bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from CYP3A4*22 Genotype and Systemic Exposure Affect Paclitaxel-Induced Neurotoxicity
Authors: de Graan Anne-Joy M. , Elens Laure , Sprowl Jason A. , Sparreboom Alex , Friberg Lena E. , van der Holt Bronno , de Raaf Pleun J. , de Bruijn Peter , Engels Frederike K. , Eskens Ferry A.L.M. , Wiemer Erik A.C. , Verweij Jaap , Mathijssen Ron H.J. , van Schaik Ron H.N.
Published: April 2023

Abstract
Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity.

Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239).

Results: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001).

Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment. Clin Cancer Res; 19(12); 3316–24. ©2013 AACR.
Data from A Phase I Dose-Escalation Trial of Trastuzumab and Alvespimycin Hydrochloride (KOS-1022; 17 DMAG) in the Treatment of Advanced Solid Tumors
Authors: Jhaveri Komal , Miller Kathy , Rosen Lee , Schneider Bryan , Chap Linnea , Hannah Alison , Zhong Ziyang , Ma Weining , Hudis Clifford , Modi Shanu
Published: April 2023

Abstract
Purpose: We conducted a phase I dose-escalation study to define the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics of alvespimycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, given in combination with trastuzumab.

Experimental Design: Patients were treated with trastuzumab followed by intravenous alvespimycin on a weekly schedule. Hsp90 client proteins were measured at baseline and serially in peripheral blood lymphocytes (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible.

Results: Twenty-eight patients (25, breast; 3, ovarian) were enrolled onto three dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m2 (n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m2), and reversible grade III keratitis in two patients (80 mg/m2). Drug-related grade III toxicity included one episode each of fatigue, diarrhea, myalgia, and back pain. Common mild to moderate toxicities included diarrhea, fatigue, myalgia, arthralgia, nausea, blurry vision, headache, back pain, and dry eyes. There was one partial response and seven cases of stable disease (range, 4–10 months), all in HER2+ MBC. In addition, an ovarian cancer patient had complete resolution of ascites and pleural effusion that lasted 24.8 months. There was no change in PK upon weekly dosing. Hsp70 effect continued to increase across four weeks and was most pronounced at 80 and 100 mg/m2.

Conclusion: The combination of alvespimycin and trastuzumab is safe and tolerable at MTD. Antitumor activity was seen in patients with refractory HER2+ MBC and ovarian cancer. The recommended dose of alvespimycin for further study in this combination is 80 mg/m2 weekly. Clin Cancer Res; 18(18); 5090–8. ©2012 AACR.
Data from A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report
Authors: Widemann Brigitte C. , Kim AeRang , Fox Elizabeth , Baruchel Sylvain , Adamson Peter C. , Ingle Ashish M. , Bender Julia Glade , Burke Michael , Weigel Brenda , Stempak Diana , Balis Frank M. , Blaney Susan M.
Published: April 2023

Abstract
Purpose: To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias.

Experimental Design: Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1.

Results: Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/aspartate aminotransferase (AST)] at the starting dose (150 mg/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/dose for solid tumors and 150 mg/m2/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%.

Conclusions: The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m2/dose and 150 mg/m2/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing. Clin Cancer Res; 18(21); 6011–22. ©2012 AACR.
Data from Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale
Authors: Komlodi-Pasztor Edina , Sackett Dan L. , Fojo Antonio Tito
Published: April 2023

Abstract
Although they have been advocated with an understandable enthusiasm, mitosis-specific agents such as inhibitors of mitotic kinases and kinesin spindle protein have not been successful clinically. These drugs were developed as agents that would build on the success of microtubule-targeting agents while avoiding the neurotoxicity that encumbers drugs such as taxanes and vinca alkaloids. The rationale for using mitosis-specific agents was based on the thesis that the clinical efficacy of microtubule-targeting agents could be ascribed to the induction of mitotic arrest. However, the latter concept, which has long been accepted as dogma, is likely important only in cell culture and rapidly growing preclinical models, and irrelevant in patient tumors, where interference with intracellular trafficking on microtubules is likely the principal mechanism of action. Here we review the preclinical and clinical data for a diverse group of inhibitors that target mitosis and identify the reasons why these highly specific, myelosuppressive compounds have failed to deliver on their promise. Clin Cancer Res; 18(1); 51–63. ©2012 AACR.
Data from Choosing Phase II Endpoints and Designs: Evaluating the Possibilities
Authors: LeBlanc Michael , Tangen Catherine
Published: April 2023

Abstract
Selecting the phase II design and endpoint to achieve the best possible chance of success for a confirmatory phase III study in a particular disease and treatment setting is challenging but critical. Simulating from existing clinical trial data sets and from mathematical models can be useful tools for evaluating statistical properties. Clin Cancer Res; 18(8); 2130–2. ©2012 AACR.
Data from Molecular Determinants of Retinoic Acid Sensitivity in Pancreatic Cancer
Authors: Gupta Sonal , Pramanik Dipankar , Mukherjee Radha , Campbell Nathaniel R. , Elumalai Sathyanarayanan , de Wilde Roeland F. , Hong Seung-Mo , Goggins Michael G. , De Jesus-Acosta Ana , Laheru Daniel , Maitra Anirban
Published: April 2023

Abstract
Purpose: To identify a predictive molecular “signature” for sensitivity to retinoic acid in pancreatic cancer.

Experimental Design: Fourteen patient-derived, low-passage pancreatic ductal adenocarcinoma (PDAC) lines with varied expression of fatty acid–binding protein 5 (FABP5) and cellular retinoic acid–binding protein 2 (CRABP2) were used to evaluate the response to all-trans retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the in vitro response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks.

Results: Response to ATRA was observed to be dependent upon differential expression of FABP5 versus CRABP2. Thus, elevated FABP5 expression was associated with minimal cytotoxicity and tumor growth inhibition and a paradoxical increase in migration and invasion. Conversely, CRABP2 expression in the absence of FABP5 was associated with significant tumor growth inhibition with ATRA, even in gemcitabine-resistant tumors. The ATRA-resistant phenotype of FABP5highCRABP2null cells could be circumvented by ectopic expression of CRABP2. Alternatively, reexpression of endogenous CRABP2 could be enabled in FABP5highCRABP2null PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the CRABP2 gene promoter. Immunohistochemical staining for FABP5 in archival human tissue microarrays identifies a subset of cases (13 of 63, ∼20%) which are negative for FABP5 expression and might be candidates for ATRA therapy.

Conclusions: The widely used agent ATRA deserves a “second look” in PDAC, but needs to be targeted to patient subsets with biopsy-proven FABP5-negative tumors, or be combined with a chromatin-modifying agent to reexpress endogenous CRABP2. Clin Cancer Res; 18(1); 280–9. ©2011 AACR.
Data from Association between VEGF Splice Isoforms and Progression-Free Survival in Metastatic Colorectal Cancer Patients Treated with Bevacizumab
Authors: Bates David O. , Catalano Paul J. , Symonds Kirsty E. , Varey Alex H.R. , Ramani Pramila , O'Dwyer Peter J. , Giantonio Bruce J. , Meropol Neal J. , Benson Al Bowen , Harper Steven J.
Published: April 2023

Abstract
Purpose: Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF165b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF165b levels treated with bevacizumab.

Experimental Design: Blinded tumor samples from the phase III trial of FOLFOX4 ± bevacizumab were assessed for VEGF165b and VEGFtotal by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF165b:VEGFtotal for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio.

Results: Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF165b:VEGFtotal ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P < 0.02), but no effect of bevacizumab on PFS in patients with VEGF165b:VEGFtotal ratio >median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF165b group, but this did not reach statistical significance. There was no difference in the high VEGF165b:VEGFtotal group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3months).

Conclusion: Low VEGF165b:VEGFtotal ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit. Clin Cancer Res; 18(22); 6384–91. ©2012 AACR.
Data from Functional, Genetic, and Epigenetic Aspects of Base and Nucleotide Excision Repair in Colorectal Carcinomas
Authors: Slyskova Jana , Korenkova Vlasta , Collins Andrew R. , Prochazka Pavel , Vodickova Ludmila , Svec Jiri , Lipska Ludmila , Levy Miroslav , Schneiderova Michaela , Liska Vaclav , Holubec Lubos , Kumar Rajiv , Soucek Pavel , Naccarati Alessio , Vodicka Pavel
Published: April 2023

Abstract
Purpose: DNA repair capacity (DRC) is a determinant not only of cancer development but also of individual response to therapy. Previously, altered base and nucleotide excision repair (BER and NER) have been described in lymphocytes of patients with sporadic colorectal cancer. We, for the first time, evaluate both excision repair capacities in human colon biopsies to study their participation in colorectal tumorigenesis.

Experimental design: Seventy pairs of tumor and adjacent healthy tissues were analyzed for BER- and NER-specific DRC by a comet repair assay. Tissue pairs were further compared for expression levels of a panel of 25 BER and NER genes complemented by their promoter methylation status.

Results: We observed a moderate increase of NER-DRC (P = 0.019), but not of BER-DRC in tumors. There was a strong correlation between both tissues for all investigated parameters (P < 0.001). However, 4 NER (CSB, CCNH, XPA, XPD) and 4 BER (NEIL1, APEX1, OGG1, PARP1) genes showed a 1.08- to 1.28-fold change difference in expression in tumors (P < 0.05). Individual gene expression levels did not correlate with overall DRC, and we did not detect any aberrant methylation of the investigated genes.

Conclusions: Our complex analysis showed that tumor cells are not deficient in BER and NER, but rather follow patterns characteristic for each individual and are comparable with adjacent tissue. Alteration of excision repair pathways is not a pronounced event in colorectal carcinogenesis. This study shows the feasibility of DRC evaluation in human solid tissues, representing a complex marker of multigene DNA repair processes. Clin Cancer Res; 18(21); 5878–87. ©2012 AACR.
Data from In Vivo Positron Emission Tomography Imaging of Protease Activity by Generation of a Hydrophobic Product from a Noninhibitory Protease Substrate
Authors: Chuang Chih-Hung , Chuang Kuo-Hsiang , Wang Hsin-Ell , Roffler Steve R. , Shiea Jen-taie , Tzou Shey-Cherng , Cheng Ta-Chun , Kao Chien-Han , Wu Shih-Yen , Tseng Wei-Lung , Cheng Chiu-Min , Hou Ming-Feng , Wang Ju-Ming , Cheng Tian-Lu
Published: April 2023

Abstract
Purpose: To develop an imaging technology for protease activities in patients that could help in prognosis prediction and in design of personalized, protease-based inhibitors and prodrugs for targeted therapy.

Experimental Design: Polyethylene glycol (PEG) was covalently attached to the N-terminus of a hydrophilic peptide substrate (GPLGVR) for matrix metalloproteinase (MMP) to increase hydrophilicity. PEG-peptide was then linked to a hydrophobic tetramethylrhodamine (TMR) domain and labeled with 18F to form a PEG-peptide-18F-TMR probe. Specific cleavage of the probe by MMP2 was tested in vitro by matrix-assisted laser desorption/ionization–time-of-flight (MALDI-TOF). In vivo imaging of MMP2-expressing tumors was evaluated by micro-PET.

Results: The hydrophobic TMR fragment (948 Da) was specifically generated by MMP2 enzymes and MMP-expressing HT1080 cells but not control MCF-7 cells. MMP-expressing HT1080 cells and tumors selectively accumulated the hydrolyzed, hydrophobic TMR fragment at sites of protease activity. Importantly, we found that 18F-labeled probe (18F-TMR) preferentially localized in HT1080 tumors but not control MCF-7 tumors as shown by micro-PET. Uptake of the probe in HT1080 tumors was 18.4 ± 1.9-fold greater than in the MCF-7 tumors 30 minutes after injection. These results suggest that the PEG-peptide-18F-TMR probe displays high selectivity for imaging MMP activity.

Conclusions: This strategy successfully images MMP expression in vivo and may be extended to other proteases to predict patient prognosis and to design personalized, protease-based inhibitors and prodrug-targeted therapies. Clin Cancer Res; 18(1); 238–47. ©2011 AACR.
Data from Circulating Tumor Cells in Patients with Testicular Germ Cell Tumors
Authors: Nastały Paulina , Ruf Christian , Becker Pascal , Bednarz-Knoll Natalia , Stoupiec Małgorzata , Kavsur Refik , Isbarn Hendrik , Matthies Cord , Wagner Walter , Höppner Dirk , Fisch Margit , Bokemeyer Carsten , Ahyai Sascha , Honecker Friedemann , Riethdorf Sabine , Pantel Klaus
Published: April 2023

Abstract
Purpose: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell–specific markers, and results were correlated with disease stage, histology, and serum tumor markers.

Experimental Design: CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell–specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system.

Results: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood.

Conclusions: The inclusion of germ cell tumor–specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery. Clin Cancer Res; 20(14); 3830–41. ©2014 AACR.
Data from Molecular Testing for Lymph Node Metastases as a Determinant of Colon Cancer Recurrence: Results from a Retrospective Multicenter Study
Authors: Sargent Daniel J. , Shi Qian , Gill Sharlene , Louvet Christophe , Everson Richard B. , Kellner Udo , Clancy Thomas E. , Pipas J. Marc , Resnick Murray B. , Meyers Michael O. , Wu Tsung-Teh , Huntsman David , Validire Pierre , Farooq Umar , Pavey Emily S. , Beaudry Guillaume , Haince Jean-Francois , Fradet Yves
Published: April 2023

Abstract
Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence.

Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified.

Results: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07–5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95% CI, 0.99–3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77, 95% CI, 0.36–1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24–5.17, P = 0.011).

Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique. Clin Cancer Res; 20(16); 4361–9. ©2014 AACR.
Data from Development, Characterization, and Reversal of Acquired Resistance to the MEK1 Inhibitor Selumetinib (AZD6244) in an In Vivo Model of Childhood Astrocytoma
Authors: Bid Hemant K. , Kibler Aaron , Phelps Doris A. , Manap Sagymbek , Xiao Linlin , Lin Jiayuh , Capper David , Oswald Duane , Geier Brian , DeWire Mariko , Smith Paul D. , Kurmasheva Raushan T. , Mo Xiaokui , Fernandez Soledad , Houghton Peter J.
Published: April 2023

Abstract
Purpose: The BT-40 low-grade childhood astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to the MEK inhibitor selumetinib (AZD6244). In this study, we developed and characterized selumetinib resistance and explored approaches to circumventing the mechanisms of acquired resistance.

Experimental Design: BT-40 xenografts were selected in vivo for selumetinib resistance. Resistant tumors were obtained and characterized, as were tumors that reverted to sensitivity. Characterization included expression profiling, assessment of MEK signature and compensatory pathways, MEK inhibition, BRAF expression, and cytokine levels. Combination treatment of BT-40/AZD–resistant tumors with the MEK inhibitor and a STAT3 inhibitor (LLL12) was assessed.

Results: Resistance was unstable, tumors reverting to selumetinib sensitivity when passaged in untreated mice, and MEK was equally inhibited in sensitive and resistant tumors by selumetinib. Drug resistance was associated with an enhanced MEK signature and increased interleukin (IL)-6 and IL-8 expression. Selumetinib treatment induced phosphorylation of STAT3 (Y705) only in resistant xenografts, and similar results were observed in BRAFV600E astrocytic cell lines intrinsically resistant to selumetinib. Treatment of BT-40–resistant tumors with selumetinib or LLL12 had no significant effect, whereas combined treatment induced complete regressions of BT-40/AZD–resistant xenografts.

Conclusions: Resistance to selumetinib selected in vivo in BT-40 tumor xenografts was unstable. In resistant tumors, selumetinib activated STAT3, and combined treatment with selumetinib and LLL12 induced complete responses in resistant BT-40 tumors. These results suggest dual targeting BRAF (V600E) signaling and STAT3 signaling may be effective in selumetinib-resistant tumors or may retard or prevent onset of resistance. Clin Cancer Res; 19(24); 6716–29. ©2013 AACR.
Data from BRAF Fusions Define a Distinct Molecular Subset of Melanomas with Potential Sensitivity to MEK Inhibition
Authors: Hutchinson Katherine E. , Lipson Doron , Stephens Philip J. , Otto Geoff , Lehmann Brian D. , Lyle Pamela L. , Vnencak-Jones Cindy L. , Ross Jeffrey S. , Pietenpol Jennifer A. , Sosman Jeffrey A. , Puzanov Igor , Miller Vincent A. , Pao William
Published: April 2023

Abstract
Purpose: Recurrent “driver” mutations at specific loci in BRAF, NRAS, KIT, GNAQ, and GNA11 define clinically relevant molecular subsets of melanoma, but more than 30% are “pan-negative” for these recurrent mutations. We sought to identify additional potential drivers in “pan-negative” melanoma.

Experimental Design: Using a targeted next-generation sequencing (NGS) assay (FoundationOne™) and targeted RNA sequencing, we identified a novel PAPSS1-BRAF fusion in a “pan-negative” melanoma. We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne™, as well as melanoma RNA, whole-genome and whole-exome sequencing data in The Cancer Genome Atlas (TCGA), to determine the potential frequency of BRAF fusions in melanoma. We characterized the signaling properties of confirmed molecular alterations by ectopic expression of engineered cDNAs in 293H cells.

Results: Activation of the mitogen-activated protein kinase (MAPK) pathway in cells by ectopic expression of PAPSS1-BRAF was abrogated by mitogen-activated protein kinase kinase (MEK) inhibition but not by BRAF inhibition. NGS data analysis of 51 additional melanomas revealed a second BRAF fusion (TRIM24-BRAF) in a “pan-negative” sample; MAPK signaling induced by TRIM24-BRAF was also MEK inhibitor sensitive. Through mining TCGA skin cutaneous melanoma dataset, we further identified two potential BRAF fusions in another 49 “pan-negative” cases.

Conclusions: BRAF fusions define a new molecular subset of melanoma, potentially comprising 4% to 8% of “pan-negative” cases. Their presence may explain an unexpected clinical response to MEK inhibitor therapy or assist in selecting patients for MEK-directed therapy. Clin Cancer Res; 19(24); 6696–702. ©2013 AACR.
Data from Let-7 Expression Is a Significant Determinant of Response to Chemotherapy through the Regulation of IL-6/STAT3 Pathway in Esophageal Squamous Cell Carcinoma
Authors: Sugimura Keijiro , Miyata Hiroshi , Tanaka Koji , Hamano Rie , Takahashi Tsuyoshi , Kurokawa Yukinori , Yamasaki Makoto , Nakajima Kiyokazu , Takiguchi Shuji , Mori Masaki , Doki Yuichiro
Published: April 2023

Abstract
Purpose: Cisplatin-based chemotherapy is widely used for esophageal cancer, sometimes in combination with surgery/radiotherapy, but poor response to chemotherapy is not uncommon. The aim of this study was to examine whether miRNA expression is useful to predict the response to chemotherapy in patients with esophageal cancer.

Experimental Design: Using pretreatment biopsy samples from 98 patients with esophageal cancer who received preoperative chemotherapy, we measured the expression level of several miRNAs whose expression was altered in cisplatin-resistant esophageal cancer cell lines compared with those parent cell lines and examined the relationship between the miRNA expression and response to chemotherapy. In vitro assays were conducted to clarify the mechanism of miRNA-induced changes in chemosensitivity.

Results: The expression levels of 15 miRNAs were altered in cisplatin-resistant cells. Of these, low expression of let-7b and let-7c in before-treatment biopsies from 74 patients of the training set correlated significantly with poor response to chemotherapy, both clinically and histopathologically. Low expression of let-7c also correlated with poor prognosis (P = 0.032). The relationship between let-7b and let-7c expression and response to chemotherapy was confirmed in the other 24 patients of the validation set. In in vitro assay, transfection of let-7c restored sensitivity to cisplatin and increased rate of apoptosis after exposure to cisplatin. Let-7c directly repressed cisplatin-activated interleukin (IL)-6/STAT3 prosurvival pathway.

Conclusions: Let-7 expression in esophageal cancer can be potentially used to predict the response to cisplatin-based chemotherapy. Let-7 modulates the chemosensitivity to cisplatin through the regulation of IL-6/STAT3 pathway in esophageal cancer. Clin Cancer Res; 18(18); 5144–53. ©2012 AACR.
Data from Metformin and Pancreatic Cancer: A Clue Requiring Investigation
Authors: Pollak Michael
Published: April 2023

Abstract
Laboratory models show antineoplastic activity of metformin under certain conditions, and pharmacoepidemiologic studies have reported reduced cancer burden among diabetics taking metformin. Therefore, the hypothesis that metformin has antineoplastic activity is receiving increasing attention. However, gaps in knowledge must be addressed before metformin can be “repurposed” for oncologic indications. Clin Cancer Res; 18(10); 2723–5. ©2012 AACR.
Data from Is the “3+3” Dose-Escalation Phase I Clinical Trial Design Suitable for Therapeutic Cancer Vaccine Development? A Recommendation for Alternative Design
Authors: Rahma Osama E. , Gammoh Emily , Simon Richard M. , Khleif Samir N.
Published: April 2023

Abstract
Purpose: Phase I clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. This design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published “Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines.” However, many questions about the design of cancer vaccine studies remain unanswered.

Experimental Design: We analyzed the toxicity profile in 239 phase I therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a dose-escalation design.

Results: The rate of grade 3/4 vaccine-related systemic toxicities was 1.25 adverse events per 100 patients and 2 per 1,000 vaccines. Only two of the 127 dose-escalation trials reported vaccine-related dose limiting toxicities, both of which used bacterial vector vaccines. Out of the 116 trials analyzed for the dose–immune response relationship, we found a statistically significant dose–immune response correlation only when the immune response was measured by antibodies (P < 0.001) or delayed type hypersensitivity (P < 0.05). However, the increase in cellular immune response did not appear further sustainable with the continued increase in dose.

Conclusions: Our analysis suggests that the risks of serious toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate with dose levels. Accordingly, the conventional dose-escalation design is not suitable for cancer vaccines with few exceptions. Here, we propose an alternative design for therapeutic cancer vaccine development. Clin Cancer Res; 20(18); 4758–67. ©2014 AACR.
Data from A Comparative and Integrative Approach Identifies ATPase Family, AAA Domain Containing 2 as a Likely Driver of Cell Proliferation in Lung Adenocarcinoma
Authors: Fouret Robert , Laffaire Julien , Hofman Paul , Beau-Faller Michèle , Mazieres Julien , Validire Pierre , Girard Philippe , Camilleri-Bröet Sophie , Vaylet Fabien , Leroy-Ladurie François , Soria Jean-Charles , Fouret Pierre
Published: April 2023

Abstract
Purpose: To identify genetic changes that could drive cancer pathogenesis in never and ever smokers with lung adenocarcinoma.

Experimental Design: We analyzed the copy number and gene expression profiles of lung adenocarcinomas in 165 patients and related the alterations to smoking status. Having found differences in the tumor profiles, we integrated copy number and gene expression data from 80 paired samples.

Results: Amplifications at 8q24.12 overlapping MYC and ATAD2 were more frequent in ever smokers. Unsupervised analysis of gene expression revealed two groups: in the group with mainly never smokers, the tumors expressed genes common to normal lung; in the group with more ever smokers, the tumors expressed “proliferative” and “invasive” gene clusters. Integration of copy number and gene expression data identified one module enriched in mitotic genes and MYC targets. Its main associated modulator was ATAD2, a cofactor of MYC. A strong dose–response relationship between ATAD2 and proliferation-related gene expression was noted in both never and ever smokers, which was verified in two independent cohorts. Both ATAD2 and MYC expression correlated with 8q24.12 amplification and were higher in ever smokers. However, only ATAD2, and not MYC, overexpression explained the behavior of proliferation-related genes and predicted a worse prognosis independently of disease stage in a large validation cohort.

Conclusions: The likely driving force behind MYC contribution to uncontrolled cell proliferation in lung adenocarcinoma is ATAD2. Deregulation of ATAD2 is mainly related to gene amplification and is more frequent in ever smokers. Clin Cancer Res; 18(20); 5606–16. ©2012 AACR.
Data from Hypermethylation of the GABRE∼miR-452∼miR-224 Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy
Authors: Kristensen Helle , Haldrup Christa , Strand Siri , Mundbjerg Kamilla , Mortensen Martin M. , Thorsen Kasper , Ostenfeld Marie Stampe , Wild Peter J. , Arsov Christian , Goering Wolfgang , Visakorpi Tapio , Egevad Lars , Lindberg Johan , Grönberg Henrik , Høyer Søren , Borre Michael , Ørntoft Torben F. , Sørensen Karina D.
Published: April 2023

Abstract
Purpose: Available tools for prostate cancer diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the GABRE∼miR-452∼miR-224 genomic locus.

Experimental Design: GABRE/miR-452/miR-224 transcriptional expression was quantified in 80 nonmalignant and 281 prostate cancer tissue samples. GABRE∼miR-452∼miR-224 promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 nonmalignant, 293 prostate cancer [radical prostatectomy (RP) cohort 1] and 198 prostate cancer tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE∼miR-452∼miR-224 methylation was evaluated by ROC, Kaplan–Meier, uni- and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA) of posttransfection transcriptional profiling data.

Results:GABRE∼miR-452∼miR-224 was significantly downregulated in prostate cancer compared with nonmalignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC = 0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular adhesion and motility. Finally, in uni- and multivariate analyses, high GABRE∼miR-452∼miR-224 promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2.

Conclusion: The GABRE∼miR-452∼miR-224 locus is downregulated and hypermethylated in prostate cancer and is a new promising epigenetic candidate biomarker for prostate cancer diagnosis and prognosis. Tumor-suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two prostate cancer cell lines, suggesting that epigenetic silencing of GABRE∼miR-452∼miR-224 may be selected for in prostate cancer. Clin Cancer Res; 20(8); 2169–81. ©2014 AACR.
Data from Quantification of Excision Repair Cross-Complementing Group 1 and Survival in p16-Negative Squamous Cell Head and Neck Cancers
Authors: Mehra Ranee , Zhu Fang , Yang Dong-Hua , Cai Kathy Q. , Weaver JoEllen , Singh Mahendra K. , Nikonova Anna S. , Golemis Erica A. , Flieder Douglas B. , Cooper Harry S. , Lango Miriam , Ridge John A. , Burtness Barbara
Published: April 2023

Abstract
Purpose: Multimodality treatment of squamous cell carcinoma of the head and neck (SCCHN) often involves radiotherapy and cisplatin-based therapy. Elevated activity of DNA repair mechanisms, such as the nucleotide excision repair (NER) pathway, of which ERCC1 is a rate-limiting element, are associated with cisplatin and possibly RT resistance. We have determined excision repair cross-complementing group 1 (ERCC1) expression in human papillomavirus (HPV)-negative SCCHN treated with surgery [±adjuvant radiotherapy/chemoradiation (CRT)].

Experimental Design: We assessed ERCC1 protein expression in archival tumors using immunofluorescence staining and automatic quantitative analysis (AQUA) with three antibodies to ERCC1 (8F1, FL297, and HPA029773). Analysis with Classification and Regression Tree (CART) methods ascertained the cutoff points between high/low ERCC1 expression. Multivariable analysis adjusted for age, T, and N stage. Kaplan–Meier curves determined median survival. ERCC1 expression at initial tumor presentation and in recurrent disease were compared. Performance characteristics of antibodies were assessed.

Results: ERCC1 low/high groups were defined on the basis of AQUA analysis with 8F1/2009, FL297, and HPA029773. Among patients treated with surgery plus adjuvant radiotherapy/CRT, longer median survival was observed in ERCC1-low versus ERCC1-high tumors (64 vs. 29 months; P = 0.02; HPA029773). Data obtained with HPA029773 indicated no survival difference among patients treated only with surgery. Recurrent cancers had lower ERCC1 AQUA scores than tumors from initial presentation. Extensive characterization indicated optimal specificity and performance by the HPA029773 antibody.

Conclusions: Using AQUA, with the specific ERCC1 antibody HPA029773, we found a statistical difference in survival among high/low-ERCC1 tumors from patients treated with surgery and adjuvant radiotherapy. Clin Cancer Res; 19(23); 6633–43. ©2013 AACR.
Data from Effect of Aromatase Inhibition on Functional Gene Modules in Estrogen Receptor–Positive Breast Cancer and Their Relationship with Antiproliferative Response
Authors: Gao Qiong , Patani Neill , Dunbier Anita K. , Ghazoui Zara , Zvelebil Marketa , Martin Lesley-Ann , Dowsett Mitch
Published: April 2023

Abstract
Purpose: To investigate potential associations between gene modules representing key biologic processes and response to aromatase inhibitors (AI) in estrogen receptor–positive (ER+) breast cancer.

Patients and Methods: Paired gene expression and Ki67 protein expression were available from 69 postmenopausal women with ER+ early breast cancer, at baseline and 2 weeks post-anastrozole treatment, in the presurgical setting. Functional gene modules (n = 26) were retrieved from published studies and their module scores were computed before and after elimination of proliferation-associated genes (PAG). Ki67 and module scores were assessed at baseline and 2 weeks post-anastrozole. Unsupervised clustering was used to assess associations between modules and Ki67.

Results: Proliferation-based modules were highly correlated with Ki67 expression both pretreatment and on-treatment. At baseline with and without PAGs, Ki67 expression was significantly inversely correlated with ERG, ESR1.2, SET, and PIK3CA modules. Modules measuring estrogen signaling strongly predicted antiproliferative response to therapy with and without PAGs. Baseline expression of insulin-like growth factor-1 (IGF-I) module predicted a poor change in Ki67-implicating genes within the module as involved in de novo resistance to AIs. High expression of Immune.2.STAT1 module pretreatment predicted poor antiproliferative response to therapy. A significant association between estrogen-regulated genes modules (ESR1, ESR1-2, SET, and ERG) was evident post AI.

Conclusions: Multiple processes and pathways are affected by AI treatment in ER+ breast cancer. Modules closely associated with ESR1 expression were predictive of good antiproliferative response to AIs, but modules representing immune activity and IGF-I/MAPK were predictive of poor Ki67 response, supporting their therapeutic targeting in combination with AIs. Clin Cancer Res; 20(9); 2485–94. ©2014 AACR.
Data from PI3K Pathway Activation Provides a Novel Therapeutic Target for Pediatric Ependymoma and Is an Independent Marker of Progression-Free Survival
Authors: Rogers Hazel A. , Mayne Cerys , Chapman Rebecca J. , Kilday John-Paul , Coyle Beth , Grundy Richard G.
Published: April 2023

Abstract
Purpose: Currently, there are few effective adjuvant therapies for pediatric ependymoma outside confocal radiation, and prognosis remains poor. The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in cancer. PI3Ks transduce signals from growth factors and cytokines, resulting in the phosphorylation and activation of AKT, which in turn induces changes in cell growth, proliferation, and apoptosis.

Experimental Design: PI3K pathway status was analyzed in ependymoma using gene expression data and immunohistochemical analysis of phosphorylated AKT (P-AKT). The effect of the PI3K pathway on cell proliferation was investigated by immunohistochemical analysis of cyclin D1 and Ki67, plus in vitro functional analysis. To identify a potential mechanism of PI3K pathway activation, PTEN protein expression and the mutation status of PI3K catalytic subunit α-isoform gene (PIK3CA) was investigated.

Results: Genes in the pathway displayed significantly higher expression in supratentorial than in posterior fossa and spinal ependymomas. P-AKT protein expression, indicating pathway activation, was seen in 72% of tumors (n = 169) and P-AKT expression was found to be an independent marker of a poorer progression-free survival. A significant association between PI3K pathway activation and cell proliferation was identified, suggesting that pathway activation was influencing this process. PTEN protein loss was not associated with P-AKT staining and no mutations were identified in PIK3CA.

Conclusions: Our results suggest that the PI3K pathway could act as a biomarker, not only identifying patients with a worse prognosis but also those that could be treated with therapies targeted against the pathway, a strategy potentially effective in a high percentage of ependymoma patients. Clin Cancer Res; 19(23); 6450–60. ©2013 AACR.
Data from BRAF/NRAS Wild-Type Melanomas Have a High Mutation Load Correlating with Histologic and Molecular Signatures of UV Damage
Authors: Mar Victoria J. , Wong Stephen Q. , Li Jason , Scolyer Richard A. , McLean Catriona , Papenfuss Anthony T. , Tothill Richard W. , Kakavand Hojabr , Mann Graham J. , Thompson John F. , Behren Andreas , Cebon Jonathan S. , Wolfe Rory , Kelly John W. , Dobrovic Alexander , McArthur Grant A.
Published: April 2023

Abstract
Purpose: The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features.

Experimental Design: DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF/NRAS mutational status were investigated.

Results: The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin (P = 0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS–mutant tumors (27 vs. 5.6 mutations per Mb; P = 0.0001). Tandem CC>TT/GG>AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (P = 0.0008) and in BRAF/NRAS WT tumors (P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1, KIT, and NOTCH1, were spread over various signaling pathways.

Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res; 19(17); 4589–98. ©2013 AACR.
Data from Pharmacologic Inhibition of Jak2–Stat5 Signaling By Jak2 Inhibitor AZD1480 Potently Suppresses Growth of Both Primary and Castrate-Resistant Prostate Cancer
Authors: Gu Lei , Liao Zhiyong , Hoang David T. , Dagvadorj Ayush , Gupta Shilpa , Blackmon Shauna , Ellsworth Elyse , Talati Pooja , Leiby Benjamin , Zinda Michael , Lallas Costas D. , Trabulsi Edouard J. , McCue Peter , Gomella Leonard , Huszar Dennis , Nevalainen Marja T.
Published: April 2023

Abstract
Purpose: Progression of prostate cancer to the lethal castrate-resistant stage coincides with loss of responsiveness to androgen deprivation and requires development of novel therapies. We previously provided proof-of-concept that Stat5a/b is a therapeutic target protein for prostate cancer. Here, we show that pharmacologic targeting of Jak2-dependent Stat5a/b signaling by the Jak2 inhibitor AZD1480 blocks castrate-resistant growth of prostate cancer.

Experimental Design: Efficacy of AZD1480 in disrupting Jak2–Stat5a/b signaling and decreasing prostate cancer cell viability was evaluated in prostate cancer cells. A unique prostate cancer xenograft mouse model (CWR22Pc), which mimics prostate cancer clinical progression in patients, was used to assess in vivo responsiveness of primary and castrate-resistant prostate cancer (CRPC) to AZD1480. Patient-derived clinical prostate cancers, grown ex vivo in organ explant cultures, were tested for responsiveness to AZD1480.

Results: AZD1480 robustly inhibited Stat5a/b phosphorylation, dimerization, nuclear translocation, DNA binding, and transcriptional activity in prostate cancer cells. AZD1480 reduced prostate cancer cell viability sustained by Jak2–Stat5a/b signaling through induction of apoptosis, which was rescued by constitutively active Stat5a/b. In mice, pharmacologic targeting of Stat5a/b by AZD1480 potently blocked growth of primary androgen-dependent as well as recurrent castrate-resistant CWR22Pc xenograft tumors, and prolonged survival of tumor-bearing mice versus vehicle or docetaxel-treated mice. Finally, nine of 12 clinical prostate cancers responded to AZD1480 by extensive apoptotic epithelial cell loss, concurrent with reduced levels of nuclear Stat5a/b.

Conclusions: We report the first evidence for efficacy of pharmacologic targeting of Stat5a/b as a strategy to inhibit castrate-resistant growth of prostate cancer, supporting further clinical development of Stat5a/b inhibitors as therapy for advanced prostate cancer. Clin Cancer Res; 19(20); 5658–74. ©2013 AACR.
Data from Pertuzumab Protects the Achilles' Heel of Trastuzumab—Emtansine
Authors: Gwin William R. , Spector Neil L.
Published: April 2023

Abstract
Trastuzumab emtansine (T-DM1) represents a significant advancement in the treatment of HER2+ breast cancers. Its clinical efficacy however will be limited by the development of therapeutic resistance. In this report, the HER3 ligand neuregulin is shown to mediate T-DM1 resistance, which was overcome by administration of pertuzumab, a steric inhibitor of HER2 dimerization. Clin Cancer Res; 20(2); 278–80. ©2013 AACR.