2 from Humoral and Cellular Immune Responses against SARS-CoV-2 after Third Dose BNT162b2 following Double-Dose Vaccination with BNT162b2 versus ChAdOx1 in Patients with Cancer
Authors: Debie Yana , Van Audenaerde Jonas R.M. , Vandamme Timon , Croes Lieselot , Teuwen Laure-Anne , Verbruggen Lise , Vanhoutte Greetje , Marcq Elly , Verheggen Lisa , Le Blon Debbie , Peeters Bart , Goossens Maria E. , Pannus Pieter , Ariën Kevin K. , Anguille Sébastien , Janssens Annelies , Prenen Hans , Smits Evelien L.J. , Vulsteke Christof , Lion Eva , Peeters Marc , van Dam Peter A.
Published: April 2023

Supplementary Tables S1-S2
Figure S6 from Humoral and Cellular Immune Responses against SARS-CoV-2 after Third Dose BNT162b2 following Double-Dose Vaccination with BNT162b2 versus ChAdOx1 in Patients with Cancer
Authors: Debie Yana , Van Audenaerde Jonas R.M. , Vandamme Timon , Croes Lieselot , Teuwen Laure-Anne , Verbruggen Lise , Vanhoutte Greetje , Marcq Elly , Verheggen Lisa , Le Blon Debbie , Peeters Bart , Goossens Maria E. , Pannus Pieter , Ariën Kevin K. , Anguille Sébastien , Janssens Annelies , Prenen Hans , Smits Evelien L.J. , Vulsteke Christof , Lion Eva , Peeters Marc , van Dam Peter A.
Published: April 2023

Supplementary Figure 6: Correlation between CD4+ and CD8+ T cell responses and SARS-CoV-2 binding antibodies post homologous or heterologous booster vaccination in cancer patients.
Supplementary tables 1-4 from Single-Cell Transcriptomics Reveals Immune Reconstitution in R/R T-ALL/LBL Patients with Donor-Derived CD7 CAR-T Therapy
Authors: Chen Wei , Shi Hui , Liu Zhuojun , Yang Fan , Liu Jia , Zhang Leqiang , Wu Yajin , Xia Yuanshi , Ou Yuxuan , Li Ruiting , Zhang Ting , Zhang Jiecheng , Ke Xiaoyan , Hu Kai , Yu Jian
Published: April 2023

Supplementary table 1-4
Supplementary Table S1 from Evaluation of a Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC 005 Prospective Trial
Authors: Visvanathan Kala , Cope Leslie , Fackler Mary Jo , Considine Michael , Sokoll Lori , Carey Lisa A. , Forero-Torres Andres , Ingle James N. , Lin Nancy U. , Nanda Rita , Storniolo Anna Maria , Tulac Suzana , Venkatesan Neesha , Wu Natalie C. , Marla Sudhakar , Campbell Scott , Bates Michael , Umbricht Christopher B. , Wolff Antonio C. , Sukumar Saraswati
Published: April 2023

Overall and within batch Coefficient of Variation for CM and each Gene.
Supplementary Figure S1 from Evaluation of a Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC 005 Prospective Trial
Authors: Visvanathan Kala , Cope Leslie , Fackler Mary Jo , Considine Michael , Sokoll Lori , Carey Lisa A. , Forero-Torres Andres , Ingle James N. , Lin Nancy U. , Nanda Rita , Storniolo Anna Maria , Tulac Suzana , Venkatesan Neesha , Wu Natalie C. , Marla Sudhakar , Campbell Scott , Bates Michael , Umbricht Christopher B. , Wolff Antonio C. , Sukumar Saraswati
Published: April 2023

Study Schema
Supplementary Figures S1-S5 from A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance
Authors: Yap Timothy A. , LoRusso Patricia M. , Wong Deborah J. , Hu-Lieskovan Siwen , Papadopoulos Kyriakos P. , Holz Josefin-Beate , Grabowska Urszula , Gradinaru Cristian , Leung Kin-Mei , Marshall Sylwia , Reader Claire S. , Russell Roslin , Sainson Richard C.A. , Seal Claire J. , Shepherd Christopher J. , Germaschewski Fiona , Gliddon Daniel , Stern Omer , Young Lesley , Brewis Neil , Kayitalire Louis , Morrow Michelle
Published: April 2023

Supplementary Figure S1: Study design for the evaluation of FS118 in subjects with advanced solid tumors whoprogressed on or after prior PD-(L)1 therapy.Supplementary Figure S2: Time on FS118 treatment in patients with primary or acquired resistance to prioranti-PD-(L)1 therapies.Supplementary Figure S3: Total time on prior ICB therapies compared to the timeon FS118 treatment in patients with primary or acquired resistance to prior antiPD-(L)1 therapies.Supplementary Figure S4: Levels of soluble LAG-3 (sLAG-3) detected inthe serum of patients in the FS118 phase 1 trial.Supplementary Figure S5: Changes in circulating immune cells in FS118-treated patients.
Supplementary Figure S8 from Genetic Heterogeneity and Tissue-specific Patterns of Tumors with Multiple PIK3CA Mutations
Authors: Sivakumar Smruthy , Jin Dexter X. , Rathod Ruchita , Ross Jeffrey , Cantley Lewis C. , Scaltriti Maurizio , Chen Jessica W. , Hutchinson Katherine E. , Wilson Timothy R. , Sokol Ethan S. , Vasan Neil
Published: April 2023

Progression-free survival of patients with PIK3CA mutant tumors in the SANDPIPER study stratified by treatment arm and the quantity of PIK3CA mutations detected.
Supplementary Figure 2 from A Phase II Clinical Trial of Nivolumab and Temozolomide for Neuroendocrine Neoplasms
Authors: Owen Dwight H. , Benner Brooke , Wei Lai , Sukrithan Vineeth , Goyal Ashima , Zhou Ye , Pilcher Carly , Suffren Sheryl-Ann , Christenson Gwen , Curtis Nancy , Jukich Megan , Schwarz Emily , Savardekar Himanshu , Norman Ruthann , Ferguson Sarah , Kleiber Barbara , Wesolowski Robert , Carson William E. , Otterson Gregory A. , Verschraegen Claire F. , Shah Manisha H. , Konda Bhavana
Published: April 2023

Evaluation of circulating CD4+ T cell subsets. (A) Changes in regulatory T cells (Tregs) during treatment compared to screening in the entire patient cohort. (B) Changes in levels of circulating CD4+ naïve (CD45RA+ CCR7+), central memory (CM; CD45RA- CCR7+), effector memory (EM; CD45RA- CCR7-), and terminal effector memory (TE; CD45RA+ CCR7-) subsets at screening and cycle 1, day 15 (C1D15) of nivolumab and temozolomide treatment in the entire study cohort. (C) Levels of co-inhibitory molecules PD-1, LAG3, TIM3, and KLRG1 on circulating CD4+ T cells on study treatment compared to screening. Each symbol represents one patient (n = 9). Line indicates mean, *p<0.05.
Figure S7 from Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases
Authors: Von Roemeling Christina A. , Doonan Bently P. , Klippel Kelena , Schultz Daniel , Hoang-Minh Lan , Trivedi Vrunda , Li Chenglong , Russell Rylynn A. , Kanumuri Raju S. , Sharma Abhisheak , Tun Han W. , Mitchell Duane A.
Published: April 2023

Supplemental Figure 7. Pattern of pNF-κB expression in human CNS tumors.
Figure S5 from Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases
Authors: Von Roemeling Christina A. , Doonan Bently P. , Klippel Kelena , Schultz Daniel , Hoang-Minh Lan , Trivedi Vrunda , Li Chenglong , Russell Rylynn A. , Kanumuri Raju S. , Sharma Abhisheak , Tun Han W. , Mitchell Duane A.
Published: April 2023

Supplemental Figure 5: Chromatogram of CA-4948.
Supplementary Data 1 from Molecular Clusters and Tumor-Immune Drivers of IgM Monoclonal Gammopathies
Authors: Mondello Patrizia , Paludo Jonas , Novak Joseph P. , Wenzl Kerstin , Yang Zhi-Zhang , Jalali Shahrzad , Krull Jordan E. , Braggio Esteban , Dasari Surendra , Manske Michelle K. , Abeykoon Jithma A. , Sarangi Vivekananda , Kapoor Prashant , Paulus Aneel , Reeder Craig B. , Ailawadhi Sikander , Chanan-Khan Asher A. , Kyle Robert A. , Gertz Morie A. , Novak Anne J. , Ansell Stephen M.
Published: April 2023

Supplementary Material
Supplementary Figure S5 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: April 2023

BRD9 co-localized with BRD4 and MYC in ribosome biogenesis gene transcription start sites (TSS).
Supplemental Table S1 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: April 2023

Univariate and multivariate analysis of BRD9 expression
Supplementary Figure S1 from A Pilot Study of Intralesional Injection of Triamcinolone Acetonide for Desmoid Tumors: Two-Year Outcomes
Authors: Wilke Benjamin K. , Garner Hillary W. , Bestic Joseph M. , Chase Lori A. , Heckman Michael G. , Schoch Jennifer J. , Attia Steven
Published: April 2023

A Scatterplot demonstrating correlation between the early changes in T2 signal intensity and 24-month tumor volume.
Supplementary Table S6 from A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma
Authors: Lee Hyun-Sung , Jang Hee-Jin , Ramineni Maheshwari , Wang Daniel Y. , Ramos Daniela , Choi Jong Min , Splawn Taylor , Espinoza Monica , Almarez Michelle , Hosey Leandria , Jo Eunji , Hilsenbeck Susan , Amos Christopher I. , Ripley R. Taylor , Burt Bryan M.
Published: April 2023

Supplementary Table 6. CyTOF antibody panel for PBMC, relevant to Figure 4.
Supplementary Figure S10 from A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma
Authors: Lee Hyun-Sung , Jang Hee-Jin , Ramineni Maheshwari , Wang Daniel Y. , Ramos Daniela , Choi Jong Min , Splawn Taylor , Espinoza Monica , Almarez Michelle , Hosey Leandria , Jo Eunji , Hilsenbeck Susan , Amos Christopher I. , Ripley R. Taylor , Burt Bryan M.
Published: April 2023

Supplementary Figure 10. Presence of follicular helper T cells in CD57(+) T cells
Supplementary Figure S3 from Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial
Authors: Landen Charles N. , Molinero Luciana , Hamidi Habib , Sehouli Jalid , Miller Austin , Moore Kathleen N. , Taskiran Cagatay , Bookman Michael , Lindemann Kristina , Anderson Charles , Berger Regina , Myers Tashanna , Beiner Mario , Reid Thomas , Van Nieuwenhuysen Els , Green Andrew , Okamoto Aikou , Aghajanian Carol , Thaker Premal H. , Blank Stephanie V. , Khor Victor K. , Chang Ching-Wei , Lin Yvonne G. , Pignata Sandro
Published: April 2023

PFS according to homologous recombination and BRCA1/2 status in the subgroup of patients with IC ≥5%.
Supplementary Figure S1 from Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR− Trial
Authors: Graeser Monika , Gluz Oleg , Biehl Claudia , Ulbrich-Gebauer Daniel , Christgen Matthias , Palatty Jenci , Kuemmel Sherko , Grischke Eva-Maria , Augustin Doris , Braun Michael , Potenberg Jochem , Wuerstlein Rachel , Krauss Katja , Schumacher Claudia , Forstbauer Helmut , Reimer Toralf , Stefek Andrea , Fischer Hans Holger , Pelz Enrico , zu Eulenburg Christine , Kates Ronald , Ni Hua , Kolberg-Liedtke Cornelia , Feuerhake Friedrich , Kreipe Hans Heinrich , Nitz Ulrike , Harbeck Nadia
Published: April 2023

CONSORT diagram
Supplementary Tables 1-8 from ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma
Authors: Blandin Anne-Florence , Giglio Ross , Graham Maya Srikanth , Garcia Guadalupe , Malinowski Seth , Woods Jared K. , Ramkissoon Shakti , Ramkissoon Lori , Dubois Frank , Schoolcraft Kathleen , Tsai Jessica , Wang Dayle , Jones Robert , Vogelzang Jayne , Pelton Kristine , Becker Sarah , Watkinson Fiona , Sinai Claire , Cohen Elizabeth F. , Booker Matthew A. , Tolstorukov Michael Y. , Haemels Veerle , Goumnerova Liliana , Wright Karen , Kieran Mark , Fehnel Katie , Reardon David , Tauziede-Espariat Arnault , Lulla Rishi , Carcamo Benjamin , Chaleff Stanley , Charest Alain , De Smet Frederik , Ligon Azra H. , Dubuc Adrian , Pages Melanie , Varlet Pascale , Wen Patrick Y. , Alexander Brian M. , Chi Susan , Alexandrescu Sanda , Kittler Ralf , Bachoo Robert , Bandopadhayay Pratiti , Beroukhim Rameen , Ligon Keith L.
Published: April 2023

Additional information tables 1 to 8.
Supplementary Figures S1-S15 from Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics
Authors: Lozano-Rabella Maria , Garcia-Garijo Andrea , Palomero Jara , Yuste-Estevanez Anna , Erhard Florian , Farriol-Duran Roc , Martín-Liberal Juan , Ochoa-de-Olza Maria , Matos Ignacio , Gartner Jared J. , Ghosh Michael , Canals Francesc , Vidal August , Piulats Josep Maria , Matías-Guiu Xavier , Brana Irene , Muñoz-Couselo Eva , Garralda Elena , Schlosser Andreas , Gros Alena
Published: April 2023

Supplementary Figure 1. Validation of HLA-I ligand tumor antigen candidates with synthetic peptides
Supplementary Figure 2. Validation of selected HLA-I ligand tumor antigen candidates identified in Mel-1 and Mel-3 with isotope-labeled peptides
Supplementary Figure 3. Frequency of nonC peptides detected in HLA-I.
Supplementary Fig. 4. HLA-I allele binding motif of all patients included in the study.
Supplementary Figure 5. A fraction of nonC-TL can be detected in publicly available immunopeptidomics datasets from human tumor biopsies
Supplementary Figure 6. Evaluation of pre-existing T-cell responses to candidate tumor antigens in cancer patients
Supplementary Figure 7. Enrichment of antigen-specific T cells from cancer patients by flow cytometry-based sorting.
Supplementary Figure 8. Deconvolution of peptide pools containing recognized CGA or melanoma-associated antigens.
Supplementary Figure 9. Functional avidity and specificity of neoantigen-specific T cells isolated from cancer patients.
Supplementary Figure 10. HLA restriction element and recognition of autologous tumor cell lines by antigen-specific T cells isolated from cancer patients.
SupplementaryFigure 11. Genomic location of the three immunogenic nonC-TL identified through IVS.
Supplementary Figure 12. Recognition of the predicted ORFs encoding the immunogenic nonC-TL by TCR transduced cells.
Supplementary Figure 13. Loss of recognition of TCL transfected with Cas9-sgRNA targeting the predicted 5’U-HOXC13 ORF.
Supplementary Figure 14. Assessment of expression and translation of the immunogenic nonC-TL in human healthy cells.
Supplementary Figure 15. NonC-TL are the main source of candidate tumor antigens identified by proteogenomics but tumor-reactive T cells preferentially recognize neoantigens derived from NSM.
Supplementary Table S3 from Intratumoral CD16+ Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy
Authors: Lee Hansol , Ferguson Angela L. , Quek Camelia , Vergara Ismael A. , Pires daSilva Ines , Allen Ruth , Gide Tuba Nur , Conway Jordan W. , Koufariotis Lambros T. , Hayward Nicholas K. , Waddell Nicola , Carlino Matteo S. , Menzies Alexander M. , Saw Robyn P.M. , Shklovskaya Elena , Rizos Helen , Lo Serigne , Scolyer Richard A. , Long Georgina V. , Palendira Umaimainthan , Wilmott James S.
Published: April 2023

Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Supplementary Table S1 from Intratumoral CD16+ Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy
Authors: Lee Hansol , Ferguson Angela L. , Quek Camelia , Vergara Ismael A. , Pires daSilva Ines , Allen Ruth , Gide Tuba Nur , Conway Jordan W. , Koufariotis Lambros T. , Hayward Nicholas K. , Waddell Nicola , Carlino Matteo S. , Menzies Alexander M. , Saw Robyn P.M. , Shklovskaya Elena , Rizos Helen , Lo Serigne , Scolyer Richard A. , Long Georgina V. , Palendira Umaimainthan , Wilmott James S.
Published: April 2023

Representativeness of study participants
Data from Macrophage Inflammatory Protein-3α Is a Novel Serum Marker for Nasopharyngeal Carcinoma Detection and Prediction of Treatment Outcomes
Authors: Chang Kai-Ping , Hao Sheng-Po , Chang Jui-Hung , Wu Chih-Ching , Tsang Ngan-Ming , Lee Yun-Shien , Hsu Chen-Lung , Ueng Shir-Hwa , Liu Shiau-Chin , Liu Yu-Lun , Wei Pei-Cih , Liang Yin , Chang Yu-Sun , Yu Jau-Song
Published: April 2023

Abstract
Purpose: We herein examine whether macrophage inflammatory protein-3α (MIP-3α) is a biomarker for nasopharyngeal carcinoma (NPC) and whether it is involved in modulating NPC cell functions.

Experimental Design: The study population comprises 275 NPC patients and 250 controls. MIP-3α levels in tissues and sera were examined by immunohistochemistry and ELISA, respectively. EBV DNA load and EBV viral capsid antigen IgA were measured by quantitative real-time PCR and immunofluorescence assay, respectively. Effects of MIP-3α on NPC cell motility were investigated by Transwell migration/invasion assays and RNA interference.

Results: MIP-3α was overexpressed in NPC tumor cells. Serum MIP-3α levels were significantly higher in untreated patients, recurrent patients and patients with distant metastases versus non-NPC controls, patients with complete remission, and long-term disease-free patients. In the prospective cohort, serum MIP-3α levels were significantly higher in untreated NPC patients with advanced tumor-node-metastasis stage versus early stage and also correlated with EBV DNA load. Measurement of MIP-3α, EBV DNA, and viral capsid antigen IgA levels in serial serum/plasma samples from treated patients at 6-month intervals revealed a high association between MIP-3α level, EBV DNA load, and disease status. Among 155 consecutive NPC patients, subjects with pretreated MIP-3α serum levels over 65 pg/mL had worse prognoses for overall survival and distant metastasis-free survival in univariate and multivariate analysis. Additionally, cell functional assays showed that MIP-3α contributed to migration and invasion of NPC cells, which could be effectively inhibited by MIP-3α knockdown.

Conclusions: MIP-3α may be a novel biomarker and prognosticator for NPC and is involved in migration and invasion of NPC cells.
Data from Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer
Authors: Briasoulis Evangelos , Pappas Periklis , Puozzo Christian , Tolis Christos , Fountzilas George , Dafni Urania , Marselos Marios , Pavlidis Nicholas
Published: April 2023

Abstract
Aim: To determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine and obtain preliminary data on biomarkers and efficacy in patients with advanced cancer.

Methods: Successive cohorts of patients received escalated doses of oral vinorelbine given thrice a week until disease progression, unacceptable toxicity (UT), or consent withdrawal. UT was any grade 4 toxicity, or grade 2 or 3 toxicity that would result to longer than 2-week break during the first 2 months of treatment. Blood samples were collected for pharmacokinetics and quantification of angiogenesis regulatory proteins.

Results: Sixty-two patients (median age, 60 years) enrolled at six dose levels from 20 to 70 mg and received treatment for median 12.25 weeks (range, 2-216+). Unacceptable toxicity occurred in two of six patients treated at 60 mg (leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg (leucopenia grade 2). The upper metronomic dose was 50 mg. Objective antitumor response documented in eight cases and 32% of patients experienced disease stability for minimum 6 months. Three responders (renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma) received nonstop treatment for over 3 years without overt toxicity. Low pretreatment levels of circulating interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were found predictors of efficacy. Steady-state concentrations of vinorelbine and its active metabolite ranged from 0.5 to 1.5 ng/mL.

Conclusions: Metronomic administration of oral vinorelbine is feasible at doses up to 50 mg thrice a week and can yield sustainable antitumor activity without overt toxicity, probably through antiangiogenic mechanism. Further clinical investigation is warranted. (Clin Cancer Res 2009;15(20):6454–61)
Data from Targeting Akt3 Signaling in Malignant Melanoma Using Isoselenocyanates
Authors: Sharma Arati , Sharma Arun K. , Madhunapantula SubbaRao V. , Desai Dhimant , Huh Sung Jin , Mosca Paul , Amin Shantu , Robertson Gavin P.
Published: April 2023

Abstract
Purpose: Melanoma is the most invasive and deadly form of skin cancer. Few agents are available for treating advanced disease to enable long-term patient survival, which is driving the search for new compounds inhibiting deregulated pathways causing melanoma. Akt3 is an important target in melanomas because its activity is increased in ∼70% of tumors, decreasing apoptosis in order to promote tumorigenesis.

Experimental Design: Because naturally occurring products can be effective anticancer agents, a library was screened to identify Akt3 pathway inhibitors. Isothiocyanates were identified as candidates, but low potency requiring high concentrations for therapeutic efficacy made them unsuitable. Therefore, more potent analogs called isoselenocyanates were created using the isothiocyanate backbone but increasing the alkyl chain length and replacing sulfur with selenium. Efficacy was measured on cultured cells and tumors by quantifying proliferation, apoptosis, toxicity, and Akt3 pathway inhibition.

Results: Isoselenocyanates significantly decreased Akt3 signaling in cultured melanoma cells and tumors. Compounds having 4 to 6 carbon alkyl side chains with selenium substituted for sulfur, called ISC-4 and ISC-6, respectively, decreased tumor development by ∼60% compared with the corresponding isothiocyanates, which had no effect. No changes in animal body weight or in blood parameters indicative of liver-, kidney-, or cardiac-related toxicity were observed with isoselenocyanates. Mechanistically, isoselenocyanates ISC-4 and ISC-6 decreased melanoma tumorigenesis by causing an ∼3-fold increase in apoptosis.

Conclusions: Synthetic isoselenocyanates are therapeutically effective for inhibiting melanoma tumor development by targeting Akt3 signaling to increase apoptosis in melanoma cells with negligible associated systemic toxicity.
Data from Genomic Profiling of Chondrosarcoma: Chromosomal Patterns in Central and Peripheral Tumors
Authors: Hallor Karolin H. , Staaf Johan , Bovée Judith V.M.G. , Hogendoorn Pancras C.W. , Cleton-Jansen Anne-Marie , Knuutila Sakari , Savola Suvi , Niini Tarja , Brosjö Otte , Bauer Henrik C.F. , Vult von Steyern Fredrik , Jonsson Kjell , Skorpil Mikael , Mandahl Nils , Mertens Fredrik
Published: April 2023

Abstract
Purpose: Histologic grade is currently the best predictor of clinical course in chondrosarcoma patients. Grading suffers, however, from extensive interobserver variability and new objective markers are needed. Hence, we have investigated DNA copy numbers in chondrosarcomas with the purpose of identifying markers useful for prognosis and subclassification.

Experimental Design: The overall pattern of genomic imbalances was assessed in a series of 67 chondrosarcomas using array comparative genomic hybridization. Statistical analyses were applied to evaluate the significance of alterations detected in subgroups based on clinical data, morphology, grade, tumor size, and karyotypic features. Also, the global gene expression profiles were obtained in a subset of the tumors.

Results: Genomic imbalances, in most tumors affecting large regions of the genome, were found in 90% of the cases. Several apparently distinctive aberrations affecting conventional central and peripheral tumors, respectively, were identified. Although rare, recurrent amplifications were found at 8q24.21-q24.22 and 11q22.1-q22.3, and homozygous deletions of loci previously implicated in chondrosarcoma development affected the CDKN2A, EXT1, and EXT2 genes. The chromosomal imbalances in two distinct groups of predominantly near-haploid and near-triploid tumors, respectively, support the notion that polyploidization of an initially hyperhaploid/hypodiploid cell population is a common mechanism of chondrosarcoma progression. Increasing patient age as well as tumor grade were associated with adverse outcome, but no copy number imbalance affected metastasis development or tumor-associated death.

Conclusion: Despite similarities in the overall genomic patterns, the present findings suggest that some regions are specifically altered in conventional central and peripheral tumors, respectively.
Data from Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy is Frequent and Associated with Poor Prognosis
Authors: Strathdee Gordon , Holyoake Tessa L. , Sim Alyson , Parker Anton , Oscier David G. , Melo Junia V. , Meyer Stefan , Eden Tim , Dickinson Anne M. , Mountford Joanne C. , Jorgensen Heather G. , Soutar Richard , Brown Robert
Published: April 2023

Abstract
Purpose: The HOX genes comprise a large family of homeodomain-containing transcription factors, present in four separate clusters, which are key regulators of embryonic development, hematopoietic differentiation, and leukemogenesis. We aimed to study the role of DNA methylation as an inducer of HOX gene silencing in leukemia.

Experimental Design: Three hundred and seventy-eight samples of myeloid and lymphoid leukemia were quantitatively analyzed (by COBRA analysis and pyrosequencing of bisulfite-modified DNA) for methylation of eight HOXA and HOXB cluster genes. The biological significance of the methylation identified was studied by expression analysis and through re-expression of HOXA5 in a chronic myeloid leukemia (CML) blast crisis cell line model.

Results: Here, we identify frequent hypermethylation and gene inactivation of HOXA and HOXB cluster genes in leukemia. In particular, hypermethylation of HOXA4 and HOXA5 was frequently observed (26-79%) in all types of leukemias studied. HOXA6 hypermethylation was predominantly restricted to lymphoid malignancies, whereas hypermethylation of other HOXA and HOXB genes was only observed in childhood leukemia. HOX gene methylation exhibited clear correlations with important clinical variables, most notably in CML, in which hypermethylation of both HOXA5 (P = 0.00002) and HOXA4 (P = 0.006) was strongly correlated with progression to blast crisis. Furthermore, re-expression of HOXA5 in CML blast crisis cells resulted in the induction of markers of granulocytic differentiation.

Conclusion: We propose that in addition to the oncogenic role of some HOX family members, other HOX genes are frequent targets for gene inactivation and normally play suppressor roles in leukemia development.
Data from Metastasis-Associated Gene Expression Changes Predict Poor Outcomes in Patients with Dukes Stage B and C Colorectal Cancer
Authors: Jorissen Robert N. , Gibbs Peter , Christie Michael , Prakash Saurabh , Lipton Lara , Desai Jayesh , Kerr David , Aaltonen Lauri A. , Arango Diego , Kruhøffer Mogens , Ørntoft Torben F. , Andersen Claus Lindbjerg , Gruidl Mike , Kamath Vidya P. , Eschrich Steven , Yeatman Timothy J. , Sieber Oliver M.
Published: April 2023

Abstract
Purpose: Colorectal cancer prognosis is currently predicted from pathologic staging, providing limited discrimination for Dukes stage B and C disease. Additional markers for outcome are required to help guide therapy selection for individual patients.

Experimental Design: A multisite single-platform microarray study was done on 553 colorectal cancers. Gene expression changes were identified between stage A and D tumors (three training sets) and assessed as a prognosis signature in stage B and C tumors (independent test and external validation sets).

Results: One hundred twenty-eight genes showed reproducible expression changes between three sets of stage A and D cancers. Using consistent genes, stage B and C cancers clustered into two groups resembling early-stage and metastatic tumors. A Prediction Analysis of Microarray algorithm was developed to classify individual intermediate-stage cancers into stage A–like/good prognosis or stage D–like/poor prognosis types. For stage B patients, the treatment adjusted hazard ratio for 6-year recurrence in individuals with stage D–like cancers was 10.3 (95% confidence interval, 1.3-80.0; P = 0.011). For stage C patients, the adjusted hazard ratio was 2.9 (95% confidence interval, 1.1-7.6; P = 0.016). Similar results were obtained for an external set of stage B and C patients. The prognosis signature was enriched for downregulated immune response genes and upregulated cell signaling and extracellular matrix genes. Accordingly, sparse tumor infiltration with mononuclear chronic inflammatory cells was associated with poor outcome in independent patients.

Conclusions: Metastasis-associated gene expression changes can be used to refine traditional outcome prediction, providing a rational approach for tailoring treatments to subsets of patients. (Clin Cancer Res 2009;15(24):7642–51)
Data from Predicting Relapse in Favorable Histology Wilms Tumor Using Gene Expression Analysis: A Report from the Renal Tumor Committee of the Children's Oncology Group
Authors: Huang Chiang-Ching , Gadd Samantha , Breslow Norman , Cutcliffe Colleen , Sredni Simone T. , Helenowski Irene B. , Dome Jeffrey S. , Grundy Paul E. , Green Daniel M. , Fritsch Michael K. , Perlman Elizabeth J.
Published: April 2023

Abstract
Purpose: The past two decades has seen significant improvement in the overall survival of patients with favorable histology Wilms tumor (FHWT); however, this progress has reached a plateau. Further improvements may rely on the ability to better stratify patients by risk of relapse. This study determines the feasibility and potential clinical utility of classifiers of relapse based on global gene expression analysis.

Experimental Design: Two hundred fifty FHWT of all stages enriched for relapses treated on National Wilms Tumor Study-5 passed quality variables and were suitable for analysis using oligonucleotide arrays. Relapse risk stratification used support vector machine; 2- and 10-fold cross-validations were applied.

Results: The number of genes associated with relapse was less than that predicted by chance alone for 106 patients (32 relapses) with stages I and II FHWT treated with chemotherapy, and no further analyses were done. This number was greater than expected by chance for 76 local stage III patients. Cross-validation including an additional 68 local stage III patients (total 144 patients, 53 relapses) showed that classifiers for relapse composed of 50 genes were associated with a median sensitivity of 47% and specificity of 70%.

Conclusions: This study shows the feasibility and modest accuracy of stratifying local stage III FHWT using a classifier of <50 genes. Validation using an independent patient population is needed. Analysis of genes differentially expressed in relapse patients revealed apoptosis, Wnt signaling, insulin-like growth factor pathway, and epigenetic modification to be mechanisms important in relapse. Potential therapeutic targets include FRAP/MTOR and CD40.
Data from Common Polymorphisms in the Prostaglandin Pathway Genes and Their Association with Breast Cancer Susceptibility and Survival
Authors: Abraham Jean E. , Harrington Patricia , Driver Kristy E. , Tyrer Jonathan , Easton Douglas F. , Dunning Alison M. , Pharoah Paul D.P.
Published: April 2023

Abstract
Purpose: There is evidence that genetic variation in the prostaglandin pathway affects cancer susceptibility and progression. Conflicting data from several studies exist for the association of PTGS2 (cyclooxygenase 2) polymorphisms with breast cancer risk. We investigated associations between common germ-line variations in seven genes in the prostaglandin pathway and breast cancer susceptibility and survival among women with invasive breast cancer in the SEARCH study.

Experimental Design: DNA samples from 9,030 cases and controls were genotyped for 64 single nucleotide polymorphisms tagging known common variants (minor allele frequency > 0.05) in PTGS1, PTGS2, TBXAS1, PTGIS, PTGES, PTGDS, and PGDS with a two-stage case-control study design.

Results: Four tagging single nucleotide polymorphisms showed modest association with breast cancer susceptibility. All four fit a recessive genetic model. Minor allele homozygotes for PTGISrs5602 [odds ratio (OR), 1.15; 95% confidence interval (95% CI), 1.04-1.27; P = 0.005], PTGISrs8183919 (OR, 1.22; 95% CI, 1.06-1.41; P = 0.006), and TBXASrs41727 (OR, 1.83; 95% CI, 1.22-2.73; P = 0.003) are associated with an increased risk compared with common allele carriers. For PTGISrs44627 minor allele homozygotes (OR, 0.66; 95% CI, 0.5-0.86; P = 0.002), a protective effect was observed.

Conclusion: Specific PTGIS and TBXAS1 variants may affect breast cancer susceptibility, but common variants in PTGS1, PTGS2, PTGES, PTGDS, and PGDS have no major role in breast cancer susceptibility. None of the variants in the seven genes studied appear to affect survival. Further larger studies correlating clinical and genotypic data are required to establish if the clinical utility of prostaglandin-targeted therapies, as chemoprevention agents, is influenced by an individual's profile of genetic variants in key prostaglandin pathway genes.
Data from Phosphoinositide 3-Kinase Mutations in Breast Cancer: A “Good” Activating Mutation?
Authors: Di Cosimo Serena , Baselga José
Published: April 2023

Abstract
Gain-of-function mutations in the catalytic subunit of phosphoinositide-3-kinase (PI3KCA) occur frequently in breast cancer. Kalinsky and colleagues show that PI3KCA mutations are associated with favorable clinicopathologic features and better clinical outcome, including survival. These findings will have to be considered in the design and interpretation of clinical trials with inhibitors of the PI3K pathway. (Clin Cancer Res 2009;15(16):5017–9)
Data from Synergistic Enhancement of CD8+ T Cell–Mediated Tumor Vaccine Efficacy by an Anti–Transforming Growth Factor-β Monoclonal Antibody
Authors: Terabe Masaki , Ambrosino Elena , Takaku Shun , O'Konek Jessica J. , Venzon David , Lonning Scott , McPherson John M. , Berzofsky Jay A.
Published: April 2023

Abstract
Purpose: Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine, having direct suppressive activity against conventional CD4+ and CD8+T cells and natural killer cells, thereby inhibiting tumor immunosurveillance. Here, we investigated possible synergy between anti–TGF-β (1D11) and a peptide vaccine on induction of antitumor immunity, and the mechanisms accounting for synergistic efficacy.

Experimental Design: The effect of combination treatment with a peptide vaccine and anti–TGF-β was examined in a subcutaneous TC1 tumor model, as well as the mechanisms of protection induced by this treatment.

Results: Anti–TGF-β significantly and synergistically improved vaccine efficacy as measured by reduction in primary tumor growth, although anti–TGF-β alone had no impact. The number of tumor antigen–specific CTL with high functional avidity as measured by IFN-γ production and lytic activity was significantly increased in vaccinated mice by TGF-β neutralization. Although TGF-β is known to play a critical role in CD4+Foxp3+ Treg cells, Treg depletion/suppression by an anti-CD25 monoclonal antibody (PC61) before tumor challenge did not enhance vaccine efficacy, and adding anti–TGF-β did not affect Treg numbers in lymph nodes or tumors or their function. Also, TGF-β neutralization had no effect on interleukin-17–producing T cells, which are induced by TGF-β and interleukin-6. Absence of type II NKT cells, which induce myeloid cells to produce TGF-β, was not sufficient to eliminate all sources of suppressive TGF-β. Finally, the synergistic protection induced by anti–TGF-β vaccine augmentation was mediated by CD8+ T cells since anti-CD8 treatment completely abrogated the effect.

Conclusions: These results suggest that TGF-β blockade may be useful for enhancing cancer vaccine efficacy. (Clin Cancer Res 2009;15(21):6560–9)
Data from A Gene Expression Signature that Can Predict the Recurrence of Tamoxifen-Treated Primary Breast Cancer
Authors: Chanrion Maïa , Negre Vincent , Fontaine Hélène , Salvetat Nicolas , Bibeau Frédéric , Grogan Gaëtan Mac , Mauriac Louis , Katsaros Dionyssios , Molina Franck , Theillet Charles , Darbon Jean-Marie
Published: April 2023

Abstract
Purpose: The identification of a molecular signature predicting the relapse of tamoxifen-treated primary breast cancers should help the therapeutic management of estrogen receptor–positive cancers.

Experimental Design: A series of 132 primary tumors from patients who received adjuvant tamoxifen were analyzed for expression profiles at the whole-genome level by 70-mer oligonucleotide microarrays. A supervised analysis was done to identify an expression signature.

Results: We defined a 36-gene signature that correctly classified 78% of patients with relapse and 80% of relapse-free patients (79% accuracy). Using 23 independent tumors, we confirmed the accuracy of the signature (78%) whose relevance was further shown by using published microarray data from 60 tamoxifen-treated patients (63% accuracy). Univariate analysis using the validation set of 83 tumors showed that the 36-gene classifier is more efficient in predicting disease-free survival than the traditional histopathologic prognostic factors and is as effective as the Nottingham Prognostic Index or the “Adjuvant!” software. Multivariate analysis showed that the molecular signature is the only independent prognostic factor. A comparison with several already published signatures demonstrated that the 36-gene signature is among the best to classify tumors from both training and validation sets. Kaplan-Meier analyses emphasized its prognostic power both on the whole cohort of patients and on a subgroup with an intermediate risk of recurrence as defined by the St. Gallen criteria.

Conclusion: This study identifies a molecular signature specifying a subgroup of patients who do not gain benefits from tamoxifen treatment. These patients may therefore be eligible for alternative endocrine therapies and/or chemotherapy.
Data from Validation of Genomics-Based Prognostic Tests in Malignant Pleural Mesothelioma
Authors: Gordon Gavin J. , Rockwell Graham N. , Godfrey Paul A. , Jensen Roderick V. , Glickman Jonathan N. , Yeap Beow Y. , Richards William G. , Sugarbaker David J. , Bueno Raphael
Published: April 2023

Abstract
Purpose: Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm with limited pretreatment prognostication strategies. In this report, we examine the accuracy of a previously proposed prognostic test in an independent cohort of MPM patients. This test uses simple ratios of gene expression levels to provide a novel prognostication scheme.

Experimental Design: Gene expression data using high-density oligonucleotide microarrays (∼22,000 genes) were obtained for a new cohort of human MPM tumors from patients undergoing similar treatments (n = 39). The relative expression levels for specific genes were also determined using real-time quantitative reverse transcription-PCR. We also used a subset of these tumors associated with widely divergent patient survival (n = 23) as a training set to identify new treatment-specific candidate prognostic molecular markers and gene ratio–based prognostic tests. The predictive nature of these newly discovered markers and gene ratio–based prognostic tests were then examined in an independent group of tumors (n = 52) using microarray data and quantitative reverse transcription-PCR.

Results: Previously described MPM prognostic genes and gene ratio–based prognostic tests predicted clinical outcome in 39 independent MPM tumor specimens in a statistically significant manner. Newly discovered treatment-specific prognostic genes and gene ratio–based prognostic tests were highly accurate and statistically significant when examined in an independent group of 52 tumors from patients undergoing similar treatment.

Conclusions: The data support the use of gene ratios in translating gene expression data into easily reproducible, statistically validated clinical tests for the prediction of outcome in MPM.
Data from Exploratory Analysis of Early Toxicity of Sunitinib in Advanced Hepatocellular Carcinoma Patients: Kinetics and Potential Biomarker Value
Authors: Zhu Andrew X. , Duda Dan G. , Ancukiewicz Marek , di Tomaso Emmanuelle , Clark Jeffrey W. , Miksad Rebecca , Fuchs Charles S. , Ryan David P. , Jain Rakesh K.
Published: April 2023

Abstract
Purpose: Sunitinib—a multitargeted tyrosine kinase inhibitor—can modulate circulating inflammatory factors in cancer patients that may be relevant for hepatocellular carcinoma (HCC) progression. However, a recent phase III study of sunitinib in HCC was halted due to its toxicity. Here, we studied the early kinetics of adverse events after sunitinib, and explored their association with circulating proteins and clinical outcome in advanced HCC in a single-arm phase II study.

Experimental Design: Toxicity was evaluated every two weeks during the first cycle of therapy. Biomarker changes from baseline were tested after adjusting for multiple comparisons. Correlation between toxicities and overall survival (OS) or time-to-tumor progression (TTP) was evaluated in a Cox model using log-transformed levels or change in biomarkers, after stratifying by stage and adjusting for baseline level.

Results: Myeloid and lymphoid blood cell counts decreased by 20% to 50% after sunitinib treatment (P < 0.05 for all). The extent of the early decrease in neutrophils and monocytes, and the development of nonhematologic toxicities (i.e., skin toxicities), were significantly associated with both OS and TTP (P < 0.05). Changes in circulating cells significantly associated with specific changes in plasma biomarkers (i.e., changes in platelets with changes in VEGF-C and soluble-VEGFR3; changes in neutrophils with changes in IL-8, TNF-α, and soluble-VEGFR2).

Conclusions: The adverse effects of sunitinib, particularly on the hematopoietic system, may be rapid and appear directly related to its activity in HCC. This exploratory study suggests that early hematopoietic toxicities may potentially predict outcome in advanced HCC after sunitinib treatment. Clin Cancer Res; 17(4); 918–27. ©2010 AACR.
Data from Volumes to Learn: Advancing Therapeutics with Innovative Computed Tomography Image Data Analysis
Authors: Maitland Michael L.
Published: April 2023

Abstract
Semi-automated methods for calculating tumor volumes from computed tomography images are a new tool for advancing the development of cancer therapeutics. Volumetric measurements, relying on already widely available standard clinical imaging techniques, could shorten the observation intervals needed to identify cohorts of patients sensitive or resistant to treatment. Clin Cancer Res; 16(18); 4493–5. ©2010 AACR.
Data from Molecular Karyotypes of Hodgkin and Reed–Sternberg Cells at Disease Onset Reveal Distinct Copy Number Alterations in Chemosensitive versus Refractory Hodgkin Lymphoma
Authors: Slovak Marilyn L. , Bedell Victoria , Hsu Ya-Hsuan , Estrine Dolores B. , Nowak Norma J. , Delioukina Maria L. , Weiss Lawrence M. , Smith David D. , Forman Stephen J.
Published: April 2023

Abstract
Purpose: To determine the recurring DNA copy number alterations (CNA) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture microdissected CD30+ Hodgkin and Reed–Sternberg (HRS) cells.

Experimental Design: Archived tissues from 27 CD30+ HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared with the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease).

Results: Gains and losses observed in more than 35% of HL samples were localized to 22 and 12 chromosomal regions, respectively. Frequent gains (>65%) were associated with growth and proliferation, NF-κB activation, cell-cycle control, apoptosis, and immune and lymphoid development. Frequent losses (>40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, and ID4, inhibitor of DNA binding 4), transcriptional repressors (TXNIP, thioredoxin interacting protein), SKP2 (S-phase kinase-associated protein 2; ubiquitin ligase component), and an antagonist of NF-κB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, and SKP2), and gains in 7q36 (SHH, sonic hedgehog homolog) and 9q34 (ABL1, CDK9, LCN2, and PTGES). Gains (>35%) in the HL chemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4, and IL10), whereas the refractory samples showed frequent loss of 4q27 (interleukin; IL21/IL2) and 17p12, and gain of 19q13.3 (BCL3/RELB).

Conclusion: We identified nonrandom CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL. Clin Cancer Res; 17(10); 3443–54. ©2011 AACR.
Data from Dasatinib Plus Nutlin-3 Shows Synergistic Antileukemic Activity in Both p53wild-type and p53mutated B Chronic Lymphocytic Leukemias by Inhibiting the Akt Pathway
Authors: Zauli Giorgio , Voltan Rebecca , Bosco Raffaella , Melloni Elisabetta , Marmiroli Sandra , Rigolin Gian Matteo , Cuneo Antonio , Secchiero Paola
Published: April 2023

Abstract
Purpose: To analyze the effect of the combination of Dasatinib, a multikinase inhibitor, plus Nutlin-3, a nongenotoxic activator of the p53 pathway, in primary B chronic lymphocytic leukemia (B-CLL) patient samples and B leukemic cell line models.

Experimental Design: The induction of cytotoxicity was evaluated in both primary B-CLL cell samples (n = 20) and in p53wild-type (EHEB, JVM-2) and p53deleted/mutated (MEC-2, BJAB) B leukemic cell lines. The role of Akt in modulating leukemic cell survival/apoptosis in response to Dasatinib or Dasatinib + Nutlin-3 was documented by functional experiments carried out using specific pharmacological inhibitors and by overexpression of membrane-targeted constitutively active form of Akt.

Results: The combination of Dasatinib + Nutlin-3 exhibited a synergistic cytotoxicity in the majority (19 out of 20) of B-CLL samples, including patients carrying 17p- (n = 4), and in both p53wild-type and p53deleted/mutated B leukemic cell lines. At the molecular level, Dasatinib significantly counteracted the Nutlin-3-mediated induction of the p53 transcriptional targets MDM2 and p21 observed in p53wild-type leukemic cells. Conversely, Nutlin-3 did not interfere with the ability of Dasatinib to decrease the phosphorylation levels of ERK1/2, p38/MAPK, and Akt in both p53wild-type and p53deleted/mutated B leukemic cell lines. A critical role of Akt downregulation in mediating the antileukemic activity of Dasatinib and Dasatinib + Nutlin-3 was demonstrated in experiments carried out by specifically modulating the Akt pathway.

Conclusions: These findings suggest that Dasatinib + Nutlin-3 might represent an innovative therapeutic combination for both p53wild-type and p53deleted/mutated B-CLL. Clin Cancer Res; 17(4); 1–9. ©2010 AACR.