bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies
Authors: Gupta Shilpa , Argilés Guillem , Munster Pamela N. , Hollebecque Antoine , Dajani Olav , Cheng Jonathan D. , Wang Ruixue , Swift Ann , Tosolini Alessandra , Piha-Paul Sarina A.
Published: April 2023

Abstract
Purpose: The PI3K/Akt/mTOR signaling pathway is aberrantly activated in many cancers. Combining ridaforolimus, an mTOR inhibitor, with MK-2206, an Akt inhibitor, may more completely block the PI3K pathway and inhibit tumor growth.

Experimental Design: This phase I study assessed dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of oral ridaforolimus plus oral MK-2206 in patients with advanced solid tumors. Efficacy was evaluated in patients with biomarker-identified estrogen receptor–positive breast cancer (low RAS gene signature and high Ki67 index) or castration-resistant prostate cancer (PTEN deficiency) with PI3K pathway addiction.

Results: Thirty-five patients were enrolled: 11 patients in part A (three breast cancer) and 24 biomarker-eligible patients in part B (16 breast cancer, eight prostate cancer). One patient with breast cancer from part A was also found to be biomarker-eligible when tested after she had clinical response. The MTD was 10 mg/d ridaforolimus 5 d/wk + 90 mg/wk MK-2206; 1 of 17 patients experienced DLT (grade 3 rash) at this dose. The most common adverse events at MTD were rash (44.4%), stomatitis (38.9%), diarrhea (27.8%), and decreased appetite (27.8%). By investigator assessment, 2 of 16 (12.5%) evaluable patients with breast cancer had partial response; by central assessment, 2 of 14 (14.3%) evaluable patients had complete response. Two patients had durable stable disease (SD) for 416 and 285 days, respectively. No patients with prostate cancer responded; one patient had SD for ≥6 months.

Conclusions: Combination ridaforolimus and MK-2206 showed promising activity and good tolerability in heavily pretreated patients with hormone-positive and -negative breast cancer exhibiting PI3K pathway dependence. Clin Cancer Res; 21(23); 5235–44. ©2015 AACR.
Data from Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo
Authors: Kimbrough Charles W. , Khanal Anil , Zeiderman Matthew , Khanal Bigya R. , Burton Neal C. , McMasters Kelly M. , Vickers Selwyn M. , Grizzle William E. , McNally Lacey R.
Published: April 2023

Abstract
Background: pH-low insertion peptides (pHLIP) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer.

Methods: A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semiquantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model.

Results: In vitro, the V7-750 probe demonstrated significantly higher fluorescence at pH 6.6 compared with pH 7.4 (S2VP10, P = 0.0119; S2013, P = 0.0160), whereas no difference was observed with the K7-750 control (S2VP10, P = 0.8783; S2013, P = 0.921). In the in vivo S2VP10 model, V7-750 probe resulted in 782.5 MSOT a.u. signal compared with 5.3 MSOT a.u. in K7-750 control in tumor (P = 0.0001). Similarly, V7-750 probe signal was 578.3 MSOT a.u. in the S2013 model compared with K7-750 signal at 5.1 MSOT a.u. (P = 0.0005). There was minimal off-target accumulation of the V7-750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging.

Conclusions: Compared with pH-insensitive controls, V7-750 pH-sensitive probe specifically targets pancreatic adenocarcinoma and has minimal off-target accumulation. The noninvasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer. Clin Cancer Res; 21(20); 4576–85. ©2015 AACR.

See related commentary by Reshetnyak, p. 4502
Data from A Phase I Study of Continuous Oral Dosing of OSI-906, a Dual Inhibitor of Insulin-Like Growth Factor-1 and Insulin Receptors, in Patients with Advanced Solid Tumors
Authors: Puzanov Igor , Lindsay Colin R. , Goff Laura , Sosman Jeff , Gilbert Jill , Berlin Jordan , Poondru Srinivasu , Simantov Ronit , Gedrich Rich , Stephens Andrew , Chan Emily , Evans T.R. Jeffry
Published: April 2023

Abstract
Purpose: OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors.

Patients and Methods: This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules.

Results: Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified.

Conclusions: At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 701–11. ©2014 AACR.

See related commentary by Yee, p. 667
Data from Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts
Authors: Bieniasz Magdalena , Radhakrishnan Parvathi , Faham Najme , De La O Jean-Paul , Welm Alana L.
Published: April 2023

Abstract
Purpose: Recent studies have demonstrated that short-form Ron (sfRon) kinase drives breast tumor progression and metastasis through robust activation of the PI3K pathway. We reasoned that upfront, concurrent inhibition of sfRon and PI3K might enhance the antitumor effects of Ron kinase inhibitor therapy while also preventing potential therapeutic resistance to tyrosine kinase inhibitors (TKI).

Experimental Design: We used patient-derived breast tumor xenografts (PDX) as high-fidelity preclinical models to determine the efficacy of single-agent or dual Ron/PI3K inhibition. We tested the Ron kinase inhibitor ASLAN002 with and without coadministration of the PI3K inhibitor NVP-BKM120 in hormone receptor–positive [estrogen receptor (ER)+/progesterone receptor (PR)+] breast PDXs with and without PIK3CA gene mutation.

Results: Breast PDX tumors harboring wild-type PIK3CA showed a robust response to ASLAN002 as a single agent. In contrast, PDX tumors harboring mutated PIK3CA demonstrated partial resistance to ASLAN002, which was overcome with addition of NVP-BKM120 to the treatment regimen. We further demonstrated that concurrent inhibition of sfRon and PI3K in breast PDX tumors with wild-type PIK3CA provided durable tumor stasis after therapy cessation, whereas discontinuation of either monotherapy facilitated tumor recurrence.

Conclusions: Our work provides preclinical rationale for targeting sfRon in patients with breast cancer, with the important stipulation that tumors harboring PIK3CA mutations may be partially resistant to Ron inhibitor therapy. Our data also indicate that tumors with wild-type PIK3CA are most effectively treated with an upfront combination of Ron and PI3K inhibitors for the most durable response. Clin Cancer Res; 21(24); 5588–600. ©2015 AACR.
Data from HAGE in Triple-Negative Breast Cancer Is a Novel Prognostic, Predictive, and Actionable Biomarker: A Transcriptomic and Protein Expression Analysis
Authors: Abdel-Fatah Tarek M.A. , McArdle Stephanie E.B. , Agarwal Devika , Moseley Paul M. , Green Andrew R. , Ball Graham R. , Pockley A. Graham , Ellis Ian O. , Rees Robert C. , Chan Stephen Y.T.
Published: April 2023

Abstract
Purpose: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC).

Experimental Design: HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n = 520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline combination Neo-ACT (n = 110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC cohort (n = 311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomization to ixabepilone (n = 68) or paclitaxel (n = 64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumors with integrated HAGE gene copy number changes, mRNA, and protein levels were analyzed.

Results: In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE+) was associated with a higher risk of death [HR, 1.3; 95% confidence interval (CI), 1.2–1.5; P = 0.000005] when compared with HAGE− cases. Patients who received ACT and expressed mRNA-HAGE+ were at a lower risk of death than those who were mRNA–HAGE− (P = 0.004). The expression of HAGE was linked to the presence of tumor-infiltrating lymphocytes (TIL), and both features were found to be independent predictors for pathologic complete response (pCR, P < 0.001) and associated with prolonged survival (P < 0.01), following AC-Neo-ACT. In patients with residual disease, HAGE+ had a 2-fold death risk increase (P = 0.018) compared with HAGE−.

Conclusions: HAGE expression is a potential prognostic marker and a predictor of response to anthracycline treatment in TNBC. A prospective clinical trial to examine the therapeutic value of HAGE for TNBC cases is warranted. Clin Cancer Res; 22(4); 905–14. ©2015 AACR.
Data from Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer
Authors: Sanz-Pamplona Rebeca , Lopez-Doriga Adriana , Paré-Brunet Laia , Lázaro Kira , Bellido Fernando , Alonso M. Henar , Aussó Susanna , Guinó Elisabet , Beltrán Sergi , Castro-Giner Francesc , Gut Marta , Sanjuan Xavier , Closa Adria , Cordero David , Morón-Duran Francisco D. , Soriano Antonio , Salazar Ramón , Valle Laura , Moreno Victor
Published: April 2023

Abstract
Purpose: Somatic mutations occur at early stages of adenoma and accumulate throughout colorectal cancer progression. The aim of this study was to characterize the mutational landscape of stage II tumors and to search for novel recurrent mutations likely implicated in colorectal cancer tumorigenesis.

Experimental Design: The exomic DNA of 42 stage II, microsatellite-stable colon tumors and their paired mucosae were sequenced. Other molecular data available in the discovery dataset [gene expression, methylation, and copy number variations (CNV)] were used to further characterize these tumors. Additional datasets comprising 553 colorectal cancer samples were used to validate the discovered mutations.

Results: As a result, 4,886 somatic single-nucleotide variants (SNV) were found. Almost all SNVs were private changes, with few mutations shared by more than one tumor, thus revealing tumor-specific mutational landscapes. Nevertheless, these diverse mutations converged into common cellular pathways, such as cell cycle or apoptosis. Among this mutational heterogeneity, variants resulting in early stop codons in the AMER1 (also known as FAM123B or WTX) gene emerged as recurrent mutations in colorectal cancer. Losses of AMER1 by other mechanisms apart from mutations such as methylation and copy number aberrations were also found. Tumors lacking this tumor suppressor gene exhibited a mesenchymal phenotype characterized by inhibition of the canonical Wnt pathway.

Conclusions: In silico and experimental validation in independent datasets confirmed the existence of functional mutations in AMER1 in approximately 10% of analyzed colorectal cancer tumors. Moreover, these tumors exhibited a characteristic phenotype. Clin Cancer Res; 21(20); 4709–18. ©2015 AACR.
Data from Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors
Authors: Ortiz-Cuaran Sandra , Scheffler Matthias , Plenker Dennis , Dahmen llona , Scheel Andreas H. , Fernandez-Cuesta Lynnette , Meder Lydia , Lovly Christine M. , Persigehl Thorsten , Merkelbach-Bruse Sabine , Bos Marc , Michels Sebastian , Fischer Rieke , Albus Kerstin , König Katharina , Schildhaus Hans-Ulrich , Fassunke Jana , Ihle Michaela A. , Pasternack Helen , Heydt Carina , Becker Christian , Altmüller Janine , Ji Hongbin , Müller Christian , Florin Alexandra , Heuckmann Johannes M. , Nuernberg Peter , Ansén Sascha , Heukamp Lukas C. , Berg Johannes , Pao William , Peifer Martin , Buettner Reinhard , Wolf Jürgen , Thomas Roman K. , Sos Martin L.
Published: April 2023

Abstract
Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).

Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.

Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS.

Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837–47. ©2016 AACR.
Data from Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma
Authors: Maréchal Raphaël , Bachet Jean-Baptiste , Calomme Annabelle , Demetter Pieter , Delpero Jean Robert , Svrcek Magali , Cros Jérôme , Bardier-Dupas Armelle , Puleo Francesco , Monges Geneviève , Hammel Pascal , Louvet Christophe , Paye François , Bachelier Philippe , Le Treut Yves Patrice , Vaillant Jean-Christophe , Sauvanet Alain , André Thierry , Salmon Isabelle , Devière Jacques , Emile Jean-François , Van Laethem Jean-Luc
Published: April 2023

Abstract
Purpose: Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density.

Experimental Design: Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated.

Results: Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P < 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023).

Conclusions: Shh and Gli1 are prognostic biomarkers for patients with resected PDAC. Clin Cancer Res; 21(5); 1215–24. ©2014 AACR.
Data from Antigen Selection Shapes the T-cell Repertoire in Chronic Lymphocytic Leukemia
Authors: Vardi Anna , Agathangelidis Andreas , Stalika Evangelia , Karypidou Maria , Siorenta Alexandra , Anagnostopoulos Achilles , Rosenquist Richard , Hadzidimitriou Anastasia , Ghia Paolo , Sutton Lesley-Ann , Stamatopoulos Kostas
Published: April 2023

Abstract
Purpose: The role of antigen(s) in shaping the T-cell repertoire in chronic lymphocytic leukemia, although relevant for understanding malignant cell interactions with cognate T cells, is largely unexplored.

Experimental Design: Here we profiled the T-cell receptor β chain gene repertoire in 58 chronic lymphocytic leukemia patients, focusing on cases assigned to well-characterized subsets with stereotyped clonotypic B-cell receptor immunoglobulins, therefore those cases most evidently selected by antigen (subsets #1, #2, and #4).

Results: Remarkable repertoire skewing and oligoclonality were observed, and differences between subsets were noted regarding both T-cell receptor β chain gene usage and the extent of clonality, with subset #2 being the least oligoclonal. Longitudinal analysis of subset #4 cases revealed that although the repertoire may fluctuate over time, certain clonotypes persist, thus alluding to persistent antigenic stimulation. Shared (“stereotyped”) clonotypes were found between different patients, reflecting selection by common antigenic elements. Cross-comparison of our dataset with public databases showed that some T-cell clonotypes may have expanded secondary to common viral infections; however, the majority of clonotypes proved to be disease-specific.

Conclusions: Overall, the T-cell receptor β chain repertoire in chronic lymphocytic leukemia is likely shaped by antigen selection and the implicated antigenic elements may concern epitopes that also select the malignant B-cell progenitors or, more intriguingly, chronic lymphocytic leukemia–derived epitopes. Clin Cancer Res; 22(1); 167–74. ©2015 AACR.
Data from BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS-Mutant Colorectal Cancer
Authors: Bartolini Alice , Cardaci Sabrina , Lamba Simona , Oddo Daniele , Marchiò Caterina , Cassoni Paola , Amoreo Carla Azzurra , Corti Giorgio , Testori Alessandro , Bussolino Federico , Pasqualini Renata , Arap Wadih , Corà Davide , Di Nicolantonio Federica , Marchiò Serena
Published: April 2023

Abstract
Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets.

Experimental Design: A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adhesion assays.

Results: BCAM and LAMA5 were identified as molecular targets within both tumor cells and TME of KRAS-mutant hepatic metastasis from colorectal cancer, where they were specifically overexpressed. Two BCAM-mimic peptides inhibited KRAS-mutant hepatic metastasis in preclinical models. Genetic suppression and biochemical inhibition of either BCAM or LAMA5 impaired adhesion of KRAS-mutant colorectal cancer cells specifically to endothelial cells, whereas adhesion to pericytes and hepatocytes was unaffected.

Conclusions: These data show that the BCAM/LAMA5 system plays a functional role in the metastatic spreading of KRAS-mutant colorectal cancer by mediating tumor–TME interactions and as such represents a valuable therapeutic candidate for this large, currently untreatable patient group. Clin Cancer Res; 22(19); 4923–33. ©2016 AACR.
Data from Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors
Authors: Goldman Jonathan , Eckhardt S. Gail , Borad Mitesh J. , Curtis Kelly K. , Hidalgo Manuel , Calvo Emiliano , Ryan David P. , Wirth Lori J. , Parikh Asit , Partyka James , Faessel Helene , Gangolli Esha , Stewart Sally , Rosen Lee S. , Bowles Daniel W.
Published: April 2023

Abstract
Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway.

Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50–1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1.

Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n = 4) and fatigue (n = 3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration–time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors).

Conclusions: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling. Clin Cancer Res; 21(5); 1002–9. ©2014 AACR.
Data from Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer
Authors: Kummar Shivaani , Oza Amit M. , Fleming Gini F. , Sullivan Daniel M. , Gandara David R. , Naughton Michael J. , Villalona-Calero Miguel A. , Morgan Robert J. , Szabo Peter M. , Youn Ahrim , Chen Alice P. , Ji Jiuping , Allen Deborah E. , Lih Chih-Jian , Mehaffey Michele G. , Walsh William D. , McGregor Paul M. , Steinberg Seth M. , Williams P. Mickey , Kinders Robert J. , Conley Barbara A. , Simon Richard M. , Doroshow James H.
Published: April 2023

Abstract
Purpose: Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).

Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression.

Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit.

Conclusion: This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival. Clin Cancer Res; 21(7); 1574–82. ©2015 AACR.
Data from Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunologic and Clinical Outcomes
Authors: McCann Katy J. , Mander Ann , Cazaly Angelica , Chudley Lindsey , Stasakova Jana , Thirdborough Stephen M. , King Andrew , Lloyd-Evans Paul , Buxton Emily , Edwards Ceri , Halford Sarah , Bateman Andrew , O'Callaghan Ann , Clive Sally , Anthoney Alan , Jodrell Duncan I. , Weinschenk Toni , Simon Petra , Sahin Ugur , Thomas Gareth J. , Stevenson Freda K. , Ottensmeier Christian H.
Published: April 2023

Abstract
Purpose: We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201–binding peptide CAP-1 from carcinoembryonic antigen (CEA605–613) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin.

Experimental Design: Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (arm-I) and 12 patients without radiological evidence of disease (arm-II). Six intramuscular vaccinations of naked DNA (1 mg/dose) were administered up to week 12. Clinical and immunologic follow-up was up to week 64 or clinical/radiological disease.

Results: DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared with 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8+ T cells, respectively. CAP-1–specific T cells were only detectable in the blood postvaccination but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (P < 0.001) and improved global immunologic responses [anti-DOM responses of greater magnitude (P < 0.001), frequency (P = 0.004), and duration] compared with patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR = 0.14, P = 0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass spectrometry, offering a mechanistic explanation for diarrhea through CD8+ T-cell attack.

Conclusions: Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody. Clin Cancer Res; 22(19); 4827–36. ©2016 AACR.
Data from First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors
Authors: Meulendijks Didier , Jacob Wolfgang , Martinez-Garcia Maria , Taus Alvaro , Lolkema Martijn P. , Voest Emile E. , Langenberg Marlies H.G. , Fleitas Kanonnikoff Tania , Cervantes Andres , De Jonge Maja J. , Sleijfer Stefan , Soerensen Morten Mau , Thomas Marlene , Ceppi Maurizio , Meneses-Lorente Georgina , James Ian , Adessi Celine , Michielin Francesca , Abiraj Keelara , Bossenmaier Birgit , Schellens Jan H.M. , Weisser Martin , Lassen Ulrik N.
Published: April 2023

Abstract
Purpose: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.

Experimental Design: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.

Results: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration–time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80–225 days).

Conclusions: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards. Clin Cancer Res; 22(4); 877–85. ©2015 AACR.
Data from The NEDD8-Activating Enzyme Inhibitor MLN4924 Disrupts Nucleotide Metabolism and Augments the Efficacy of Cytarabine
Authors: Nawrocki Steffan T. , Kelly Kevin R. , Smith Peter G. , Keaton Mignon , Carraway Hetty , Sekeres Mikkael A. , Maciejewski Jaroslaw P. , Carew Jennifer S.
Published: April 2023

Abstract
Purpose: New therapies are urgently needed for patients with acute myelogenous leukemia (AML). The novel NEDDylation inhibitor MLN4924 (pevonedistat) has demonstrated significant preclinical antileukemic activity and preliminary efficacy in patients with AML in a phase I trial. On the basis of its antimyeloid and DNA-damaging properties, we investigated the ability of MLN4924 to augment conventional cytarabine (ara-C) therapy.

Experimental Design: The effects of MLN4924/ara-C on viability, clonogenic survival, apoptosis, DNA damage, and relevant pharmacodynamic targets were determined. The efficacy and pharmacodynamics of MLN4924/ara-C were assessed in an AML xenograft model.

Results: Cotreatment of AML cell lines and primary patient specimens with MLN4924 and ara-C led to diminished clonogenic survival, increased apoptosis, and synergistic levels of DNA damage. RNAi demonstrated that stabilization of CDT-1, an event previously shown to mediate the DNA-damaging effects of MLN4924, was not a key regulator of sensitivity to the MLN4924/ara-C combination. Global metabolic profiling revealed that MLN4924 disrupts nucleotide metabolism and depletes intracellular nucleotide pools in AML cells. Subsequent experiments showed that MLN4924 promoted increased incorporation of ara-C into the DNA of AML cells. This effect as well as the therapeutic benefit of the MLN4924/ara-C combination was antagonized by supplementation with the nucleotide building block ribose. Coadministration of MLN4924 and ara-C to mice bearing FLT3-ITD+ AML xenografts stably inhibited disease progression and increased DNA damage in vivo.

Conclusions: Our findings provide strong rationale for clinical investigation of the MLN4924/ara-C combination and establish a new link between therapeutic inhibition of NEDDylation and alterations in nucleotide metabolism. Clin Cancer Res; 21(2); 439–47. ©2014 AACR.
Data from Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells
Authors: Yoon Changhwan , Cho Soo-Jeong , Aksoy Bülent Arman , Park Do Joong , Schultz Nikolaus , Ryeom Sandra W. , Yoon Sam S.
Published: April 2023

Abstract
Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbors mutations in RHOA, but little is known about the role of RhoA in DGA.

Experimental Design: We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples.

Results: RhoA activity was higher in DGA compared with IGA cell lines and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSCs) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78% to 81%. DGA spheroid cells had 3- to 5-fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40% to 50%, RhoA inhibition by 32% to 60%, and the combination by 77% to 83%. In 288 patient tumors, increased RhoA activity correlated with worse overall survival in DGA patients (P = 0.017) but not in IGA patients (P = 0.612).

Conclusions: RhoA signaling promotes CSC phenotypes in DGA cells. Increased RhoA activity is correlated with worse overall survival in DGA patients, and RhoA inhibition can reverse chemotherapy resistance in DGA CSC and in tumor xenografts. Thus, the RhoA pathway is a promising new target in DGA patients. Clin Cancer Res; 22(4); 971–83. ©2015 AACR.
Data from Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder
Authors: Wang Wei-Jan , Li Chien-Feng , Chu Yu-Yi , Wang Yu-Hui , Hour Tzyh-Chyuan , Yen Chia-Jui , Chang Wen-Chang , Wang Ju-Ming
Published: April 2023

Abstract
Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy.

Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity.

Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel.

Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201. Clin Cancer Res; 23(2); 503–13. ©2016 AACR.
Data from Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma
Authors: Krytska Kateryna , Ryles Hannah T. , Sano Renata , Raman Pichai , Infarinato Nicole R. , Hansel Theodore D. , Makena Monish R. , Song Michael M. , Reynolds C. Patrick , Mossé Yael P.
Published: April 2023

Abstract
Purpose: The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations. Thus, understanding mechanisms of resistance and defining circumvention strategies for the clinic is critical.

Experimental Design: The sensitivity of human neuroblastoma–derived cell lines, cell line–derived, and patient-derived xenograft (PDX) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide (topo/cyclo) was examined. Cultured cells and xenografts were evaluated for effects of these drugs on proliferation, signaling, and cell death, and assessment of synergy.

Results: In neuroblastoma murine xenografts harboring the most common ALK mutations, including those mutations associated with resistance to crizotinib (but not in those with wild-type ALK), crizotinib combined with topo/cyclo enhanced tumor responses and mouse event-free survival. Crizotinib + topo/cyclo showed synergistic cytotoxicity and higher caspase-dependent apoptosis than crizotinib or topo/cyclo alone in neuroblastoma cell lines with ALK aberrations (mutation or amplification).

Conclusions: Combining crizotinib with chemotherapeutic agents commonly used in treating newly diagnosed patients with high-risk neuroblastoma restores sensitivity in preclinical models harboring both sensitive ALK aberrations and de novo–resistant ALK mutations. These data support clinical testing of crizotinib and conventional chemotherapy with the goal of integrating ALK inhibition into multiagent therapy for ALK-aberrant neuroblastoma patients. Clin Cancer Res; 22(4); 948–60. ©2015 AACR.
Data from Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein–Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression
Authors: Jones Richard J. , Iempridee Tawin , Wang Xiaobin , Lee Hans C. , Mertz Janet E. , Kenney Shannon C. , Lin Heather C. , Baladandayuthapani Veerabhadran , Dawson Christopher W. , Shah Jatin J. , Weber Donna M. , Orlowski Robert Z.
Published: April 2023

Abstract
Purpose: Lenalidomide, thalidomide, and pomalidomide (LTP) are immunomodulatory agents approved for use in multiple myeloma, but in some settings, especially with alkylating agents, an increase in Hodgkin lymphoma and other secondary primary malignancies (SPM) has been noted. Some of these malignancies have been linked to Epstein–Barr virus (EBV), raising the possibility that immunomodulatory drugs disrupt latent EBV infection.

Experimental Design: We studied the ability of LTP to reactivate latently infected EBV-positive cell lines in vitro and in vivo, and evaluated the EBV viral load in archived serum samples from patients who received a lenalidomide, thalidomide, and dexamethasone (LTD) combination.

Results: Treatment of EBV-infected B-cell lines with LTP at physiologically relevant concentrations induced the immediate early gene BZLF1, the early gene BMRF1, and the late proteins VCA and BCFR1. This occurred in the potency order pomalidomide > lenalidomide > thalidomide, and the nucleoside analogue ganciclovir enhanced the cytotoxic effects of lenalidomide and pomalidomide in Burkitt lymphoma cells in vitro and in vivo. EBV reactivation was related to PI3K stimulation and Ikaros suppression, and blocked by the PI3Kδ inhibitor idelalisib. Combinations of lenalidomide with dexamethasone or rituximab increased EBV reactivation compared with lenalidomide alone and, importantly, lenalidomide with melphalan produced even greater reactivation.

Conclusions: We conclude LTP may reactivate EBV-positive resting memory B cells thereby enhancing EBV lytic cycle and host immune suppression. Clin Cancer Res; 22(19); 4901–12. ©2016 AACR.
Data from Phase I Study of Intermittent Oral Dosing of the Insulin-like Growth Factor-1 and Insulin Receptors Inhibitor OSI-906 in Patients With Advanced Solid Tumors
Authors: Jones Robin L. , Kim Edward S. , Nava-Parada Pilar , Alam Salma , Johnson Faye M. , Stephens Andrew W. , Simantov Ronit , Poondru Srinivasu , Gedrich Rich , Lippman Scott M. , Kaye Stan B. , Carden Craig P.
Published: April 2023

Abstract
Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors.

Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1–3 every 14 days; S2, days 1–5 every 14 days; S3, days 1–7 every 14 days]. A fed-fasting expansion cohort was included in the study.

Results: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3–4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1–2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses.

Conclusion: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 693–700. ©2014 AACR.

See related commentary by Yee, p. 667
Data from Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway
Authors: Lou Hong , Villagran Guillermo , Boland Joseph F. , Im Kate M. , Polo Sarita , Zhou Weiyin , Odey Ushie , Juárez-Torres Eligia , Medina-Martínez Ingrid , Roman-Basaure Edgar , Mitchell Jason , Roberson David , Sawitzke Julie , Garland Lisa , Rodríguez-Herrera Maria , Wells David , Troyer Jennifer , Pinto Francisco Castillo , Bass Sara , Zhang Xijun , Castillo Miriam , Gold Bert , Morales Hesler , Yeager Meredith , Berumen Jaime , Alvirez Enrique , Gharzouzi Eduardo , Dean Michael
Published: April 2023

Abstract
Purpose: Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization.

Experimental Design: We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence.

Results: Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression.

Conclusions: PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy. Clin Cancer Res; 21(23); 5360–70. ©2015 AACR.
Data from Loss-of-Function Mutations in Calcitonin Receptor (CALCR) Identify Highly Aggressive Glioblastoma with Poor Outcome
Authors: Pal Jagriti , Patil Vikas , Kumar Anupam , Kaur Kavneet , Sarkar Chitra , Somasundaram Kumaravel
Published: April 2023

Abstract
Purpose: Despite significant advances in the understanding of the biology, the prognosis of glioblastoma (GBM) remains dismal. The objective was to carry out whole-exome sequencing (WES) of Indian glioma and integrate with that of TCGA to find clinically relevant mutated pathways.

Experimental Design: WES of different astrocytoma samples (n = 42; Indian cohort) was carried out and compared with that of TCGA cohort. An integrated analysis of mutated genes from Indian and TCGA cohorts was carried out to identify survival association of pathways with genetic alterations. Patient-derived glioma stem-like cells, glioma cell lines, and mouse xenograft models were used for functional characterization of calcitonin receptor (CALCR) and establish it as a therapeutic target.

Results: A similar mutation spectrum between the Indian cohort and TCGA cohort was demonstrated. An integrated analysis identified GBMs with defective “neuroactive ligand–receptor interaction” pathway (n = 23; 9.54%) that have significantly poor prognosis (P < 0.0001). Furthermore, GBMs with mutated calcitonin receptor (CALCR) or reduced transcript levels predicted poor prognosis. Exogenously added calcitonin (CT) inhibited various properties of glioma cells and pro-oncogenic signaling pathways in a CALCR-dependent manner. Patient-derived mutations in CALCR abolished these functions with the degree of loss of function negatively correlating with patient survival. WT CALCR, but not the mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro. Furthermore, calcitonin inhibited patient-derived neurosphere growth and in vivo glioma tumor growth in a mouse model.

Conclusions: We demonstrate CT–CALCR signaling axis is an important tumor suppressor pathway in glioma and establish CALCR as a novel therapeutic target for GBM. Clin Cancer Res; 24(6); 1448–58. ©2017 AACR.