bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Overcoming Resistance to DNA-Targeted Agents by Epigenetic Activation of Schlafen 11 (SLFN11) Expression with Class I Histone Deacetylase Inhibitors
Authors: Tang Sai-Wen , Thomas Anish , Murai Junko , Trepel Jane B. , Bates Susan E. , Rajapakse Vinodh N. , Pommier Yves
Published: April 2023

Abstract
Purpose: Schlafen 11 (SLFN11), a putative DNA/RNA helicase is a dominant genomic determinant of response to DNA-damaging agents and is frequently not expressed in cancer cells. Whether histone deacetylase (HDAC) inhibitors can be used to release SLFN11 and sensitize SLFN11-inactivated cancers to DNA-targeted agents is tested here.

Experimental Design: SLFN11 expression was examined in The Cancer Genome Atlas (TCGA), in cancer cell line databases and in patients treated with romidepsin. Isogenic cells overexpressing or genetically inactivated for SLFN11 were used to investigate the effect of HDAC inhibitors on SLFN11 expression and sensitivity to DNA-damaging agents.

Results: SLFN11 expression is suppressed in a broad fraction of common cancers and cancer cell lines. In cancer cells not expressing SLFN11, transfection of SLFN11 sensitized the cells to camptothecin, topotecan, hydroxyurea, and cisplatin but not to paclitaxel. SLFN11 mRNA and protein levels were strongly induced by class I (romidepsin, entinostat), but not class II (roclinostat) HDAC inhibitors in a broad panel of cancer cells. SLFN11 expression was also enhanced in peripheral blood mononuclear cells of patients with circulating cutaneous T-cell lymphoma treated with romidepsin. Consistent with the epigenetic regulation of SLFN11, camptothecin and class I HDAC inhibitors were synergistic in many of the cell lines tested.

Conclusions: This study reports the prevalent epigenetic regulation of SLFN11 and the dominant stimulatory effect of HDAC inhibitors on SLFN11 expression. Our results provide a rationale for combining class I HDAC inhibitors and DNA-damaging agents to overcome epigenetic inactivation of SLFN11-mediated resistance to DNA-targeted agents. Clin Cancer Res; 24(8); 1944–53. ©2018 AACR.
Data from T-cell Homing Therapy for Reducing Regulatory T Cells and Preserving Effector T-cell Function in Large Solid Tumors
Authors: Hu Jiemiao , Sun Chuang , Bernatchez Chantale , Xia Xueqing , Hwu Patrick , Dotti Gianpietro , Li Shulin
Published: April 2023

Abstract
Purpose: Infused autologous tumor-infiltrating lymphocytes (TIL) and tumor-targeted chimeric antigen receptor (CAR) T cells typically surround malignant lesions or penetrate small tumor nodules but fail to penetrate large solid tumors, significantly compromising their antitumor impact. Strategies to overcome this primary challenge are largely required.

Experimental Design: We tested the effects of IL12 plus doxorubicin on T-cell penetration and efficacy in solid tumors in a murine lung cancer model, a murine breast carcinoma lung metastasis model, and two human xenograft tumor models bearing large tumors (>10 mm).

Results: Intriguingly, this simple approach increased the numbers, the distribution, and the depth of penetration of infused CD8+ T cells in these tumors, including both TILs and CAR T cells. This combined treatment halted tumor progression and significantly extended survival time. Studies of the underlying mechanism revealed multiple effects. First, the combined treatment maintained the high ratios of immune-stimulatory receptors to immune-inhibitory receptors on infiltrated CD8+ T cells, reduced the accumulation of immunosuppressive regulatory T cells, and enhanced the numbers of T-bet+ effector T cells in the tumors. Second, doxorubicin induced chemokines CXCL9 and CXCL10, which may attract NKG2D+CD8+ T cells to tumors, and this effect was boosted by IL12-induced IFNγ accumulation in tumors, promoting the penetration of NKG2D+CD8+ T cells.

Conclusions: The deep penetration of infused T cells associated with combined IL12 plus doxorubicin yielded striking therapeutic effects in murine and human xenograft solid tumors. This approach might broaden the application of T-cell therapy to a wider range of solid tumors. Clin Cancer Res; 24(12); 2920–34. ©2018 AACR.

See related commentary by Berraondo et al., p. 2716
Data from Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma
Authors: Krumbholz Manuela , Hellberg Julia , Steif Benedikt , Bäuerle Tobias , Gillmann Clarissa , Fritscher Torsten , Agaimy Abbas , Frey Benjamin , Juengert Joerg , Wardelmann Eva , Hartmann Wolfgang , Juergens Heribert , Dirksen Uta , Metzler Markus
Published: April 2023

Abstract
Purpose: The application of the tumor-specific genomic fusion sequence as noninvasive biomarker for therapy monitoring in Ewing sarcoma (EwS) has been evaluated.

Experimental Design: EwS xenograft mouse models were used to explore detectability in small plasma volumes and correlation of genomic EWSR1-FLI1 copy numbers with tumor burden. Furthermore, 234 blood samples from 20 EwS patients were analyzed before and during multimodal treatment. EWSR1 fusion sequence levels in patients' plasma were quantified using droplet digital PCR and compared with tumor volumes calculated from MRI or CT imaging studies.

Results: Kinetics of EWSR1 fusion sequence copy numbers in the plasma are correlated with changes of the tumor volume in patients with localized and metastatic disease. The majority of patients showed a fast reduction of cell-free tumor DNA (ctDNA) during initial chemotherapy. Recurrence of increasing ctDNA levels signalized relapse development.

Conclusions: Genomic fusion sequences represent promising noninvasive biomarkers for improved therapy monitoring in EwS. Until now, response assessment is largely based on MRI and CT imaging, implying restrictions on closely repeated performance and limitations on the differentiation between vital tumor and reactive stromal tissue. Particularly in patients with prognostic unfavorable disseminated disease, ctDNA is a valuable addition for the assessment of therapy response. Clin Cancer Res; 22(17); 4356–65. ©2016 AACR.
Data from HER3 Targeting Sensitizes HNSCC to Cetuximab by Reducing HER3 Activity and HER2/HER3 Dimerization: Evidence from Cell Line and Patient-Derived Xenograft Models
Authors: Wang Dongsheng , Qian Guoqing , Zhang Hongzheng , Magliocca Kelly R. , Nannapaneni Sreenivas , Amin A.R.M. Ruhul , Rossi Michael , Patel Mihir , El-Deiry Mark , Wadsworth J. Trad , Chen Zhengjia , Khuri Fadlo R. , Shin Dong M. , Saba Nabil F. , Chen Zhuo G.
Published: April 2023

Abstract
Purpose: Our previous work suggested that HER3 inhibition sensitizes head and neck squamous cell carcinoma (HNSCC) to EGFR inhibition with cetuximab. This study aimed to define the role of HER3 in cetuximab resistance and the antitumor mechanisms of EGFR/HER3 dual targeting in HNSCC.

Experimental Design: We treated cetuximab-resistant HNSCC UMSCC1-C and parental UMSCC1-P cell lines with anti-EGFR antibody cetuximab, anti-HER3 antibody MM-121, and their combination. We assessed activities of HER2, HER3, and downstream signaling pathways by Western blotting and cell growth by sulforhodamine B (SRB) and colony formation assays. HER3-specific shRNA was used to confirm the role of HER3 in cetuximab response. The combined efficacy and alterations in biomarkers were evaluated in UMSCC1-C xenograft and patient-derived xenograft (PDX) models.

Results: Cetuximab treatment induced HER3 activation and HER2/HER3 dimerization in HNSCC cell lines. Combined treatment with cetuximab and MM-121 blocked EGFR and HER3 activities and inhibited the PI3K/AKT and ERK signaling pathways and HNSCC cell growth more effectively than each antibody alone. HER3 knockdown reduced HER2 activation and resensitized cells to cetuximab. Cetuximab-resistant xenografts and PDX models revealed greater efficacy of dual EGFR and HER3 inhibition compared with single antibodies. In PDX tissue samples, cetuximab induced HER3 expression and MM-121 reduced AKT activity.

Conclusions: Clinically relevant PDX models demonstrate that dual targeting of EGFR and HER3 is superior to EGFR targeting alone in HNSCC. Our study illustrates the upregulation of HER3 by cetuximab as one mechanism underlying resistance to EGFR inhibition in HNSCC, supporting further clinical investigations using multiple targeting strategies in patients who have failed cetuximab-based therapy. Clin Cancer Res; 23(3); 677–86. ©2016 AACR.
Data from Hyperpolarized [1-13C]-Pyruvate Magnetic Resonance Spectroscopic Imaging of Prostate Cancer In Vivo Predicts Efficacy of Targeting the Warburg Effect
Authors: Scroggins Bradley T. , Matsuo Masayuki , White Ayla O. , Saito Keita , Munasinghe Jeeva P. , Sourbier Carole , Yamamoto Kazutoshi , Diaz Vivian , Takakusagi Yoichi , Ichikawa Kazuhiro , Mitchell James B. , Krishna Murali C. , Citrin Deborah E.
Published: April 2023

Abstract
Purpose: To evaluate the potential of hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging (MRSI) of prostate cancer as a predictive biomarker for targeting the Warburg effect.

Experimental Design: Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts. The conversion of pyruvate to lactate in xenografts was measured with hyperpolarized [1-13C]-pyruvate MRSI after systemic delivery of [1-13C] pyruvic acid. Steady-state metabolomic analysis of xenograft tumors was performed with mass spectrometry and steady-state lactate concentrations were measured with proton (1H) MRS. Perfusion and oxygenation of xenografts were measured with electron paramagnetic resonance (EPR) imaging with OX063. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 μg/mouse/day for 5 days × 2 weekly cycles). Lactate production, pyruvate uptake, extracellular acidification rates, and oxygen consumption of the prostate cancer cell lines were analyzed in vitro. LDH activity was assessed in tumor homogenates.

Results: DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with hyperpolarized [1-13C]-pyruvate MRSI compared with PC3 and a corresponding greater sensitivity to LDH inhibition. No difference was observed between PC3 and DU145 xenografts in steady-state measures of pyruvate fermentation, oxygenation, or perfusion. The two cell lines exhibited similar sensitivity to FX-11 in vitro. LDH activity correlated to FX-11 sensitivity.

Conclusions: Hyperpolarized [1-13C]-pyruvate MRSI of prostate cancer predicts efficacy of targeting the Warburg effect. Clin Cancer Res; 24(13); 3137–48. ©2018 AACR.
Data from Small-Cell Carcinomas of the Bladder and Lung Are Characterized by a Convergent but Distinct Pathogenesis
Authors: Chang Matthew T. , Penson Alexander , Desai Neil B. , Socci Nicholas D. , Shen Ronglai , Seshan Venkatraman E. , Kundra Ritika , Abeshouse Adam , Viale Agnes , Cha Eugene K. , Hao Xueli , Reuter Victor E. , Rudin Charles M. , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Schultz Nikolaus , Berger Michael F. , Iyer Gopa , Solit David B. , Al-Ahmadie Hikmat A. , Taylor Barry S.
Published: April 2023

Abstract
Purpose: Small-cell carcinoma of the bladder (SCCB) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCCB is histologically indistinguishable from small-cell lung cancer, a shared pathogenesis and cell of origin has been proposed. The aim of this study is to determine whether SCCBs arise from a preexisting urothelial carcinoma or share a molecular pathogenesis in common with small-cell lung cancer.

Experimental Design: We performed an integrative analysis of 61 SCCB tumors to identify histology- and organ-specific similarities and differences.

Results: SCCB has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. TP53, RB1, and TERT promoter mutations were present in nearly all samples. Although these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small-cell lineage differentiation, they were unlikely the founding transforming event, as they were often preceded by diverse and less common driver mutations, many of which are common in bladder urothelial cancers, but not small-cell lung tumors. Most patient tumors (72%) also underwent genome doubling (GD). Although arising at different chronologic points in the evolution of the disease, GD was often preceded by biallelic mutations in TP53 with retention of two intact copies.

Conclusions: Our findings indicate that small-cell cancers of the bladder and lung have a convergent but distinct pathogenesis, with SCCBs arising from a cell of origin shared with urothelial bladder cancer. Clin Cancer Res; 24(8); 1965–73. ©2017 AACR.

See related commentary by Oser and Jänne, p. 1775
Data from Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers
Authors: Wang Qiong J. , Yu Zhiya , Hanada Ken-ichi , Patel Krishna , Kleiner David , Restifo Nicholas P. , Yang James C.
Published: April 2023

Abstract
Purpose: CD70 expression in normal tissues is restricted to activated lymphoid tissues. Targeting CD70 on CD70-expressing tumors could mediate “on-target, off-tumor” toxicity. This study was to evaluate the feasibility and safety of using anti-human CD70 CARs to treat cancer patients whose tumors express CD70.

Experimental Design: Seven anti-human CD70 CARs with binding moieties from human CD27 combined with CD3-zeta and different costimulatory domains from CD28 and/or 41BB were constructed. In vitro functionality of these receptors was compared and in vivo treatment efficacy was evaluated in a xenograft mouse model. A homologous, all murine anti-CD70 CAR model was also used to assess treatment-related toxicities.

Results: The CAR consisting of the extracellular binding portion of CD27 fused with 41BB and CD3-zeta (trCD27-41BB-zeta) conferred the highest IFNγ production against CD70-expressing tumors in vitro, and NSG mice bearing established CD70-expressing human tumors could be cured by human lymphocytes transduced with this CAR. In the murine CD27-CD3-zeta CAR model, significant reduction of established tumors and prolonged survival were achieved using CAR-transduced splenocytes in a dose-dependent manner. Host preirradiation enhanced treatment efficacy but increased treatment-related toxicities such as transient weight loss and hematopoetic suppression. The treatment did not appear to block adaptive host immune responses.

Conclusions: Preclinical testing supports the safety and efficacy of a CD27-containing CAR targeting CD70-expressing tumors. Clin Cancer Res; 23(9); 2267–76. ©2016 AACR.
Data from T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma
Authors: Woroniecka Karolina , Chongsathidkiet Pakawat , Rhodin Kristen , Kemeny Hanna , Dechant Cosette , Farber S. Harrison , Elsamadicy Aladine A. , Cui Xiuyu , Koyama Shohei , Jackson Christina , Hansen Landon J. , Johanns Tanner M. , Sanchez-Perez Luis , Chandramohan Vidyalakshmi , Yu Yen-Rei Andrea , Bigner Darell D. , Giles Amber , Healy Patrick , Dranoff Glenn , Weinhold Kent J. , Dunn Gavin P. , Fecci Peter E.
Published: April 2023

Abstract
Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM.

Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. T-cell receptor Vβ chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers.

Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations.

Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. Clin Cancer Res; 24(17); 4175–86. ©2018 AACR.

See related commentary by Jackson and Lim, p. 4059
Data from Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients
Authors: Greif Philipp A. , Hartmann Luise , Vosberg Sebastian , Stief Sophie M. , Mattes Raphael , Hellmann Ines , Metzeler Klaus H. , Herold Tobias , Bamopoulos Stefanos A. , Kerbs Paul , Jurinovic Vindi , Schumacher Daniela , Pastore Friederike , Bräundl Kathrin , Zellmeier Evelyn , Ksienzyk Bianka , Konstandin Nikola P. , Schneider Stephanie , Graf Alexander , Krebs Stefan , Blum Helmut , Neumann Martin , Baldus Claudia D. , Bohlander Stefan K. , Wolf Stephan , Görlich Dennis , Berdel Wolfgang E. , Wörmann Bernhard J. , Hiddemann Wolfgang , Spiekermann Karsten
Published: April 2023

Abstract
Purpose: To study mechanisms of therapy resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations.

Experimental Design: We performed exome sequencing of matched diagnosis, remission, and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters.

Results: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing preleukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse.

Conclusions: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML. Clin Cancer Res; 24(7); 1716–26. ©2018 AACR.
Data from Cell-Free DNA and Circulating Tumor Cells: Comprehensive Liquid Biopsy Analysis in Advanced Breast Cancer
Authors: Rossi Giovanna , Mu Zhaomei , Rademaker Alfred W. , Austin Laura K. , Strickland Kimberly S. , Costa Ricardo Lima Barros , Nagy Rebecca J. , Zagonel Vittorina , Taxter Timothy J. , Behdad Amir , Wehbe Firas H. , Platanias Leonidas C. , Gradishar William J. , Cristofanilli Massimo
Published: April 2023

Abstract
Purpose: Liquid biopsy provides a real-time assessment of metastatic breast cancer (MBC). We evaluated the utility of combining circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) to predict prognosis in MBC.

Experimental Design: We conducted a retrospective study of 91 patients with locally advanced breast cancer and MBC. CTCs were enumerated by CellSearch; the plasma-based assay was performed utilizing Guardant360 and the survival analysis using Kaplan–Meier curves.

Results: Eighty-four patients had stage IV cancer, and 7 patients had no metastases. Eighty patients had CTC analysis: median number 2 (0–5,612). Blood samples [232 of 277 (84%)] had mutations. The average ctDNA fraction was 4.5% (0–88.2%) and number of alterations 3 (0–27); the most commonly mutated genes were TP53 (52%), PIK3CA (40%), and ERBB2 (20%). At the time of analysis, 36 patients (39.6%) were dead. The median follow-up for CTCs was 9 months; for ctDNA, it was 9.9 months. For CTCs and ctDNA, respectively, progression-free survival (PFS) was 4.2 and 5.2 months and overall survival (OS) was 18.7 and 21.5 months. There was a statistically significant difference in PFS and OS for baseline CTCs < 5 versus CTCs ≥ 5 (P = 0.021 and P = 0.0004, respectively); %ctDNA < 0.5 versus ≥ 0.5 (P = 0.003 and P = 0.012); number of alterations < 2 versus ≥ 2 (P = 0.059 borderline and P = 0.0015). A significant association by Fisher exact test was found between the number of alterations and the %ctDNA in the baseline sample (P < 0.0001).

Conclusions: The study demonstrated that liquid biopsy is an effective prognostic tool. Clin Cancer Res; 24(3); 560–8. ©2017 AACR.
Data from Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP
Authors: Piggott Luke , Silva Andreia , Robinson Timothy , Santiago-Gómez Angelica , Simões Bruno M. , Becker Michael , Fichtner Iduna , Andera Ladislav , Young Philippa , Morris Christine , Barrett-Lee Peter , Alchami Fouad , Piva Marco , Vivanco Maria dM. , Clarke Robert B. , Gee Julia , Clarkson Richard
Published: April 2023

Abstract
Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.

Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors.

Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.

Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452–63. ©2018 AACR.
Data from STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair
Authors: Maranto Cristina , Udhane Vindhya , Hoang David T. , Gu Lei , Alexeev Vitali , Malas Kareem , Cardenas Karmel , Brody Jonathan R. , Rodeck Ulrich , Bergom Carmen , Iczkowski Ken A. , Jacobsohn Ken , See William , Schmitt Sara M. , Nevalainen Marja T.
Published: April 2023

Abstract
Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.

Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.

Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.

Conclusions: This work introduces a novel concept of a pivotal role of Jak2–Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2–Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917–31. ©2018 AACR.
Data from Serum Metabolomic Profiles Identify ER-Positive Early Breast Cancer Patients at Increased Risk of Disease Recurrence in a Multicenter Population
Authors: Hart Christopher D. , Vignoli Alessia , Tenori Leonardo , Uy Gemma Leonora , Van To Ta , Adebamowo Clement , Hossain Syed Mozammel , Biganzoli Laura , Risi Emanuela , Love Richard R. , Luchinat Claudio , Di Leo Angelo
Published: April 2023

Abstract
Purpose: Detecting signals of micrometastatic disease in patients with early breast cancer (EBC) could improve risk stratification and allow better tailoring of adjuvant therapies. We previously showed that postoperative serum metabolomic profiles were predictive of relapse in a single-center cohort of estrogen receptor (ER)–negative EBC patients. Here, we investigated this further using preoperative serum samples from ER-positive, premenopausal women with EBC who were enrolled in an international phase III trial.

Experimental Design: Proton nuclear magnetic resonance (NMR) spectroscopy of 590 EBC samples (319 with relapse or ≥6 years clinical follow-up) and 109 metastatic breast cancer (MBC) samples was performed. A Random Forest (RF) classification model was built using a training set of 85 EBC and all MBC samples. The model was then applied to a test set of 234 EBC samples, and a risk of recurrence score was generated on the basis of the likelihood of the sample being misclassified as metastatic.

Results: In the training set, the RF model separated EBC from MBC with a discrimination accuracy of 84.9%. In the test set, the RF recurrence risk score correlated with relapse, with an AUC of 0.747 in ROC analysis. Accuracy was maximized at 71.3% (sensitivity, 70.8%; specificity, 71.4%). The model performed independently of age, tumor size, grade, HER2 status and nodal status, and also of Adjuvant! Online risk of relapse score.

Conclusions: In a multicenter group of EBC patients, we developed a model based on preoperative serum metabolomic profiles that was prognostic for disease recurrence, independent of traditional clinicopathologic risk factors. Clin Cancer Res; 23(6); 1422–31. ©2017 AACR.
Data from Lifetime Genistein Intake Increases the Response of Mammary Tumors to Tamoxifen in Rats
Authors: Zhang Xiyuan , Cook Katherine L. , Warri Anni , Cruz Idalia M. , Rosim Mariana , Riskin Jeffrey , Helferich William , Doerge Daniel , Clarke Robert , Hilakivi-Clarke Leena
Published: April 2023

Abstract
Purpose: Whether it is safe for estrogen receptor–positive (ER+) patients with breast cancer to consume soy isoflavone genistein remains controversial. We compared the effects of genistein intake mimicking either Asian (lifetime) or Caucasian (adulthood) intake patterns to that of starting its intake during tamoxifen therapy using a preclinical model.

Experimental Design: Female Sprague-Dawley rats were fed an AIN93G diet supplemented with 0 (control diet) or 500 ppm genistein from postnatal day 15 onward (lifetime genistein). Mammary tumors were induced with 7,12-dimethylbenz(a)anthracene (DMBA), after which a group of control diet–fed rats were switched to genistein diet (adult genistein). When the first tumor in a rat reached 1.4 cm in diameter, tamoxifen was added to the diet and a subset of previously only control diet–fed rats also started genistein intake (post-diagnosis genistein).

Results: Lifetime genistein intake reduced de novo resistance to tamoxifen, compared with post-diagnosis genistein groups. Risk of recurrence was lower both in the lifetime and in the adult genistein groups than in the post-diagnosis genistein group. We observed downregulation of unfolded protein response (UPR) and autophagy-related genes (GRP78, IRE1α, ATF4, and Beclin-1) and genes linked to immunosuppression (TGFβ and Foxp3) and upregulation of cytotoxic T-cell marker CD8a in the tumors of the lifetime genistein group, compared with controls, post-diagnosis, and/or adult genistein groups.

Conclusions: Genistein intake mimicking Asian consumption patterns improved response of mammary tumors to tamoxifen therapy, and this effect was linked to reduced activity of UPR and prosurvival autophagy signaling and increased antitumor immunity. Clin Cancer Res; 23(3); 814–24. ©2017 AACR.
Data from Genomic Correlates of Response to Everolimus in Aggressive Radioiodine-refractory Thyroid Cancer: A Phase II Study
Authors: Hanna Glenn J. , Busaidy Naifa L. , Chau Nicole G. , Wirth Lori J. , Barletta Justine A. , Calles Antonio , Haddad Robert I. , Kraft Stefan , Cabanillas Maria E. , Rabinowits Guilherme , O'Neill Anne , Limaye Sewanti A. , Alexander Erik K. , Moore Francis D. , Misiwkeiwicz Krystof , Thomas Tom , Nehs Matthew , Marqusee Ellen , Lee Stephanie L. , Jänne Pasi A. , Lorch Jochen H.
Published: April 2023

Abstract
Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.

Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.

Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.

Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546–53. ©2018 AACR.
Data from The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome
Authors: Ricciardelli Carmela , Bianco-Miotto Tina , Jindal Shalini , Butler Lisa M. , Leung Samuel , McNeil Catriona M. , O'Toole Sandra A. , Ebrahimie Esmaeil , Millar Ewan K.A. , Sakko Andrew J. , Ruiz Alexandra I. , Vowler Sarah L. , Huntsman David G. , Birrell Stephen N. , Sutherland Robert L. , Palmieri Carlo , Hickey Theresa E. , Tilley Wayne D.
Published: April 2023

Abstract
Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival.

Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n = 219; validation cohort, n = 418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts.

Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P = 0.015) and validation (HR, 0.50; P = 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERα-positive tumors and AR positivity ≥78% had the best survival in both cohorts (P < 0.0001). Among the combined ERα-positive cases, those with comparable or higher levels of AR (AR:ERα-positivity ratio >0.87) had the best outcomes (P < 0.0001).

Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer. Clin Cancer Res; 24(10); 2328–41. ©2018 AACR.
Data from Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study
Authors: Norquist Barbara M. , Brady Mark F. , Harrell Maria I. , Walsh Tom , Lee Ming K. , Gulsuner Suleyman , Bernards Sarah S. , Casadei Silvia , Burger Robert A. , Tewari Krishnansu S. , Backes Floor , Mannel Robert S. , Glaser Gretchen , Bailey Cheryl , Rubin Stephen , Soper John , Lankes Heather A. , Ramirez Nilsa C. , King Mary Claire , Birrer Michael J. , Swisher Elizabeth M.
Published: April 2023

Abstract
Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.

Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).

Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57–0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50–0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66–0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59–0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40–0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25–0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.

Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777–83. ©2017 AACR.
Data from Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer
Authors: Camblin Adam J. , Pace Emily A. , Adams Sharlene , Curley Michael D. , Rimkunas Victoria , Nie Lin , Tan Gege , Bloom Troy , Iadevaia Sergio , Baum Jason , Minx Charlene , Czibere Akos , Louis Chrystal U. , Drummond Daryl C. , Nielsen Ulrik B. , Schoeberl Birgit , Pipas J. Marc , Straubinger Robert M. , Askoxylakis Vasileios , Lugovskoy Alexey A.
Published: April 2023

Abstract
Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies.

Experimental Design: Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic cancer xenograft models were determined.

Results: Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro. Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivo.

Conclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. Clin Cancer Res; 24(12); 2873–85. ©2018 AACR.
Data from Phase I Study of MEDI3617, a Selective Angiopoietin-2 Inhibitor Alone and Combined with Carboplatin/Paclitaxel, Paclitaxel, or Bevacizumab for Advanced Solid Tumors
Authors: Hyman David M. , Rizvi Naiyer , Natale Ronald , Armstrong Deborah K. , Birrer Michael , Recht Lawrence , Dotan Efrat , Makker Vicky , Kaley Thomas , Kuruvilla Denison , Gribbin Matthew , McDevitt Jennifer , Lai Dominic W. , Dar Mohammed
Published: April 2023

Abstract
Purpose: This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti–angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy.

Patients and Methods: This phase I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy [5–1,500 mg every 3 weeks (Q3W)] or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed.

Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer [prolonged grade 3 edema-associated adverse events (AE) occurred]. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively.

Conclusions: Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued. Clin Cancer Res; 24(12); 2749–57. ©2018 AACR.
Data from Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study
Authors: Moeung Sotheara , Chevreau Christine , Broutin Sophie , Guitton Jérôme , Lelièvre Bénédicte , Ciccolini Joseph , Massart Christophe , Fléchon Aude , Delva Rémy , Gravis Gwenaëlle , Lotz Jean-Pierre , Bay Jacques-Olivier , Gross-Goupil Marine , Paci Angelo , Marsili Sabrina , Malard Laurence , Chatelut Etienne , Thomas Fabienne
Published: April 2023

Abstract
Purpose: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling interpatient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative.

Experimental Design: Eighty-nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/mL over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients, and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction.

Results: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentiles, respectively). The new covariate equation [CL (mL/min) = 130.7 × (Scr/83)−0.826 × (BW/76)+0.907 × (Age/36)−0.223 with Scr in μmol/L, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared with other equations.

Conclusions: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young male patients, could be used if TDM cannot be implemented. Clin Cancer Res; 23(23); 7171–9. ©2017 AACR.
Data from Idelalisib Impacts Cell Growth through Inhibiting Translation-Regulatory Mechanisms in Mantle Cell Lymphoma
Authors: Yang Qingshan , Chen Lisa S. , Ha Min Jin , Do Kim-Anh , Neelapu Sattva S. , Gandhi Varsha
Published: April 2023

Abstract
Purpose: PI3K is a critical node in the B-cell receptor pathway, which is responsible for survival and proliferation of B-cell malignancies. Idelalisib, a PI3Kδ-isoform–specific inhibitor, has been approved to treat B-cell malignancies. Although biological activity of the drug has been evaluated, molecular mechanisms and signaling pathway disruption leading to the biological effects of idelalisib are not yet well defined. Prior laboratory reports have identified transcription and translation as the primary events for attenuation of PI3Kα isoform. We hypothesized that PI3Kδ-isoform inhibition by idelalisib should also affect gene transcription and protein translation.

Experimental Design: Using three mantle cell lymphoma cell lines and primary cells from patients, biological consequences such as apoptosis/cell-cycle analysis, as well as RNA/protein synthesis were evaluated. Proteomics analyses (RPPA and immunoblot assays) defined molecular events downstream of PI3K/AKT cassette.

Results: Idelalisib treatment resulted in inhibition of protein synthesis, which correlated with reduction in cell size and cell growth. A moderate loss of viability without any change in cell-cycle profile was observed. Idelalisib treatment inhibited AKT activation, an immediate downstream PI3K effector, and also reduced phosphorylation levels of downstream AKT/mTOR pathway proteins such as PRAS40. In addition, idelalisib treatment impeded activation of the MAPK pathway, and MEK, ERK and p90RSK phosphorylation levels were reduced. Reduction in AKT, PDK1, and MEK phosphorylation correlated with protein synthesis inhibition.

Conclusions: Collectively, these results clarify the molecular mechanisms of actions and may provide biomarkers and targets for combination with idelalisib in B-cell malignancies. Clin Cancer Res; 23(1); 181–92. ©2016 AACR.
Data from Emerging Role of MicroRNAs as Liquid Biopsy Biomarkers in Gastrointestinal Cancers
Authors: Shigeyasu Kunitoshi , Toden Shusuke , Zumwalt Timothy J. , Okugawa Yoshinaga , Goel Ajay
Published: April 2023

Abstract
Cancer has emerged as a leading cause of mortality worldwide, claiming more than 8 million lives annually. Gastrointestinal cancers account for about 35% of these mortalities. Recent advances in diagnostic and treatment strategies have reduced mortality among patients with gastrointestinal cancer, yet a significant number of patients still develop late-stage cancer, where treatment options are inadequate. Emerging interests in “liquid biopsies” have encouraged investigators to identify and develop clinically relevant noninvasive genomic and epigenomic signatures that can be exploited as biomarkers capable of detecting premalignant and early-stage cancers. In this context, microRNAs (miRNA), which are small, noncoding RNAs that are frequently dysregulated in cancers, have emerged as promising entities for such diagnostic purposes. Even though the future looks promising, current approaches for detecting miRNAs in blood and other biofluids remain inadequate. This review summarizes existing efforts to exploit circulating miRNAs as cancer biomarkers and evaluates their potential and challenges as liquid biopsy–based biomarkers for gastrointestinal cancers. Clin Cancer Res; 23(10); 2391–9. ©2017 AACR.