bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Phase I Single-Agent Study of Twice-Weekly Consecutive-Day Dosing of the Proteasome Inhibitor Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma or Lymphoma
Authors: Alsina Melissa , Trudel Suzanne , Furman Richard R. , Rosen Peter J. , O'Connor Owen A. , Comenzo Raymond L. , Wong Alvin , Kunkel Lori A. , Molineaux Christopher J. , Goy Andre
Published: April 2023

Abstract
Purpose: Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies.

Experimental design: Carfilzomib (doses ranging from 1.2–27 mg/m2) was administered i.v. on 2 consecutive days for 3 weeks of a 4-week cycle. Single-agent dose escalation (n = 37) was followed by a dose-expansion phase (n = 11) that comprised 2 cohorts (carfilzomib or carfilzomib + dexamethasone). During dose expansion, carfilzomib was administered starting with 20 mg/m2 during the first week (days 1, 2) and then escalated to 27 mg/m2 thereafter.

Results: A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events were manageable and primarily of grade I or II. The main hematologic adverse events of ≥ grade III were anemia and thrombocytopenia. Notably, there were no observations of grade III or more peripheral neuropathy. Carfilzomib was cleared rapidly with an elimination half-life of less than 30 minutes but still induced dose-dependent inhibition of the 20S chymotrypsin-like proteasome activity. At doses of 15 to 27 mg/m2, there was evidence of activity among patients with multiple myeloma and with non-Hodgkin lymphoma.

Conclusions: Escalated dosing of carfilzomib on a schedule of 2 consecutive days for 3 weeks of a 4-week cycle was tolerable and showed promising activity. This dose regimen has been selected for ongoing and future clinical studies, including PX-171-003A1 and the pivotal trial ASPIRE. Clin Cancer Res; 18(17); 4830–40. ©2012 AACR.
Data from Relapsed Classic E-Cadherin (CDH1)–Mutated Invasive Lobular Breast Cancer Shows a High Frequency of HER2 (ERBB2) Gene Mutations
Authors: Ross Jeffrey S. , Wang Kai , Sheehan Christine E. , Boguniewicz Ann B. , Otto Geoff , Downing Sean R. , Sun James , He Jie , Curran John A. , Ali Siraj , Yelensky Roman , Lipson Doron , Palmer Gary , Miller Vincent A. , Stephens Philip J.
Published: April 2023

Abstract
Purpose: We queried whether comprehensive genomic profiling using a next-generation sequencing–based assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC).

Experimental Design: DNA sequencing (Illumina HiSeq 2000) was conducted for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor-ligated, hybridization-captured libraries using DNA isolated from formalin-fixed paraffin-embedded sections from 22 histologically verified ILC.

Results: A total of 75 genomic alterations were identified with an average of 3.4 alterations per tumor (range, 1–6), of which 35 were actionable for an average of 1.59 actionable alterations per patient (range, 0–3). Nineteen of 22 (86%) of the ILC samples harbored at least one actionable alteration. Six (27%) cases featured alterations in ERRB2 including 4 (18%) with ERBB2 mutation, 1 (5%) with an ERBB2 gene fusion, and 1 (5%) with an ERBB2 copy number gain (amplification). The enrichment of ERBB2 mutations/fusion in CDH1-mutated ILC (5 of 22, 23%) compared with the 5 ERBB2 mutations in a series of 286 non-CDH1-mutated breast cancers from which the ILC cases were obtained (5 of 286, 2%) was significant (P = 0.0006).

Conclusions: Comprehensive genomic profiling of relapsed CDH1-mutated ILC revealed actionable genomic alterations in 86% of cases, featured a high incidence of ERBB2 alterations, and can reveal actionable alterations that can inform treatment decisions for patients with ILC. Clin Cancer Res; 19(10); 2668–76. ©2013 AACR.
Data from Meta-Analysis of the Prognostic Value of Circulating Tumor Cells in Breast Cancer
Authors: Zhang Liling , Riethdorf Sabine , Wu Gang , Wang Tao , Yang Kunyu , Peng Gang , Liu Junli , Pantel Klaus
Published: April 2023

Abstract
Purpose: The prognostic value of circulating tumor cells (CTC) detected in breast cancer patients is currently under debate. Different time points of blood collections and various CTC assays have been used in the past decades. Here, we conducted the first comprehensive meta-analysis of published literature on the prognostic relevance of CTC, including patients with early and advanced disease.

Experimental Design: A comprehensive search for articles published between January 1990 and January 2012 was conducted; reviews of each study were conducted and data were extracted. The main outcomes analyzed were overall survival (OS) and disease-free survival (DFS) in early-stage breast cancer patients, as well as progression-free survival (PFS) and OS in metastatic breast cancer patients. Pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also conducted.

Results: Forty-nine eligible studies enrolling 6,825 patients were identified. The presence of CTC was significantly associated with shorter survival in the total population. The prognostic value of CTC was significant in both early (DFS: HR, 2.86; 95% CI, 2.19–3.75; OS: HR, 2.78; 95% CI, 2.22–3.48) and metastatic breast cancer (PFS: HR, 1.78; 95% CI, 1.52–2.09; OS: HR, 2.33; 95% CI, 2.09–2.60). Further subgroup analyses showed that our results were stable irrespective of the CTC detection method and time point of blood withdrawal.

Conclusion: Our present meta-analysis indicates that the detection of CTC is a stable prognosticator in patients with early-stage and metastatic breast cancer. Further studies are required to explore the clinical utility of CTC in breast cancer. Clin Cancer Res; 18(20); 5701–10. ©2012 AACR.
Data from Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma: Intent-to-Treat Analysis and Efficacy after Failure to Prior Immunotherapies
Authors: Besser Michal J. , Shapira-Frommer Ronnie , Itzhaki Orit , Treves Avraham J. , Zippel Douglas B. , Levy Daphna , Kubi Adva , Shoshani Noa , Zikich Dragoslav , Ohayon Yaara , Ohayon Daniel , Shalmon Bruria , Markel Gal , Yerushalmi Ronit , Apter Sara , Ben-Nun Alon , Ben-Ami Eytan , Shimoni Avichai , Nagler Arnon , Schachter Jacob
Published: April 2023

Abstract
Purpose: Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies.

Experimental Design: Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning.

Results: TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8+ cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment.

Conclusion: Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed. Clin Cancer Res; 19(17); 4792–800. ©2013 AACR.
Data from Prognostic and Predictive Significance of Plasma HGF and IL-8 in a Phase III Trial of Chemoradiation with or without Tirapazamine in Locoregionally Advanced Head and Neck Cancer
Authors: Le Quynh-Thu , Fisher Richard , Oliner Kelly S. , Young Richard J. , Cao Hongbin , Kong Christina , Graves Edward , Hicks Rodney J. , McArthur Grant A. , Peters Lester , O'Sullivan Brian , Giaccia Amato , Rischin Danny
Published: April 2023

Abstract
Purpose: Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin.

Experimental Design: Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16INK4A staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with 18F-fluoroazomycin arabinoside (18FAZA)–positron emission tomography.

Results: Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053); elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16INK4A-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect; the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with 18FAZA tumor standard uptake value.

Conclusions: IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients. Clin Cancer Res; 18(6); 1798–807. ©2012 AACR.
Data from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance
Authors: Byers Lauren Averett , Diao Lixia , Wang Jing , Saintigny Pierre , Girard Luc , Peyton Michael , Shen Li , Fan Youhong , Giri Uma , Tumula Praveen K. , Nilsson Monique B. , Gudikote Jayanthi , Tran Hai , Cardnell Robert J.G. , Bearss David J. , Warner Steven L. , Foulks Jason M. , Kanner Steven B. , Gandhi Varsha , Krett Nancy , Rosen Steven T. , Kim Edward S. , Herbst Roy S. , Blumenschein George R. , Lee J. Jack , Lippman Scott M. , Ang K. Kian , Mills Gordon B. , Hong Waun K. , Weinstein John N. , Wistuba Ignacio I. , Coombes Kevin R. , Minna John D. , Heymach John V.
Published: April 2023

Abstract
Purpose: Epithelial–mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using non–small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study.

Experimental Design: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified.

Results: Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies.

Conclusion: We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype. Clin Cancer Res; 19(1); 279–90. ©2012 AACR.
Data from Identification of Prognosis-Relevant Subgroups in Patients with Chemoresistant Triple-Negative Breast Cancer
Authors: Yu Ke-Da , Zhu Rui , Zhan Ming , Rodriguez Angel A. , Yang Wei , Wong Stephen , Makris Andreas , Lehmann Brian D. , Chen Xi , Mayer Ingrid , Pietenpol Jennifer A. , Shao Zhi-Ming , Symmans W. Fraser , Chang Jenny C.
Published: April 2023

Abstract
Purpose: Patients with triple-negative breast cancer (TNBC) and residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. We hypothesize that there are subgroups of patients with chemoresistant TNBC with different prognosis.

Experimental Design: Forty-nine chemoresistant cases from 111 patients with TNBC treated with neoadjuvant chemotherapy (M.D. Anderson Cancer Center, Houston, TX) constituted the discovery cohort, and 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital, Houston, TX) were chosen for validation. Extended validation was carried out in 269 operable TNBC predicted to be chemoresistant by expression pattern from published datasets.

Results: We established a seven-gene prognostic signature using dChip and gene set enrichment analyses. In the independent validation cohort, the classifier predicted correctly with positive predictive value of 75.0% and negative predictive value (i.e., relapse-free survival; RFS) of 76.9% at 3 years. Those predicted to relapse had a HR of 4.67 [95% confidence interval (CI): 1.27–17.15] for relapse in 3 years. In extended validation, patients predicted not to relapse exhibited 3-year RFS of 78.9%, whereas the 3-year RFS was 48.5% for patients predicted to relapse, with HR of 2.61 (95% CI: 1.52–4.49). The TNBC subgroup that predicted to have relatively favorable prognosis was characterized by high expression of “luminal-like” genes [androgen-receptor (AR) and GATA3], whereas the subgroup with worse prognosis was characterized by expression of cancer stem-cell markers.

Conclusion: We developed a clinically relevant signature for patients with chemoresistant TNBC. For these women, new therapeutic strategies like targeting AR activation or cancer stem cells may need to be developed. Clin Cancer Res; 19(10); 2723–33. ©2013 AACR.
Data from Development of an Fc-Enhanced Anti–B7-H3 Monoclonal Antibody with Potent Antitumor Activity
Authors: Loo Deryk , Alderson Ralph F. , Chen Francine Z. , Huang Ling , Zhang Wenjun , Gorlatov Sergey , Burke Steve , Ciccarone Valentina , Li Hua , Yang Yinhua , Son Tom , Chen Yan , Easton Ann N. , Li Jonathan C. , Rillema Jill R. , Licea Monica , Fieger Claudia , Liang Tony W. , Mather Jennie P. , Koenig Scott , Stewart Stanford J. , Johnson Syd , Bonvini Ezio , Moore Paul A.
Published: April 2023

Abstract
Purpose: The goal of this research was to harness a monoclonal antibody (mAb) discovery platform to identify cell-surface antigens highly expressed on cancer and develop, through Fc optimization, potent mAb therapies toward these tumor-specific antigens.

Experimental Design: Fifty independent mAbs targeting the cell-surface immunoregulatory B7-H3 protein were obtained through independent intact cell-based immunizations using human tissue progenitor cells, cancer cell lines, or cell lines displaying cancer stem cell properties. Binding studies revealed this natively reactive B7-H3 mAb panel to bind a range of independent B7-H3 epitopes. Immunohistochemical analyses showed that a subset displayed strong reactivity to a broad range of human cancers while exhibiting limited binding to normal human tissues. A B7-H3 mAb displaying exquisite tumor/normal differential binding was selected for humanization and incorporation of an Fc domain modified to enhance effector-mediated antitumor function via increased affinity for the activating receptor CD16A and decreased binding to the inhibitory receptor CD32B.

Results: MGA271, the resulting engineered anti–B7-H3 mAb, mediates potent antibody-dependent cellular cytotoxicity against a broad range of tumor cell types. Furthermore, in human CD16A-bearing transgenic mice, MGA271 exhibited potent antitumor activity in B7-H3–expressing xenograft models of renal cell and bladder carcinoma. Toxicology studies carried out in cynomolgus monkeys revealed no significant test article-related safety findings.

Conclusions: This data supports evaluation of MGA271 clinical utility in B7-H3–expressing cancer, while validating a combination of a nontarget biased approach of intact cell immunizations and immunohistochemistry to identify novel cancer antigens with Fc-based mAb engineering to enable potent antitumor activity. Clin Cancer Res; 18(14); 3834–45. ©2012 AACR.
Data from Influence of Smoking on the Pharmacokinetics and Toxicity Profiles of Taxane Therapy
Authors: de Graan Anne-Joy M. , Loos Walter J. , Friberg Lena E. , Baker Sharyn D. , van der Bol Jessica M. , van Doorn Leni , Wiemer Erik A.C. , van der Holt Bronno , Verweij Jaap , Mathijssen Ron H.J.
Published: April 2023

Abstract
Purpose: Cigarette smoke is known to interact with the metabolism of several anticancer drugs. It may also affect the incidence and severity of adverse events and efficacy of chemotherapy. The main objective of this study was to examine the effects of smoking on the pharmacokinetics and toxicities of patients treated with docetaxel or paclitaxel.

Experimental Design: Smoking status, toxicity profiles, and pharmacokinetic parameters (calculated by nonlinear mixed-effect modeling population analysis) were determined in 566 patients (429 nonsmokers and 137 smokers) treated with docetaxel or paclitaxel.

Results: Smokers treated with docetaxel showed less grade IV neutropenia (35% vs. 52%; P = 0.01) than nonsmokers. Smokers treated with paclitaxel had less grade III–IV leukopenia than nonsmokers (12% vs. 25%; P = 0.03), and the white blood cell (WBC) nadir was lower in nonsmokers (median, 2.7 × 109/L; range, 0.05 × 109 to 11.6 × 109/L) than in smokers (median, 3.3 × 109/L; range 0.8 × 109 to 10.2 × 109/L; P = 0.02). Of interest, significantly lower WBC counts and absolute neutrophil counts at baseline were seen in nonsmoking patients treated with paclitaxel (P = 0.0001). Pharmacokinetic parameters were similar in smokers and nonsmokers for both taxanes.

Conclusion: Cigarette smoking does not alter the pharmacokinetic determinants of docetaxel and paclitaxel. Smokers treated with docetaxel and paclitaxel have less neutropenia and leukopenia, but further research is warranted to elucidate this potential protective effect. Clin Cancer Res; 18(16); 4425–32. ©2012 AACR.
Data from Establishment and Characterization of Novel Cell Lines from Sinonasal Undifferentiated Carcinoma
Authors: Takahashi Yoko , Kupferman Michael E. , Bell Diana , Jiffar Tilahun , Lee June Goo , Xie Tong-Xin , Li Ning-Wei , Zhao Mei , Frederick Mitchell J. , Gelbard Alexander , Myers Jeffrey N. , Hanna Ehab Y.
Published: April 2023

Abstract
Purpose: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer. Despite the use of multimodality treatment, the overall prognosis remains poor. To better understand the biologic features of SNUC and help develop new therapies for the disease, we established SNUC cell lines and characterized their biologic behaviors.

Experimental Design: Cell lines were established from a patient with a T4N0M0 SNUC of the right maxillary sinus who was treated with surgical resection at our center. Tumor colonies were harvested and were sequentially replated onto larger plates. Two populations were developed and labeled MDA8788-6 and MDA8788-7. These cell lines were characterized with molecular, biomarker, functional, and histologic analyses.

Results: Short tandem repeat genotyping revealed that the cell line is isogenic to the parental tumor, and cytogenetic analysis identified 12 chromosomal translocations. The SNUC cell lines do not form colonies in soft agar but are tumorigenic and nonmetastatic in an orthotopic mouse model of sinonasal cancer. Western blot analysis revealed that both MDA8788 cell lines express epithelial markers but do not express mesenchymal markers or the endocrine marker synaptophysin.

Conclusions: This is the first report of the establishment of stable human-derived SNUC cell lines. The lines were highly tumorigenic and maintain the histologic and molecular features of the original tumor. These cell lines should serve as useful tools for the future study of SNUC biology and the development and testing of novel therapies for this deadly disease. Clin Cancer Res; 18(22); 6178–87. ©2012 AACR.
Data from Frequent Inactivation of Cysteine Dioxygenase Type 1 Contributes to Survival of Breast Cancer Cells and Resistance to Anthracyclines
Authors: Jeschke Jana , O'Hagan Heather M. , Zhang Wei , Vatapalli Rajita , Calmon Marilia Freitas , Danilova Ludmila , Nelkenbrecher Claudia , Van Neste Leander , Bijsmans Ingrid T.G.W. , Van Engeland Manon , Gabrielson Edward , Schuebel Kornel E. , Winterpacht Andreas , Baylin Stephen B. , Herman James G. , Ahuja Nita
Published: April 2023

Abstract
Purpose: Genome-wide DNA methylation analyses have identified hundreds of candidate DNA-hypermethylated genes in cancer. Comprehensive functional analyses provide an understanding of the biologic significance of this vast amount of DNA methylation data that may allow the determination of key epigenetic events associated with tumorigenesis.

Experimental Design: To study mechanisms of cysteine dioxygenase type 1 (CDO1) inactivation and its functional significance in breast cancer in a comprehensive manner, we screened for DNA methylation and gene mutations in primary breast cancers and analyzed growth, survival, and reactive oxygen species (ROS) production in breast cancer cells with restored CDO1 function in the context of anthracycline treatment.

Results: DNA methylation-associated silencing of CDO1 in breast cancer is frequent (60%), cancer specific, and correlates with disease progression and outcome. CDO1 function can alternatively be silenced by repressive chromatin, and we describe protein-damaging missense mutations in 7% of tumors without DNA methylation. Restoration of CDO1 function in breast cancer cells increases levels of ROS and leads to reduced viability and growth, as well as sensitization to anthracycline treatment. Priming with 5-azacytidine of breast cancer cells with epigenetically silenced CDO1 resulted in restored expression and increased sensitivity to anthracyclines.

Conclusion: We report that silencing of CDO1 is a critical epigenetic event that contributes to the survival of oxidative-stressed breast cancer cells through increased detoxification of ROS and thus leads to the resistance to ROS-generating chemotherapeutics including anthracyclines. Our study shows the importance of CDO1 inactivation in breast cancer and its clinical potential as a biomarker and therapeutic target to overcome resistance to anthracyclines. Clin Cancer Res; 19(12); 3201–11. ©2013 AACR.
Data from A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas
Authors: Kummar Shivaani , Ji Jiuping , Morgan Robert , Lenz Heinz-Josef , Puhalla Shannon L. , Belani Chandra P. , Gandara David R. , Allen Deborah , Kiesel Brian , Beumer Jan H. , Newman Edward M. , Rubinstein Larry , Chen Alice , Zhang Yiping , Wang Lihua , Kinders Robert J. , Parchment Ralph E. , Tomaszewski Joseph E. , Doroshow James H.
Published: April 2023

Abstract
Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies.

Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days.

Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration.

Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma. Clin Cancer Res; 18(6); 1726–34. ©2012 AACR.
Data from Functional Kinomics Identifies Candidate Therapeutic Targets in Head and Neck Cancer
Authors: Moser Russell , Xu Chang , Kao Michael , Annis James , Lerma Luisa Angelica , Schaupp Christopher M. , Gurley Kay E. , Jang In Sock , Biktasova Asel , Yarbrough Wendell G. , Margolin Adam A. , Grandori Carla , Kemp Christopher J. , Méndez Eduardo
Published: April 2023

Abstract
Purpose: To identify novel therapeutic drug targets for p53-mutant head and neck squamous cell carcinoma (HNSCC).

Experimental Design: RNAi kinome viability screens were performed on HNSCC cells, including autologous pairs from primary tumor and recurrent/metastatic lesions, and in parallel on murine squamous cell carcinoma (MSCC) cells derived from tumors of inbred mice bearing germline mutations in Trp53, and p53 regulatory genes: Atm, Prkdc, and p19Arf. Cross-species analysis of cell lines stratified by p53 mutational status and metastatic phenotype was used to select 38 kinase targets. Both primary and secondary RNAi validation assays were performed on additional HNSCC cell lines to credential these kinase targets using multiple phenotypic endpoints. Kinase targets were also examined via chemical inhibition using a panel of kinase inhibitors. A preclinical study was conducted on the WEE1 kinase inhibitor, MK-1775.

Results: Our functional kinomics approach identified novel survival kinases in HNSCC involved in G2–M cell-cycle checkpoint, SFK, PI3K, and FAK pathways. RNAi-mediated knockdown and chemical inhibition of the WEE1 kinase with a specific inhibitor, MK-1775, had a significant effect on both viability and apoptosis. Sensitivity to the MK-1775 kinase inhibitor is in part determined by p53 mutational status, and due to unscheduled mitotic entry. MK-1775 displays single-agent activity and potentiates the efficacy of cisplatin in a p53-mutant HNSCC xenograft model.

Conclusions: WEE1 kinase is a potential therapeutic drug target for HNSCC. This study supports the application of a functional kinomics strategy to identify novel therapeutic targets for cancer. Clin Cancer Res; 20(16); 4274–88. ©2014 AACR.
Data from Antibody-Dependent Cell-Mediated Cytotoxicity Overcomes NK Cell Resistance in MLL-Rearranged Leukemia Expressing Inhibitory KIR Ligands but Not Activating Ligands
Authors: Chan Wing Keung , Kung Sutherland May , Li Ying , Zalevsky Jonathan , Schell Sarah , Leung Wing
Published: April 2023

Abstract
Purpose: Leukemias with MLL gene rearrangement are associated with a poor prognosis. Natural killer (NK) cell therapy is a potential treatment, but leukemia cells may be resistant. Here, we sought to determine the susceptibility of MLL-rearranged leukemia cells to NK cell lysis and to develop a novel immunotherapeutic approach to optimize NK cell therapy, including the use of an antibody against leukemia-associated antigen and the elimination of killer-cell immunoglobulin-like receptor (KIR)–mediated inhibition.

Experimental Design: Three MLL-rearranged leukemia cell lines (RS4;11, SEM, and MV4-11) and primary leukemia blasts were assessed for surface phenotype and susceptibility to NK cell lysis with or without antibodies against CD19 (XmAb5574), CD33 (lintuzumab), or KIR ligands.

Results: All three cell lines were resistant to NK cell lysis, had some inhibitory KIR ligands and protease inhibitor-9, and expressed low levels of NKG2D activating ligands and adhesion molecules. After treatment with XmAb5574 or lintuzumab, MLL-rearranged leukemia cells were efficiently killed by NK cells. The addition of pan–major histocompatibility complex class I antibody, which blocked inhibitory KIR-HLA interaction, further augmented degranulation in all three KIR2DL1, KIR2DL2/3, and KIR3DL1 subsets of NK cells based on the rule of missing-self recognition. A mouse model showed a decreased rate of leukemia progression in vivo as monitored by bioluminescence imaging and longer survival after antibody treatment.

Conclusion: Our data support the use of a triple immunotherapy approach, including an antibody directed against tumor-associated antigen, KIR-mismatched NK cell transplantation, and inhibitory KIR blockade, for the treatment of NK cell–resistant MLL-rearranged leukemias. Clin Cancer Res; 18(22); 6296–305. ©2012 AACR.
Data from Functional p38 MAPK Identified by Biomarker Profiling of Pancreatic Cancer Restrains Growth through JNK Inhibition and Correlates with Improved Survival
Authors: Zhong Yi , Naito Yoshiki , Cope Leslie , Naranjo-Suarez Salvador , Saunders Tyler , Hong Seung-Mo , Goggins Michael G. , Herman Joseph M. , Wolfgang Christopher L. , Iacobuzio-Donahue Christine A.
Published: April 2023

Abstract
Purpose: Numerous biomarkers for pancreatic cancer have been reported. We determined the extent to which such biomarkers are expressed throughout metastatic progression, including those that effectively predict biologic behavior.

Experimental Design: Biomarker profiling was performed for 35 oncoproteins in matched primary and metastatic pancreatic cancer tissues from 36 rapid autopsy patients. Proteins of significance were validated by immunolabeling in an independent sample set, and functional studies were performed in vitro and in vivo.

Results: Most biomarkers were similarly expressed or lost in expression in most samples analyzed, and the matched primary and metastases from a specific patient were most similar to each other than to other patients. However, a subset of proteins showed extensive interpatient heterogeneity, one of which was p38 MAPK. Strong positive pp38 MAPK immunolabeling was significantly correlated with improved postresection survival by multivariate analysis (median overall survival 27.9 months, P = 0.041). In pancreatic cancer cells, inhibition of functional p38 by SB202190 increased cell proliferation in vitro in both low-serum and low-oxygen conditions. High functional p38 activity in vitro corresponded to lower levels of pJNK protein expression, and p38 inhibition resulted in increased pJNK and pMKK7 by Western blot analysis. Moreover, JNK inhibition by SP600125 or MKK7 siRNA knockdown antagonized the effects of p38 inhibition by SB202190. In vivo, SP600125 significantly decreased growth rates of xenografts with high p38 activity compared with those without p38 expression.

Conclusions: Functional p38 MAPK activity contributes to overall survival through JNK signaling, thus providing a rationale for JNK inhibition in pancreatic cancer management. Clin Cancer Res; 20(23); 6200–11. ©2014 AACR.
Data from Clinical Significance of the Genetic Landscape of Pancreatic Cancer and Implications for Identification of Potential Long-term Survivors
Authors: Yachida Shinichi , White Catherine M. , Naito Yoshiki , Zhong Yi , Brosnan Jacqueline A. , Macgregor-Das Anne M. , Morgan Richard A. , Saunders Tyler , Laheru Daniel A. , Herman Joseph M. , Hruban Ralph H. , Klein Alison P. , Jones Siân , Velculescu Victor , Wolfgang Christopher L. , Iacobuzio-Donahue Christine A.
Published: April 2023

Abstract
Purpose: Genetic alterations of KRAS, CDKN2A, TP53, and SMAD4 are the most frequent events in pancreatic cancer. We determined the extent to which these 4 alterations are coexistent in the same carcinoma, and their impact on patient outcome.

Experimental Design: Pancreatic cancer patients who underwent an autopsy were studied (n = 79). Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A, and TP53 and immunolabeled for CDKN2A, TP53, and SMAD4 protein products. The number of altered driver genes in each carcinoma was correlated to clinicopathologic features. Kaplan–Meier estimates were used to determine median disease free and overall survival, and a Cox proportional hazards model used to compare risk factors.

Results: The number of genetically altered driver genes in a carcinoma was variable, with only 29 patients (37%) having an alteration in all 4 genes analyzed. The number of altered driver genes was significantly correlated with disease free survival (P = 0.008), overall survival (P = 0.041), and metastatic burden at autopsy (P = 0.002). On multivariate analysis, the number of driver gene alterations in a pancreatic carcinoma remained independently associated with overall survival (P = 0.046). Carcinomas with only 1 to 2 driver alterations were enriched for those patients with the longest survival (median 23 months, range 1 to 53).

Conclusions: Determinations of the status of the 4 major driver genes in pancreatic cancer, and specifically the extent to which they are coexistent in an individual patients cancer, provides distinct information regarding disease progression and survival that is independent of clinical stage and treatment status. Clin Cancer Res; 18(22); 6339–47. ©2012 AACR.
Data from Expression of Androgen and Estrogen Signaling Components and Stem Cell Markers to Predict Cancer Progression and Cancer-Specific Survival in Patients with Metastatic Prostate Cancer
Authors: Fujimura Tetsuya , Takahashi Satoru , Urano Tomohiko , Takayama Kenichi , Sugihara Toru , Obinata Daisuke , Yamada Yuta , Kumagai Jimpei , Kume Haruki , Ouchi Yasuyoshi , Inoue Satoshi , Homma Yukio
Published: April 2023

Abstract
Purpose: Genes of androgen and estrogen signaling cells and stem cell–like cells play crucial roles in prostate cancer. This study aimed to predict clinical failure by identifying these prostate cancer-related genes.

Experimental Design: We developed models to predict clinical failure using biopsy samples from a training set of 46 and an independent validation set of 30 patients with treatment-naïve prostate cancer with bone metastasis. Cancerous and stromal tissues were separately collected by laser-captured microdissection. We analyzed the association between clinical failure and mRNA expression of the following genes androgen receptor (AR) and its related genes (APP, FOX family, TRIM 36, Oct1, and ACSL 3), stem cell–like molecules (Klf4, c-Myc, Oct 3/4, and Sox2), estrogen receptor (ER), Her2, PSA, and CRP.

Results: Logistic analyses to predict prostate-specific antigen (PSA) recurrence showed an area under the curve (AUC) of 1.0 in both sets for Sox2, Her2, and CRP expression in cancer cells, AR and ERα expression in stromal cells, and clinical parameters. We identified 10 prognostic factors for cancer-specific survival (CSS): Oct1, TRIM36, Sox2, and c-Myc expression in cancer cells; AR, Klf4, and ERα expression in stromal cells; and PSA, Gleason score, and extent of disease. On the basis of these factors, patients were divided into favorable-, intermediate-, and poor-risk groups according to the number of factors present. Five-year CSS rates for the 3 groups were 90%, 32%, and 12% in the training set and 75%, 48%, and 0% in the validation set, respectively.

Conclusions: Expression levels of androgen- and estrogen signaling components and stem cell markers are powerful prognostic tools. Clin Cancer Res; 20(17); 4625–35. ©2014 AACR.
Data from A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases
Authors: Tabernero Josep , Elez Maria Elena , Herranz Maria , Rico Isabel , Prudkin Ludmila , Andreu Jordi , Mateos Jose , Carreras Maria Josep , Han May , Gifford James , Credi Marc , Yin Wei , Agarwal Shefali , Komarnitsky Philip , Baselga Jose
Published: April 2023

Abstract
Purpose: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases.

Patients and Methods: Patients with p-Met (phosphorylated c-Met)–positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed.

Results: No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (−53%), p-ERK (−43%), p-Akt (−2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4–10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year.

Conclusions: Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle. Clin Cancer Res; 20(10); 2793–804. ©2014 AACR.
Data from Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas
Authors: Wakimoto Hiroaki , Tanaka Shota , Curry William T. , Loebel Franziska , Zhao Dan , Tateishi Kensuke , Chen Juxiang , Klofas Lindsay K. , Lelic Nina , Kim James C. , Dias-Santagata Dora , Ellisen Leif W. , Borger Darrell R. , Fendt Sarah-Maria , Vander Heiden Matthew G. , Batchelor Tracy T. , Iafrate A. John , Cahill Daniel P. , Chi Andrew S.
Published: April 2023

Abstract
Purpose: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas.

Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients.

Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non–xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011).

Conclusion: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. Clin Cancer Res; 20(11); 2898–909. ©2014 AACR.
Data from Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer
Authors: Roh Ju-Won , Huang Jie , Hu Wei , Yang XiaoYun , Jennings Nicholas B. , Sehgal Vasudha , Sohn Bo Hwa , Han Hee Dong , Lee Sun Joo , Thanapprapasr Duangmani , Bottsford-Miller Justin , Zand Behrouz , Dalton Heather J. , Previs Rebecca A. , Davis Ashley N. , Matsuo Koji , Lee Ju-Seog , Ram Prahlad , Coleman Robert L. , Sood Anil K.
Published: April 2023

Abstract
Purpose: Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer.

Experimental Design: Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer.

Results: PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and mitogen-activated protein kinase (MAPK). Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis.

Conclusions: These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer. Clin Cancer Res; 20(10); 2740–50. ©2014 AACR.
Data from Exposure–Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma
Authors: Feng Yan , Roy Amit , Masson Eric , Chen Tai-Tsang , Humphrey Rachel , Weber Jeffrey S.
Published: April 2023

Abstract
Purpose: This retrospective analysis was conducted to characterize ipilimumab exposure–response relationships for measures of efficacy and safety in patients with advanced melanoma.

Experimental Design: Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials. The relationships between steady–state ipilimumab trough concentration (Cminss), complete or partial tumor response (CR or PR), and safety [immune-related adverse events (irAEs)] were described by logistic regression models. The relationship between exposure and overall survival was characterized using a Cox proportional–hazards model.

Results: The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (P < 0.001). Model-based estimates indicate that the probabilities of a CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%, and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at 0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively.

Conclusions: Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of irAEs. The efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial. Clin Cancer Res; 19(14); 3977–86. ©2013 AACR.