bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer
Authors: Tsuji Junko , Li Tianyu , Grinshpun Albert , Coorens Tim , Russo Douglas , Anderson Leilani , Rees Rebecca , Nardone Agostina , Patterson Candace , Lennon Niall J. , Cibulskis Carrie , Leshchiner Ignaty , Tayob Nabihah , Tolaney Sara M. , Tung Nadine , McDonnell Donald P. , Krop Ian E. , Winer Eric P. , Stewart Chip , Getz Gad , Jeselsohn Rinath
Published: April 2023

AbstractPurpose:
Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated.
Patients and Methods:
We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2− advanced breast cancer who progressed on prior ET (N = 36; NCT02448771).
Results:
The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0–7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5–13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment.
Conclusions:
The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2− breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.
Data from Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance
Authors: Serra Violeta , Wang Anderson T. , Castroviejo-Bermejo Marta , Polanska Urszula M. , Palafox Marta , Herencia-Ropero Andrea , Jones Gemma N. , Lai Zhongwu , Armenia Joshua , Michopoulos Filippos , Llop-Guevara Alba , Brough Rachel , Gulati Aditi , Pettitt Stephen J. , Bulusu Krishna C. , Nikkilä Jenni , Wilson Zena , Hughes Adina , Wijnhoven Paul W.G. , Ahmed Ambar , Bruna Alejandra , Gris-Oliver Albert , Guzman Marta , Rodríguez Olga , Grueso Judit , Arribas Joaquin , Cortés Javier , Saura Cristina , Lau Alan , Critchlow Susan , Dougherty Brian , Caldas Carlos , Mills Gordon B. , Barrett J. Carl , Forment Josep V. , Cadogan Elaine , Lord Christopher J. , Cruz Cristina , Balmaña Judith , O'Connor Mark J.
Published: April 2023

AbstractPurpose:
PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance.
Experimental Design:
We analyzed breast and ovarian patient-derived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Biomarker analysis was conducted at the genetic and protein level. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models.
Results:
Although WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress.
Conclusions:
Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance including tumors without an underlying HRR deficiency. These preclinical insights are now being tested in several clinical trials where the PARPi is administered with either the WEE1i or the ATRi.
Data from Radiotherapy Induces Innate Immune Responses in Patients Treated for Prostate Cancers
Authors: Cheema Amrita K. , Li Yaoxiang , Ventimiglia Mary , Kowalczyk Keith , Hankins Ryan , Bandi Gaurav , Janowski Einsley-Marie , Grindrod Scott , Villagra Alejandro , Dritschilo Anatoly
Published: April 2023

AbstractPurpose:
Radiotherapy is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced radiotherapy technologies enable treatment with large fractions and highly conformal radiation doses to effect free-radical damage to cellular DNA leading to cell-cycle arrest, cell death, and innate immune response (IIR) stimulation.
Experimental Design:
To understand systemic clinical responses after radiation exposure, proteomic and metabolomic analyses were performed on plasma obtained from patients with cancer at intervals after prostate stereotactic body radiotherapy. Pathway and multivariate analyses were used to delineate molecular alterations following radiotherapy and its correlation with clinical outcomes.
Results:
DNA damage response increased within the first hour after treatment and returned to baseline by 1 month. IIR signaling also increased within 1 hour of treatment but persisted for up to 3 months thereafter. Furthermore, robust IIR and metabolite elevations, consistent with an early proinflammatory M1-mediated innate immune activation, were observed in patients in remission, whereas patients experiencing prostate serum antigen–determined disease progression demonstrated less robust immune responses and M2-mediated metabolite elevations.
Conclusions:
To our knowledge, these data are the first report of longitudinal proteomic and metabolomic molecular responses in patients after radiotherapy for cancers. The data supports innate immune activation as a critical clinical response of patients receiving radiotherapy for prostate cancer. Furthermore, we propose that the observed IIR may be generalized to the treatment of other cancer types, potentially informing multidisciplinary therapeutic strategies for cancer treatment.
Data from ENPP1 Immunobiology as a Therapeutic Target
Authors: Ruiz-Fernández de Córdoba Borja , Martínez-Monge Rafael , Lecanda Fernando
Published: April 2023

Abstract
ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiologic processes. However, ENPP1 is frequently overexpressed in local relapses and tumor metastases, which are associated with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor microenvironment (TME) by tilting the balance of ATP/adenosine (Ado) in conjunction with other components (CD38, CD39/ENTPD1, and CD73/NT5E). Moreover, ENPP1 intersects with the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2´,3´-cyclic GMP–AMP. Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimulatory effect, and their combination with other therapeutic modalities, such as immune-checkpoint blockade, STING activation, DNA damage response (DDR) inhibitors, and radiotherapy (RT), represents a promising avenue to boost antitumor–immune responses and to improve current clinical outcomes in several tumors. This comprehensive review summarizes the current state of the art and opens new perspectives for novel treatment strategies.
Data from Tumor Dynamic Model-Based Decision Support for Phase Ib/II Combination Studies: A Retrospective Assessment Based on Resampling of the Phase III Study IMpower150
Authors: Bruno René , Marchand Mathilde , Yoshida Kenta , Chan Phyllis , Li Haocheng , Zou Wei , Mercier Francois , Chanu Pascal , Wu Benjamin , Lee Anthony , Li Chunze , Jin Jin Y. , Maitland Michael L. , Reck Martin , Socinski Mark A.
Published: April 2023

Purpose:
Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into go/no-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy.
Patients and Methods:
Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1,202 patients with non–small cell lung cancer. We resampled baseline characteristics and longitudinal sum of longest diameters of tumor lesions of patients from both arms, atezolizumab+ bevacizumab+chemotherapy (ABCP) versus BCP, to mimic Phase Ib/II studies of 15 to 40 patients/arm with 6 to 24 weeks follow-up. TGI metrics were estimated using a bi-exponential TGI model. Effect sizes were calculated as TGI metrics ratio of medians (MedR), objective response rate (ORR) difference (d), and progression-free survival (PFS), hazard ratio (HR) between arms. Correct and incorrect go decisions were evaluated as the probability to achieve desired effect sizes in ABCP versus BCP and BCP versus BCP, respectively, across 500 replicated subsamples for each design.
Results:
For 40 patients/24 weeks follow-up, correct go decisions based on probability tumor growth rate (KG) MedR <0.90, dORR >0.10, and PFS HR <0.70 were 83%, 69%, and 58% with incorrect go decision rates of 4%, 12%, and 11%, respectively. For other designs, the ranking did not change with TGI metrics consistently overperforming RECIST endpoints. The predicted overall survival (OS) HR was around 0.80 in most of the scenarios investigated.
Conclusions:
Model-based estimate of KG MedR is an exploratory endpoint that informs early clinical decisions for combination studies.
Data from Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL
Authors: Aldoss Ibrahim , Khaled Samer K. , Wang Xiuli , Palmer Joycelynne , Wang Yan , Wagner Jamie R. , Clark Mary C. , Simpson Jennifer , Paul Jinny , Vyas Vibhuti , Chien Sheng-Hsuan , Stein Anthony , Pullarkat Vinod , Salhotra Amandeep , Al Malki Monzr M. , Aribi Ahmed , Sandhu Karamjeet , Thomas Sandra H. , Budde Lihua E. , Marcucci Guido , Brown Christine E. , Forman Stephen J.
Published: April 2023

AbstractPurpose:
A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).
Patients and Methods:
In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II.
Results:
The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22–72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05–0.48; P = 0.001).
Conclusions:
Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD.

See related commentary by El Marabti and Abdel-Wahab, p. 694
Data from Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR− Trial
Authors: Graeser Monika , Gluz Oleg , Biehl Claudia , Ulbrich-Gebauer Daniel , Christgen Matthias , Palatty Jenci , Kuemmel Sherko , Grischke Eva-Maria , Augustin Doris , Braun Michael , Potenberg Jochem , Wuerstlein Rachel , Krauss Katja , Schumacher Claudia , Forstbauer Helmut , Reimer Toralf , Stefek Andrea , Fischer Hans Holger , Pelz Enrico , zu Eulenburg Christine , Kates Ronald , Ni Hua , Kolberg-Liedtke Cornelia , Feuerhake Friedrich , Kreipe Hans Heinrich , Nitz Ulrike , Harbeck Nadia
Published: April 2023

AbstractPurpose:
To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR− trial (NCT01817452).
Experimental Design:
Patients with cT1-cT4c, cN0–3 HER2+/HR− early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression.
Results:
In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08–2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13–2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38–0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43–0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04–3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures.
Conclusions:
Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR− EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.
Supplementary Fig. S2 from Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth of liver metastases of lung cancer
Authors: Kawata Eri , Ashihara Eishi , Kimura Shinya , Takenaka Kazumasa , Sato Kiyoshi , Tanaka Ruriko , Yokota Asumi , Kamitsuji Yuri , Takeuchi Miki , Kuroda Junya , Tanaka Fumihiro , Yoshikawa Toshikazu , Maekawa Taira
Published: April 2023

Supplementary Fig. S2 from Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth of liver metastases of lung cancer
Supplementary Table S1 from Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors
Authors: Baird Richard D. , Kitzen Jos , Clarke Paul A. , Planting Andre , Reade Sarah , Reid Alison , Welsh Lyndsey , López Lázaro Luis , de las Heras Begona , Judson Ian R. , Kaye Stan B. , Eskens Ferry , Workman Paul , deBono Johann S. , Verweij Jaap
Published: April 2023

Supplementary Table S1 from Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors
Supplementary Figure 1 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer
Authors: Ohori Hisatsugu , Yamakoshi Hiroyuki , Tomizawa Masaki , Shibuya Masatoshi , Kakudo Yuichi , Takahashi Atsuko , Takahashi Shin , Kato Satoshi , Suzuki Takao , Ishioka Chikashi , Iwabuchi Yoshiharu , Shibata Hiroyuki
Published: April 2023

Supplementary Figure 1 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer
Supplementary Fig. S1 from Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides
Authors: de Wolf Cornelia , Jansen Robert , Yamaguchi Hiroaki , de Haas Marcel , van de Wetering Koen , Wijnholds Jan , Beijnen Jos , Borst Piet
Published: April 2023

Supplementary Fig. S1 from Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides
Supplementary Data from 2-Methoxyestradiol Inhibits Barrett's Esophageal Adenocarcinoma Growth and Differentiation through Differential Regulation of the β-Catenin–E-Cadherin Axis
Authors: Kambhampati Suman , Banerjee Snigdha , Dhar Kakali , Mehta Smita , Haque Inamul , Dhar Gopal , Majumder Monami , Ray Gibanananda , Vanveldhuizen Peter J. , Banerjee Sushanta K.
Published: April 2023

Supplementary Data from 2-Methoxyestradiol Inhibits Barrett's Esophageal Adenocarcinoma Growth and Differentiation through Differential Regulation of the β-Catenin–E-Cadherin Axis
Supplementary Fig. S2 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake
Authors: Shang Yonglei , Mao Yifan , Batson Jennifer , Scales Suzie J. , Phillips Gail , Lackner Mark R. , Totpal Klara , Williams Simon , Yang Jihong , Tang Zhijun , Modrusan Zora , Tan Christine , Liang Wei-Ching , Tsai Siao Ping , Vanderbilt Alexander , Kozuka Kenji , Hoeflich Klaus , Tien Janet , Ross Sarajane , Li Congfen , Lee Sang Hoon , Song An , Wu Yan , Stephan Jean-Philippe , Ashkenazi Avi , Zha Jiping
Published: April 2023

Supplementary Fig. S2 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake
Supplementary Figure 1 from MK-5108, a Highly Selective Aurora-A Kinase Inhibitor, Shows Antitumor Activity Alone and in Combination with Docetaxel
Authors: Shimomura Toshiyasu , Hasako Shinichi , Nakatsuru Yoko , Mita Takashi , Ichikawa Koji , Kodera Tsutomu , Sakai Takumi , Nambu Tadahiro , Miyamoto Mayu , Takahashi Ikuko , Miki Satomi , Kawanishi Nobuhiko , Ohkubo Mitsuru , Kotani Hidehito , Iwasawa Yoshikazu
Published: April 2023

Supplementary Figure 1 from MK-5108, a Highly Selective Aurora-A Kinase Inhibitor, Shows Antitumor Activity Alone and in Combination with Docetaxel
Supplementary Figure 4 from Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response
Authors: Dong Jianying , Demarest Stephen J. , Sereno Arlene , Tamraz Susan , Langley Emma , Doern Adam , Snipas Tracey , Perron Keli , Joseph Ingrid , Glaser Scott M. , Ho Steffan N. , Reff Mitchell E. , Hariharan Kandasamy
Published: April 2023

Supplementary Figure 4 from Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response
Supplementary Fig. S5 from Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1
Authors: Sullivan Richard , Graham Charles H.
Published: April 2023

Supplementary Fig. S5 from Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1
Supplementary Fig. S1 from Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1
Authors: Sullivan Richard , Graham Charles H.
Published: April 2023

Supplementary Fig. S1 from Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1
Supplementary Figure 1 from Cannabidiol Enhances the Inhibitory Effects of Δ9-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival
Authors: Marcu Jahan P. , Christian Rigel T. , Lau Darryl , Zielinski Anne J. , Horowitz Maxx P. , Lee Jasmine , Pakdel Arash , Allison Juanita , Limbad Chandani , Moore Dan H. , Yount Garret L. , Desprez Pierre-Yves , McAllister Sean D.
Published: April 2023

Supplementary Figure 1 from Cannabidiol Enhances the Inhibitory Effects of Δ9-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival
Supplementary Figure S3 from Identification of genes and molecular pathways involved in the progression of premalignant oral epithelia
Authors: Banerjee Abhijit G. , Bhattacharyya Indraneel , Vishwanatha Jamboor K.
Published: April 2023

Supplementary Figure S3 from Identification of genes and molecular pathways involved in the progression of premalignant oral epithelia
Supplementary Figure 4 from Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands
Authors: Wood Tabitha E. , Dalili Shadi , Simpson Craig D. , Sukhai Mahadeo A. , Hurren Rose , Anyiwe Kika , Mao Xinliang , Suarez Saiz Fernando , Gronda Marcela , Eberhard Yanina , MacLean Neil , Ketela Troy , Reed John C. , Moffat Jason , Minden Mark D. , Batey Robert A. , Schimmer Aaron D.
Published: April 2023

Supplementary Figure 4 from Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands
Supplementary Data from ErbB-Inhibitory Protein: A Modified Ectodomain of Epidermal Growth Factor Receptor Synergizes with Dasatinib to Inhibit Growth of Breast Cancer Cells
Authors: Nautiyal Jyoti , Yu Yingjie , Aboukameel Amro , Kanwar Shailender S. , Das Jayanta K. , Du Jianhua , Patel Bhaumik B. , Sarkar Fazlul H. , Rishi Arun K. , Mohammad Ramzi M. , Majumdar Adhip P.N.
Published: April 2023

Supplementary Data from ErbB-Inhibitory Protein: A Modified Ectodomain of Epidermal Growth Factor Receptor Synergizes with Dasatinib to Inhibit Growth of Breast Cancer Cells
Supplementary Table from MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance
Authors: Moriyama Taiki , Ohuchida Kenoki , Mizumoto Kazuhiro , Yu Jun , Sato Norihiro , Nabae Toshinaga , Takahata Shunichi , Toma Hiroki , Nagai Eishi , Tanaka Masao
Published: April 2023

Supplementary Table from MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance
Supplementary Table S4 from Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index
Authors: McDonagh Charlotte F. , Kim Kristine M. , Turcott Eileen , Brown Lindsay L. , Westendorf Lori , Feist Tiffany , Sussman Django , Stone Ivan , Anderson Martha , Miyamoto Jamie , Lyon Robert , Alley Stephen C. , Gerber Hans-Peter , Carter Paul J.
Published: April 2023

Supplementary Table S4 from Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index
Supplementary Data from Celecoxib antagonizes perifosine's anticancer activity involving a cyclooxygenase-2-dependent mechanism
Authors: Elrod Heath A. , Yue Ping , Khuri Fadlo R. , Sun Shi-Yong
Published: April 2023

Supplementary Data from Celecoxib antagonizes perifosine's anticancer activity involving a cyclooxygenase-2-dependent mechanism
Supplementary Figure 3 from Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer
Authors: Sakai Ryo , Kagawa Shunsuke , Yamasaki Yasumoto , Kojima Toru , Uno Futoshi , Hashimoto Yuuri , Watanabe Yuichi , Urata Yasuo , Tanaka Noriaki , Fujiwara Toshiyoshi
Published: April 2023

Supplementary Figure 3 from Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer
Supplementary Figure 2 from Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer
Authors: Sakai Ryo , Kagawa Shunsuke , Yamasaki Yasumoto , Kojima Toru , Uno Futoshi , Hashimoto Yuuri , Watanabe Yuichi , Urata Yasuo , Tanaka Noriaki , Fujiwara Toshiyoshi
Published: April 2023

Supplementary Figure 2 from Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer
Supplementary Data from AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer
Authors: Yang Shu , Ngo Van Chanh , Lew Guo Bin , Chong Lih Wen Valerie , Lee Swee Shean , Ong Wei Jie Richard , Lam Wei Ling Irene , Thng Choon Hua , Koong Heng Nung , Ong Hock Soo , Chung Alexander , Chow Pierce , Lee Jonathan , Soo Khee Chee , Huynh Hung
Published: April 2023

Supplementary Data from AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer
Supplementary Fig. from Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib
Authors: Padera Timothy P. , Kuo Angera H. , Hoshida Tohru , Liao Shan , Lobo Jennifer , Kozak Kevin R. , Fukumura Dai , Jain Rakesh K.
Published: April 2023

Supplementary Fig. from Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib
Supplementary Fig. S1 from Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors
Authors: Johansson Gunnar , Mahller Yonatan Y. , Collins Margaret H. , Kim Mi-Ok , Nobukuni Takahiro , Perentesis John , Cripe Timothy P. , Lane Heidi A. , Kozma Sara C. , Thomas George , Ratner Nancy
Published: April 2023

Supplementary Fig. S1 from Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors
Supplementary Figure 2 from Multigene Expression–Based Predictors for Sensitivity to Vorinostat and Velcade in Non–Small Cell Lung Cancer
Authors: Nagji Alykhan S. , Cho Sang-Hoon , Liu Yuan , Lee Jae K. , Jones David R.
Published: April 2023

Supplementary Figure 2 from Multigene Expression–Based Predictors for Sensitivity to Vorinostat and Velcade in Non–Small Cell Lung Cancer
Supplementary Data from Inhibition of Mer and Axl Receptor Tyrosine Kinases in Astrocytoma Cells Leads to Increased Apoptosis and Improved Chemosensitivity
Authors: Keating Amy K. , Kim Grace K. , Jones Ashley E. , Donson Andrew M. , Ware Kathryn , Mulcahy Jean M. , Salzberg Dana B. , Foreman Nicholas K. , Liang Xiayuan , Thorburn Andrew , Graham Douglas K.
Published: April 2023

Supplementary Data from Inhibition of Mer and Axl Receptor Tyrosine Kinases in Astrocytoma Cells Leads to Increased Apoptosis and Improved Chemosensitivity
Supplementary Figure 2 from Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells
Authors: Moiseeva Elena P. , Almeida Gabriela M. , Jones George D.D. , Manson Margaret M.
Published: April 2023

PDF file, 93KB, MDA-MB-231 cells were grown in the presence of curcumin, DIM or DMSO.
Supplementary Table S1 from Identification of biomarkers for tumor endothelial cell proliferation through gene expression profiling
Authors: Hardwick James S. , Yang Yi , Zhang Chunsheng , Shi Bin , McFall Rosemary , Koury Elizabeth J. , Hill Susan L. , Dai Hongyue , Wasserman Robert , Phillips Robert L. , Weinstein Edward J. , Kohl Nancy E. , Severino Michael E. , Lamb John R. , Sepp-Lorenzino Laura
Published: April 2023

Supplementary Table S1 from Identification of biomarkers for tumor endothelial cell proliferation through gene expression profiling
Supplementary Methods, Figures 1-2 from Gossypol Induces Apoptosis by Activating p53 in Prostate Cancer Cells and Prostate Tumor–Initiating Cells
Authors: Volate Suresh R. , Kawasaki Brian T. , Hurt Elaine M. , Milner John A. , Kim Young S. , White Jeffrey , Farrar William L.
Published: April 2023

Supplementary Methods, Figures 1-2 from Gossypol Induces Apoptosis by Activating p53 in Prostate Cancer Cells and Prostate Tumor–Initiating Cells
Data from Identification of small-molecule inhibitors of autotaxin that inhibit melanoma cell migration and invasion
Authors: Saunders Lauren P. , Ouellette Amy , Bandle Russ , Chang William Chozen , Zhou Hongwen , Misra Raj N. , De La Cruz Enrique M. , Braddock Demetrios T.
Published: April 2023

Abstract
Autotaxin (ATX) is a prometastatic enzyme initially isolated from the conditioned medium of human melanoma cells that stimulates a myriad of biological activities, including angiogenesis and the promotion of cell growth, survival, and differentiation through the production of lysophosphatidic acid (LPA). ATX increases the aggressiveness and invasiveness of transformed cells, and ATX levels directly correlate with tumor stage and grade in several human malignancies. To study the role of ATX in the pathogenesis of malignant melanoma, we developed antibodies and small-molecule inhibitors against recombinant human protein. Immunohistochemistry of paraffin-embedded human tissue shows that ATX levels are markedly increased in human primary and metastatic melanoma relative to benign nevi. Chemical screens identified several small-molecule inhibitors with binding constants ranging from nanomolar to low micromolar. Cell migration and invasion assays with melanoma cell lines show that ATX markedly stimulates melanoma cell migration and invasion, an effect suppressed by ATX inhibitors. The migratory phenotype can be rescued by the addition of the enzymatic product of ATX, LPA, confirming that the observed inhibition is linked to suppression of LPA production by ATX. Chemical analogues of the inhibitors show structure-activity relationships important for ATX inhibition and indicate pathways for their optimization. These studies suggest that ATX is an approachable molecular target for the rational design of chemotherapeutic agents directed against malignant melanoma. [Mol Cancer Ther 2008;7(10):3352–62]
Data from Antimitogenic and chemosensitizing effects of the methylation inhibitor zebularine in ovarian cancer
Authors: Balch Curtis , Yan Pearlly , Craft Teresa , Young Suzanne , Skalnik David G. , Huang Tim H-M. , Nephew Kenneth P.
Published: April 2023

Abstract
Deoxycytosine methylation within CpG islands of tumor suppressor genes plays a prominent role in the development and progression of drug-resistant ovarian cancer. Consequently, epigenetic therapies directed toward tumor suppressor demethylation/reexpression could potentially reverse malignant phenotypes and chemosensitize recalcitrant tumors. In this report, we examined the demethylating agent zebularine [1-(β-d-ribofuranosyl)-1,2-dihydropyrimidin-2-one], in comparison with the well-known methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-dC), for its ability to inhibit ovarian cancer cell proliferation and to demethylate and induce tumor suppressor genes. Zebularine exerted significant (>5-aza-dC) antiproliferative effects against the ovarian cancer cell lines Hey, A2780, and the cisplatin-resistant A2780/CP in a dose-dependent manner (65% versus 35% inhibition at 48 hours, zebularine versus 5-aza-dC). Moreover, 48-hour treatment with 0.2 mmol/L zebularine significantly induced demethylation of the tumor suppressors ras-associated domain family 1A and human MutL homologue-1. RASSF1A gene reexpression was also observed, as was reexpression of two other tumor suppressors, ARHI and BLU, although levels differed from those induced by 5-aza-dC. Global analyses of DNA methylation revealed similar overall demethylation (2.5- to 3-fold) by 5-aza-dC and zebularine as determined by methyl acceptance assay. However, differences in demethylation of individual loci were observed as determined by differential methylation hybridization. Finally, we found that zebularine could resensitize the drug-resistant cell line A2780/CP to cisplatin, with a 16-fold reduction in the IC50 of that conventional agent. In summary, zebularine seems to be a promising clinical candidate, singly or combined with conventional regimens, for the therapy of drug-resistant ovarian cancer.
Data from CNOB/ChrR6, a new prodrug enzyme cancer chemotherapy
Authors: Thorne Steve H. , Barak Yoram , Liang Wenchuan , Bachmann Michael H. , Rao Jianghong , Contag Christopher H. , Matin A.
Published: April 2023

Abstract
We report the discovery of a new prodrug, 6-chloro-9-nitro-5-oxo-5H-benzo(a)phenoxazine (CNOB). This prodrug is efficiently activated by ChrR6, the highly active prodrug activating bacterial enzyme we have previously developed. The CNOB/ChrR6 therapy was effective in killing several cancer cell lines in vitro. It also efficiently treated tumors in mice with up to 40% complete remission. 9-Amino-6-chloro-5H-benzo(a)phenoxazine-5-one (MCHB) was the only product of CNOB reduction by ChrR6. MCHB binds DNA; at nonlethal concentration, it causes cell accumulation in the S phase, and at lethal dose, it induces cell surface Annexin V and caspase-3 and caspase-9 activities. Further, MCHB colocalizes with mitochondria and disrupts their electrochemical potential. Thus, killing by CNOB involves MCHB, which likely induces apoptosis through the mitochondrial pathway. An attractive feature of the CNOB/ChrR6 regimen is that its toxic product, MCHB, is fluorescent. This feature proved helpful in in vitro studies because simple fluorescence measurements provided information on the kinetics of CNOB activation within the cells, MCHB killing mechanism, its generally efficient bystander effect in cells and cell spheroids, and its biodistribution. The emission wavelength of MCHB also permitted its visualization in live animals, allowing noninvasive qualitative imaging of MCHB in mice and the tumor microenvironment. This feature may simplify exploration of barriers to the penetration of MCHB in tumors and their amelioration. [Mol Cancer Ther 2009;8(2):333–41]
Data from Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A
Authors: Gu Yongchuan , Patterson Adam V. , Atwell Graham J. , Chernikova Sophia B. , Brown J. Martin , Thompson Larry H. , Wilson William R.
Published: April 2023

Abstract
PR-104 is a dinitrobenzamide mustard currently in clinical trial as a hypoxia-activated prodrug. Its major metabolite, PR-104A, is metabolized to the corresponding hydroxylamine (PR-104H) and amine (PR-104M), resulting in activation of the nitrogen mustard moiety. We characterize DNA damage responsible for cytotoxicity of PR-104A by comparing sensitivity of repair-defective hamster Chinese hamster ovary cell lines with their repair-competent counterparts. PR-104H showed a repair profile similar to the reference DNA cross-linking agents chlorambucil and mitomycin C, with marked hypersensitivity of XPF−/−, ERCC1−/−, and Rad51D−/− cells but not of XPD−/− or DNA-PKCS−/− cells. This pattern confirmed the expected dependence on the ERCC1-XPF endonuclease, implicated in unhooking DNA interstrand cross-links at blocked replication forks, and homologous recombination repair (HRR) in restarting collapsed forks. However, even under anoxia, the hypersensitivity of XPF−/−, ERCC1−/−, and Rad51D−/− cells to PR-104A itself was lower than for chlorambucil. To test whether this reflects inefficient PR-104A reduction, a soluble form of human NADPH:cytochrome P450 oxidoreductase was stably expressed in Rad51D−/− cells and their HRR-restored counterpart. This expression increased hypoxic metabolism of PR-104A to PR-104H and PR-104M as well as hypoxia-selective cytotoxicity of PR-104A and its dependence on HRR. We conclude that PR-104A cytotoxicity is primarily due to DNA interstrand cross-linking by its reduced metabolites, although under conditions of inefficient PR-104A reduction (low reductase expression or aerobic cells), a second mechanism contributes to cell killing. This study shows that hypoxia, reductase activity, and DNA interstrand cross-link repair proficiency are key variables that interact to determine PR-104A sensitivity. [Mol Cancer Ther 2009;8(6):1714–23]
Data from SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2
Authors: Peck Barrie , Chen Chun-Yuan , Ho Ka-Kei , Di Fruscia Paolo , Myatt Stephen S. , Coombes R. Charles , Fuchter Matthew J. , Hsiao Chwan-Deng , Lam Eric W.-F.
Published: April 2023

Abstract
SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 μmol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G1 at comparable concentrations. In vitro SIRT assays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermide-induced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844–55. ©2010 AACR.
Data from Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers
Authors: Santarosa Manuela , Del Col Laura , Tonin Elena , Caragnano Angela , Viel Alessandra , Maestro Roberta
Published: April 2023

Abstract
BRCA1-associated tumors are characterized by an elevated genomic instability and peculiar expression profiles. Nevertheless, tailored treatments for BRCA1 mutation carriers have only been partially investigated up to now. The implementation of therapeutic strategies specific for these patients has been in part hindered by the paucity of proper preneoplastic and neoplastic BRCA1-deficient tumor cell models. In this study, we took advantage of the RNA interference technology to generate a series of partially transformed (HBL100) and tumorigenic (MCF7 and T47D) breast cancer cell lines in which BRCA1 expression was silenced at different levels. These cell models were probed by clonogenic assay for their response to several DNA-damaging agents commonly used in cancer therapy (mitomycin C, cisplatin, doxorubicin, and etoposide). Our models confirmed the peculiar sensitivity to interstrand cross-link inducers associated with BRCA1 deficiency. Intriguingly, the increased sensitivity to these compounds displayed by BRCA1-defective cells was not correlated with the extent of apoptotic cell death but rather associated to an increased fraction of growth-arrested, enlarged, multinucleated β-galactosidase–positive senescent cells. Overall, our results support a role for BRCA1 in the regulation of interstrand cross-link–induced premature senescence and suggest a reconsideration of the therapeutic power of mitomycin/platinum-based treatments in BRCA1 carriers. Moreover, our data further prompt the setup of strategies for the imaging of the senescence response in vivo. [Mol Cancer Ther 2009;8(4):844–54]
Data from Inhibition of Fatty Acid Synthase Suppresses c-Met Receptor Kinase and Induces Apoptosis in Diffuse Large B-Cell Lymphoma
Authors: Uddin Shahab , Hussain Azhar R. , Ahmed Maqbool , Bu Rong , Ahmed Saeeda O. , Ajarim Dahish , Al-Dayel Fouad , Bavi Prashant , Al-Kuraya Khawla S.
Published: April 2023

Abstract
Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. In this study, we investigated the role of FASN in a large series of DLBCL tissues in a tissue microarray (TMA) format followed by in vitro studies using DLBCL cell lines. FASN was found to be expressed in 62.6% DLBCL samples and was seen in highly proliferative tumors, manifested by high Ki67 (P < 0.0001). Significant association was found between tumors expressing high FASN and c-Met tyrosine kinase (P < 0.0002), as well as p-AKT (P = 0.0309). In vitro, pharmacological FASN inhibition and small interference RNA (siRNA) targeted against FASN triggered caspase-dependent apoptosis and suppressed expression of c-Met kinase in DLBCL cell lines, which further highlighted the molecular link between FASN and c-Met kinase. Finally, simultaneous targeting of FASN and c-Met with specific chemical inhibitors induced a synergistically stimulated apoptotic response in DLBCL cell lines. These findings provide evidence that FASN, via c-Met tyrosine kinase, plays a critical role in the carcinogenesis of DLBCL and strongly suggest that targeting FASN may have therapeutic value in treatment of DLBCL. Mol Cancer Ther; 9(5); 1244–55. ©2010 AACR.
Data from Neuroblastoma-derived secretory protein is a novel secreted factor overexpressed in neuroblastoma
Authors: Vasudevan Sanjeev A. , Shang Xiaoyi , Chang Shirong , Ge Ningling , Diaz-Miron Jose L. , Russell Heidi V. , Hicks M. John , Ludwig Andrew D. , Wesson Catherine L. , Burlingame Susan M. , Kim Eugene S. , Khan Javed , Yang Jianhua , Nuchtern Jed G.
Published: April 2023

Abstract
Secreted proteins such as growth factors, cytokines, and chemokines play important roles in tumor development. Through expression microarray and bioinformatic analysis, we discovered a novel secreted protein, neuroblastoma-derived secretory protein (NDSP). The NDSP gene is found on chromosome 1q25.2 and encodes a 167 amino acid protein with a putative signal peptide. Using real-time PCR and immunoblotting, we find that NDSP is specifically overexpressed in neuroblastoma at much higher levels than other adult and pediatric malignancies and normal tissues. NDSP is an 18-kDa protein that can be secreted by NDSP-transfected HEK-293T cells, as well as, neuroblastoma cell lines endogenously expressing NDSP. Inhibiting NDSP expression in neuroblastoma cell lines with retrovirally transduced NDSP small hairpin interfering RNA, sh-NDSP, results in decreased cellular proliferation and colony formation. We also find inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation in the sh-NDSP cell line. Treating the parental cell line with MAP/ERK kinase 1/2 inhibitors, which diminish ERK1/2 phosphorylation, results in decreased cell proliferation. Culturing these transduced cells with recombinant NDSP, reintroducing NDSP overexpression in the knockdown cell line, or inducing Ras oncogene overexpression for constitutive ERK1/2 activation results in a reversal of the growth-inhibited phenotype and proliferation rates similar to the control cells. In addition, reintroduction of NDSP overexpression in the sh-NDSP cell line results in ERK1/2 phosphorylation similar to control. We conclude that NDSP is specifically overexpressed in neuroblastoma and actively secreted from tumor cells. Furthermore, NDSP serves as a growth factor for neuroblastoma tumor cells through activation of the ERK-mediated proliferation pathway. [Mol Cancer Ther 2009;8(8):2478–89]
Data from Inhibition of Mer and Axl Receptor Tyrosine Kinases in Astrocytoma Cells Leads to Increased Apoptosis and Improved Chemosensitivity
Authors: Keating Amy K. , Kim Grace K. , Jones Ashley E. , Donson Andrew M. , Ware Kathryn , Mulcahy Jean M. , Salzberg Dana B. , Foreman Nicholas K. , Liang Xiayuan , Thorburn Andrew , Graham Douglas K.
Published: April 2023

Abstract
Astrocytomas account for the majority of malignant brain tumors diagnosed in both adult and pediatric patients. The therapies available to treat these neoplasms are limited, and the prognosis associated with high-grade lesions is extremely poor. Mer (MerTK) and Axl receptor tyrosine kinases (RTK) are expressed at abnormally high levels in a variety of malignancies, and these receptors are known to activate strong antiapoptotic signaling pathways that promote oncogenesis. In this study, we found that Mer and Axl mRNA transcript and protein expression were elevated in astrocytic patient samples and cell lines. shRNA-mediated knockdown of Mer and Axl RTK expression led to an increase in apoptosis in astrocytoma cells. Apoptotic signaling pathways including Akt and extracellular signal–regulated kinase 1/2, which have been shown to be activated in resistant astrocytomas, were downregulated with Mer and Axl inhibition whereas poly(ADP-ribose) polymerase cleavage was increased. Furthermore, Mer and Axl shRNA knockdown led to a profound decrease of astrocytoma cell proliferation in soft agar and a significant increase in chemosensitivity in response to temozolomide, carboplatin, and vincristine treatment. Our results suggest Mer and Axl RTK inhibition as a novel method to improve apoptotic response and chemosensitivity in astrocytoma and provide support for these oncogenes as attractive biological targets for astrocytoma drug development. Mol Cancer Ther; 9(5); 1298–307. ©2010 AACR.