bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Cytochrome P450 1B1 Gene Polymorphisms as Predictors of Anticancer Drug Activity: Studies with In vitro Models
Authors: Laroche-Clary Audrey , Morvan Valérie Le , Yamori Takao , Robert Jacques
Published: March 2024

Abstract
Cytochrome P450 1B1 (CYP1B1) is found in tumor tissue and is suspected to play a role in oncogenesis and drug resistance. CYP1B1 gene polymorphisms have been associated with the risk of developing lung and other cancers. They may be associated with tumor response to anticancer drugs. We have determined 4 frequent nonsynonymous gene polymorphisms of CYP1B1 in the human tumor cell lines panels of the National Cancer Institute (NCI) and the Japanese Foundation for Cancer Research (JFCR): rs10012 (R48G), rs1056827 (A119S), rs1056836 (L432V), and rs1800440 (N453S). Numerous anticancer drugs have been tested against these panels that offer the opportunity to detect associations between gene polymorphisms and drug sensitivity. CYP1B1 single nucleotide polymorphisms were in marked linkage disequilibrium. The L432V allelic variants were significantly associated with reduced sensitivity to DNA-interacting anticancer agents, alkylators, camptothecins, topoisomerase II inhibitors, and some antimetabolites. For instance, in the NCI panel, cell lines homozygous for the V432 allele were globally 2-fold resistant to alkylating agents (P = 5 × 10−10) and 4.5-fold to camptothecins (P = 6.6 × 10−9) than cell lines homozygous for the L432 allele. Similar features were exhibited by the JFCR panel. Cell lines homozygous for the V432 allele were globally less sensitive to DNA-interfering drugs than cell lines having at least 1 common allele. There was no significant association between mRNA expression of CYP1B1 and CYP1B1 genotype, and no significant association between CYP1B1 mRNA expression and drug cytotoxicity. These observations open the way to clinical studies exploring the role of CYP1B1 gene polymorphisms for predicting tumor sensitivity to chemotherapy. Mol Cancer Ther; 9(12); 3315–21. ©2010 AACR.
Data from Novel Neutralizing Hedgehog Antibody MEDI-5304 Exhibits Antitumor Activity by Inhibiting Paracrine Hedgehog Signaling
Authors: Michaud Neil R. , Wang Youzhen , McEachern Kristen A. , Jordan Jerold J. , Mazzola Anne Marie , Hernandez Axel , Jalla Sanjoo , Chesebrough Jon W. , Hynes Mark J. , Belmonte Matthew A. , Wang Lidong , Kang Jaspal S. , Jovanović Jelena , Laing Naomi , Jenkins David W. , Hurt Elaine , Liang Meina , Frantz Christopher , Hollingsworth Robert E. , Simeone Diane M. , Blakey David C. , Bedian Vahe
Published: March 2024

Abstract
The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH. Mol Cancer Ther; 13(2); 386–98. ©2013 AACR.
Data from Antitumor Effects in Gastrointestinal Stromal Tumors Using Photodynamic Therapy with a Novel Glucose-Conjugated Chlorin
Authors: Tanaka Mamoru , Kataoka Hiromi , Yano Shigenobu , Ohi Hiromi , Moriwaki Kazuhiro , Akashi Haruo , Taguchi Takahiro , Hayashi Noriyuki , Hamano Shingo , Mori Yoshinori , Kubota Eiji , Tanida Satoshi , Joh Takashi
Published: March 2024

Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Except for surgical resection, no effective treatment strategies have been established. Photodynamic therapy (PDT) consists of intravenous administration of a photosensitizer, activated by a specific wavelength of light, which produces reactive oxygen species that directly kill tumor cells. We analyzed the efficacy of PDT using a newly developed photosensitizer, 5,10,15,20-tetrakis [4-[β-d-glucopyranosylthio-2,3,5,6-tetrafluorophenyl]-2,3,[methano[N-methyl] iminomethano] chlorin (H2TFPC-SGlc), for the GIST treatment. Various photosensitizers were administered in vitro to GIST (GIST-T1) and fibroblast (WI-38) cells, followed by irradiation, after which cell death was compared. We additionally established xenograft mouse models with GIST-T1 tumors and examined the accumulation and antitumor effects of these photosensitizers in vivo. In vitro, the expression of the glucose transporters GLUT1, GLUT3, and GLUT4, the cellular uptake of H2TFPC-SGlc, and apoptosis mediated by PDT with H2TFPC-SGlc were significantly higher in GIST-T1 than in WI-38 cells. In vivo, H2TFPC-SGlc accumulation was higher in xenograft tumors of GIST-T1 cells than in the adjacent normal tissue, and tumor growth was significantly suppressed following PDT. PDT with novel H2TFPC-SGlc is potentially useful for clinical applications about the treatment of GIST. Mol Cancer Ther; 13(4); 767–75. ©2014 AACR.
Data from Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo
Authors: Huang Lynn Y.L. , Chang Chia-Chi , Lee Ying-Shuan , Chang Jia-Ming , Huang Jiann-Jyh , Chuang Shih-Hsien , Kao Kuo-Jang , Lau Gillian M.G. , Tsai Pei-Yi , Liu Chia-Wei , Lin Her-Sheng , Lau Johnson Y.N.
Published: March 2024

Abstract
Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI50 = 14.29–73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI50 > 10 μmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers. Mol Cancer Ther; 13(6); 1419–30. ©2014 AACR.
Data from MAP17 (PDZKIP1) Expression Determines Sensitivity to the Proteasomal Inhibitor Bortezomib by Preventing Cytoprotective Autophagy and NFκB Activation in Breast Cancer
Authors: Muñoz-Galván Sandra , Gutierrez Gabriel , Perez Marco , Carnero Amancio
Published: March 2024

Abstract
MAP17 is a small nonglycosylated membrane protein that is overexpressed in a high percentage of carcinomas. High levels of MAP17 enhance the tumorigenic properties of tumor cells by increasing oxidative stress, which is dependent on Na+-coupled cotransport. Here, we show that MAP17 is associated with proteins involved in protein degradation and that proteasome inhibition induces autophagy. To analyze whether MAP17 could also alter this process, we used the proteasome inhibitor bortezomib (Velcade, PS-341), which is approved for the treatment of multiple myeloma and mantle cell lymphoma, although it has a high rate of resistance emergence and poor efficacy in solid tumors. We provide evidence that bortezomib induces a cytoprotective effect by activating autophagy and NFκB nuclear translocation, responses that are repressed in the presence of high levels of MAP17 both in vitro and in vivo. Indeed, patients with multiple myeloma treated with bortezomib showed higher response rates and a longer time to progression associated with increased levels of MAP17 expression. The MAP17-induced sensitivity to bortezomib is dependent on the oxidative status of the cells and the activity of Na+-coupled transporters because treatment with antioxidants or the inhibitor furosemide restores the cytoprotective activity induced by bortezomib. Therefore, bortezomib induces a prosurvival response through cytoprotective autophagy and NFκB nuclear translocation, which is repressed by high levels of MAP17. We propose that the levels of MAP17 could be used as a prognostic marker to predict the response to bortezomib in hematologic malignancies and in other tissues that are not commonly responsive to the drug. Mol Cancer Ther; 14(6); 1454–65. ©2015 AACR.
Data from Bone Marrow–Derived Mesenchymal Stromal Cells Promote Survival and Drug Resistance in Tumor Cells
Authors: Bergfeld Scott A. , Blavier Laurence , DeClerck Yves A.
Published: March 2024

Abstract
Bone marrow mesenchymal stromal cells (BMMSC) have antitumorigenic activities. Here, we hypothesized that circulating BMMSC are incorporated into tumors and protect tumor cells from therapy-induced apoptosis. Adherent cells harvested from murine bone marrow and expressing phenotypic and functional characteristics of BMMSC were tested for their antitumor activity against murine 4T1 mammary adenocarcinoma and LL/2 Lewis lung carcinoma cells. BMMSC but not NIH3T3 or murine skin fibroblasts stimulated the expansion of 4T1 cells in three-dimensional (3D) cocultures, and conditioned medium (CM) from these cells increased the viability of 4T1 and LL/2 cells in two-dimensional (2D) cultures. 4T1 cells exposed to BMMSC CM exhibited a 2-fold reduction in apoptosis under low serum concentrations (0.5% to 1%). Furthermore, exposure of 4T1 and LL/2 cells to BMMSC CM increased their viability in the presence of paclitaxel or doxorubicin at therapeutic concentrations. This effect was accompanied by reductions in caspase-3 activity and Annexin V expression. When coinjected with 4T1 cells in the mammary fat pad of mice subsequently treated with doxorubicin, BMMSC (and not fibroblasts) also inhibited drug-induced apoptosis in tumor cells by 44%. We demonstrated that BMMSC were attracted by 4T1 and LL/2 cells but not by NIH3T3 cells in vitro and that when injected intravenously in 4T1 tumor-bearing mice, these cells (and not NIH3T3) were specifically detected in tumors within 12 to 18 days in which they preferentially localized at the invasive front. Overall, our data identify BMMSC as an important mediator of tumor cell survival and treatment resistance in primary tumors. Mol Cancer Ther; 13(4); 962–75. ©2014 AACR.
Data from The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma
Authors: Klingenberg Marcel , Becker Jürgen , Eberth Sonja , Kube Dieter , Wilting Jörg
Published: March 2024

Abstract
Burkitt lymphoma is a rare malignancy arising from B cells. Current chemotherapeutic regimens achieve excellent overall survival rates in children, but less impressive rates in adults. There are cases with poor outcome caused by toxic effects of the therapy, tumor lysis syndrome, or metastatic spread of lymphomas to the central nervous system. Modulators of reactive oxygen species are currently discussed as potential drugs for the treatment of cancer. The NADPH oxidase 4 inhibitor imipramine-blue might satisfy the aforementioned requirements, and was studied here. We used MTT assay, crystal violet assay, and thymidine 3H-incorporation assay to analyze the effects of imipramine-blue on Burkitt lymphoma (BL2, BL2B95, BL30B95, BL41B95), neuroblastoma (KELLY, SH-SY5Y, SMS-KAN), cervix carcinoma (HeLa), breast cancer (MDA-MB231), angiosarcoma (AS-M), human embryonic kidney (HEK293WT), and nonmalignant (FLP1) cell lines. The effects of imipramine-blue on BL2B95 cells in vivo were investigated in xenografts on the chick chorioallantoic membrane (CAM). We report that imipramine-blue is a potent growth inhibitor for several cancer cell lines in vitro with IC50 values comparable to those of doxorubicin (0.16–7.7 μmol/L). Tumor size of BL2B95 cells inoculated in the CAM was reduced significantly (P < 0.05) after treatment with 10 μmol/L imipramine-blue. Lymphogenic dissemination of BL2B95 and the formation of blood and lymphatic vessels in experimental tumors were not affected. We show that imipramine-blue can be used to decrease the viability of cancer cell lines in vitro and in vivo. Imipramine-blue reduces the size of experimental Burkitt lymphoma significantly but does not affect the dissemination of BL2B95 cells, angiogenesis, and lymphangiogenesis. Mol Cancer Ther; 13(4); 833–41. ©2014 AACR.
Data from Targeting STAT5 in Hematologic Malignancies through Inhibition of the Bromodomain and Extra-Terminal (BET) Bromodomain Protein BRD2
Authors: Liu Suhu , Walker Sarah R. , Nelson Erik A. , Cerulli Robert , Xiang Michael , Toniolo Patricia A. , Qi Jun , Stone Richard M. , Wadleigh Martha , Bradner James E. , Frank David A.
Published: March 2024

Abstract
The transcription factor signal STAT5 is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematologic malignancies. Given the importance of bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacologic bromodomain inhibitor could inhibit STAT5-dependent gene expression. We found that the small-molecule bromodomain and extra-terminal (BET) bromodomain inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET bromodomain subfamily of proteins, it seems that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T-cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knockdown or JQ1 treatment shows strong synergy with tyrosine kinase inhibitors (TKI) in inducing apoptosis in leukemia cells. In contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and TKIs may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation. Mol Cancer Ther; 13(5); 1194–205. ©2014 AACR.
Data from Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models
Authors: Tan Nguyen , Wong Maureen , Nannini Michelle A. , Hong Rebecca , Lee Leslie B. , Price Stephen , Williams Karen , Savy Pierre Pascal , Yue Peng , Sampath Deepak , Settleman Jeffrey , Fairbrother Wayne J. , Belmont Lisa D.
Published: March 2024

Abstract
Although mitogen-activated protein (MAP)–extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic BH3-only protein BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non–small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-xL (BCL2/BCL2L1) antagonist, and a novel MAP kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell-cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture. Addition of the phosphatidylinositol 3-kinase (PI3K, PIK3CA) inhibitor GDC-0941 to this treatment combination increases cell killing compared with double- or single-agent treatment. Taken together, these data suggest the efficacy of agents that target the MAPK and PI3K pathways can be improved by combination with a Bcl-2 family inhibitor. Mol Cancer Ther; 12(6); 853–64. ©2013 AACR.
Data from Discovery of a Novel Orally Active Small-Molecule gp130 Inhibitor for the Treatment of Ovarian Cancer
Authors: Xu Shili , Grande Fedora , Garofalo Antonio , Neamati Nouri
Published: March 2024

Abstract
Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is not well-established. Currently, there are no small-molecule inhibitors of gp130 under clinical development. In this study, we show that gp130 is an attractive drug target in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-molecule gp130 inhibitor. SC144 shows greater potency in human ovarian cancer cell lines than in normal epithelial cells. SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and further inhibits the expression of downstream target genes. In addition, SC144 shows potent inhibition of gp130 ligand–triggered signaling. Oral administration of SC144 delays tumor growth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues. Mol Cancer Ther; 12(6); 937–49. ©2013 AACR.
Data from Modeling Targeted Inhibition of MEK and PI3 Kinase in Human Pancreatic Cancer
Authors: Junttila Melissa R. , Devasthali Vidusha , Cheng Jason H. , Castillo Joseph , Metcalfe Ciara , Clermont Anne C. , Otter Douglas Den , Chan Emily , Bou-Reslan Hani , Cao Tim , Forrest William , Nannini Michelle A. , French Dorothy , Carano Richard , Merchant Mark , Hoeflich Klaus P. , Singh Mallika
Published: March 2024

Abstract
Activating mutations in the KRAS oncogene occur in approximately 90% of pancreatic cancers, resulting in aberrant activation of the MAPK and the PI3K pathways, driving malignant progression. Significant efforts to develop targeted inhibitors of nodes within these pathways are underway and several are currently in clinical trials for patients with KRAS-mutant tumors, including patients with pancreatic cancer. To model MEK and PI3K inhibition in late-stage pancreatic cancer, we conducted preclinical trials with a mutant Kras-driven genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma development. Treatment of advanced disease with either a MEK (GDC-0973) or PI3K inhibitor (GDC-0941) alone showed modest tumor growth inhibition and did not significantly enhance overall survival. However, combination of the two agents resulted in a significant survival advantage as compared with control tumor-bearing mice. To model the clinical scenario, we also evaluated the combination of these targeted agents with gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer. The addition of MEK or PI3K inhibition to gemcitabine, or the triple combination regimen, incrementally enhanced overall survival as compared with gemcitabine alone. These results are reminiscent of the survival advantage conferred in this model and in patients by the combination of gemcitabine and erlotinib, an approved therapeutic regimen for advanced nonresectable pancreatic cancer. Taken together, these data indicate that inhibition of MEK and PI3K alone or in combination with chemotherapy do not confer a dramatic improvement as compared with currently available therapies for patients with pancreatic cancer. Mol Cancer Ther; 14(1); 40–47. ©2014 AACR.
Data from Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression
Authors: Teicher Beverly A. , Polley Eric , Kunkel Mark , Evans David , Silvers Thomas , Delosh Rene , Laudeman Julie , Ogle Chad , Reinhart Russell , Selby Michael , Connelly John , Harris Erik , Monks Anne , Morris Joel
Published: March 2024

Abstract
The diversity in sarcoma phenotype and genotype make treatment of this family of diseases exceptionally challenging. Sixty-three human adult and pediatric sarcoma lines were screened with 100 FDA-approved oncology agents and 345 investigational agents. The investigational agents' library enabled comparison of several compounds targeting the same molecular entity allowing comparison of target specificity and heterogeneity of cell line response. Gene expression was derived from exon array data and microRNA expression was derived from direct digital detection assays. The compounds were screened against each cell line at nine concentrations in triplicate with an exposure time of 96 hours using Alamar blue as the endpoint. Results are presented for inhibitors of the following targets: aurora kinase, IGF-1R, MEK, BET bromodomain, and PARP1. Chemical structures, IC50 heat maps, concentration response curves, gene expression, and miR expression heat maps are presented for selected examples. In addition, two cases of exceptional responders are presented. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sarcoma.cancer.gov. These data provide a unique resource to the cancer research community. Mol Cancer Ther; 14(11); 2452–62. ©2015 AACR.
Data from Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3–BAIAP2L1
Authors: Nakanishi Yoshito , Akiyama Nukinori , Tsukaguchi Toshiyuki , Fujii Toshihiko , Satoh Yasuko , Ishii Nobuya , Aoki Masahiro
Published: March 2024

Abstract
Recent cancer genome profiling studies have identified many novel genetic alterations, including rearrangements of genes encoding FGFR family members. However, most fusion genes are not functionally characterized, and their potentials in targeted therapy are unclear. We investigated a recently discovered gene fusion between FGFR3 and BAI1-associated protein 2-like 1 (BAIAP2L1). We identified 4 patients with bladder cancer and 2 patients with lung cancer harboring the FGFR3–BAIAP2L1 fusion through PCR and FISH assay screens. To investigate the oncogenic potential of the fusion gene, we established an FGFR3–BAIAP2L1 transfectant with Rat-2 fibroblast cells (Rat-2_F3-B). The FGFR3–BAIAP2L1 fusion had transforming activity in Rat2 cells, and Rat-2_F3-B cells were highly tumorigenic in mice. Rat-2_F3-B cells showed in vitro and in vivo sensitivity in the selective FGFR inhibitor CH5183284/Debio 1347, indicating that FGFR3 kinase activity is critical for tumorigenesis. Gene signature analysis revealed that FGFR3–BAIAP2L1 activates growth signals, such as the MAPK pathway, and inhibits tumor-suppressive signals, such as the p53, RB1, and CDKN2A pathways. We also established Rat-2_F3-B-ΔBAR cells expressing an FGFR3–BAIAP2L1 variant lacking the Bin–Amphiphysin–Rvs (BAR) dimerization domain of BAIAP2L1, which exhibited decreased tumorigenic activity, FGFR3 phosphorylation, and F3-B-ΔBAR dimerization, compared with Rat-2_F3-B cells. Collectively, these data suggest that constitutive dimerization through the BAR domain promotes constitutive FGFR3 kinase activation and is essential for its potent oncogenic activity. Mol Cancer Ther; 14(3); 704–12. ©2015 AACR.
Data from BRCA2 and RAD51 Promote Double-Strand Break Formation and Cell Death in Response to Gemcitabine
Authors: Jones Rebecca M. , Kotsantis Panagiotis , Stewart Grant S. , Groth Petra , Petermann Eva
Published: March 2024

Abstract
Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors. Mol Cancer Ther; 13(10); 2412–21. ©2014 AACR.
Data from Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2
Authors: Smith Bryan D. , Kaufman Michael D. , Leary Cynthia B. , Turner Benjamin A. , Wise Scott C. , Ahn Yu Mi , Booth R. John , Caldwell Timothy M. , Ensinger Carol L. , Hood Molly M. , Lu Wei-Ping , Patt Tristan W. , Patt William C. , Rutkoski Thomas J. , Samarakoon Thiwanka , Telikepalli Hanumaiah , Vogeti Lakshminarayana , Vogeti Subha , Yates Karen M. , Chun Lawrence , Stewart Lance J. , Clare Michael , Flynn Daniel L.
Published: March 2024

Abstract
Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood–brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases. Mol Cancer Ther; 14(9); 2023–34. ©2015 AACR.
Data from Triple-Negative Breast Cancer Patients Treated at MD Anderson Cancer Center in Phase I Trials: Improved Outcomes with Combination Chemotherapy and Targeted Agents
Authors: Ganesan Prasanth , Moulder Stacy , Lee J. Jack , Janku Filip , Valero Vicente , Zinner Ralph G. , Naing Aung , Fu Siqing , Tsimberidou Apostolia M. , Hong David , Stephen Bettzy , Stephens Philip , Yelensky Roman , Meric-Bernstam Funda , Kurzrock Razelle , Wheler Jennifer J.
Published: March 2024

Abstract
Patients with metastatic triple-negative breast cancer (TNBC) have poor treatment outcomes. We reviewed the electronic records of consecutive patients with metastatic TNBC treated in phase I clinic at MD Anderson Cancer Center (Houston, TX) between Augu st 2005 and May 2012. One hundred and six patients received at least 1 phase I trial. Twelve of 98 evaluable patients (12%) had either complete response (CR; n = 1), partial response (PR; n = 7), or stable disease ≥6 months (SD; n = 4). Patients treated on matched therapy (n = 16) compared with those on nonmatched therapy (n = 90) had improved SD ≥ 6 months/PR/CR (33% vs. 8%; P = 0.018) and longer progression-free survival (PFS; median, 6.4 vs. 1.9 months; P = 0.001). Eleven of 57 evaluable patients (19%) treated with combination chemotherapy and targeted therapy had SD ≥ 6 months/PR/CR versus 1 of 41 evaluable patients (2%) treated on other phase I trials (P = 0.013), and longer PFS (3.0 vs. 1.6 months; P < 0.0001). Patients with molecular alterations in the PI3K/AKT/mTOR pathway treated on matched therapy (n = 16) had improved PFS compared with those with and without molecular alterations treated on nonmatched therapy (n = 27; 6.4 vs. 3.2 months; P = 0.036). On multivariate analysis, improved PFS was associated with treatment with combined chemotherapy and targeted agents (P = 0.0002), ≤2 metastatic sites (P = 0.003), therapy with PI3K/AKT/mTOR inhibitors for those with cognate pathway abnormalities (P = 0.018), and treatment with antiangiogenic agents (P = 0.023). In summary, combinations of chemotherapy and angiogenesis and/or PI3K/AKT/mTOR inhibitors demonstrated improved outcomes in patients with metastatic TNBC. Mol Cancer Ther; 13(12); 3175–84. ©2014 AACR.
Data from EpCAM-Selective Elimination of Carcinoma Cells by a Novel MAP-Based Cytolytic Fusion Protein
Authors: Hristodorov Dmitrij , Amoury Manal , Mladenov Radoslav , Niesen Judith , Arens Katharina , Berges Nina , Hein Lea , Di Fiore Stefano , Pham Anh-Tuan , Huhn Michael , Helfrich Wijnand , Fischer Rainer , Thepen Theo , Barth Stefan
Published: March 2024

Abstract
In normal epithelia, the epithelial cell adhesion molecule (EpCAM) expression is relatively low and only present at the basolateral cell surface. In contrast, EpCAM is aberrantly overexpressed in various human carcinomas. Therefore, EpCAM is considered to be a highly promising target for antibody-based cancer immunotherapy. Here, we present a new and fully human cytolytic fusion protein (CFP), designated “anti–EpCAM(scFv)-MAP,” that is comprised of an EpCAM-specific antibody fragment (scFv) genetically fused to the microtubule-associated protein tau (MAP). Anti–EpCAM(scFv)-MAP shows potent EpCAM-restricted proapoptotic activity toward rapidly proliferating carcinoma cells. In vitro assays confirmed that treatment with anti–EpCAM(scFv)-MAP resulted in the colocalization and stabilization of microtubules, suggesting that this could be the potential mode of action. Dose-finding experiments indicated that anti–EpCAM(scFv)-MAP is well tolerated in mice. Using noninvasive far-red in vivo imaging in a tumor xenograft mouse model, we further demonstrated that anti–EpCAM(scFv)-MAP inhibited tumor growth in vivo. In conclusion, our data suggest that anti–EpCAM(scFv)-MAP may be of therapeutic value for the targeted elimination of EpCAM+ carcinomas. Mol Cancer Ther; 13(9); 2194–202. ©2014 AACR.
Data from Pharmacological Profiling of Kinase Dependency in Cell Lines across Triple-Negative Breast Cancer Subtypes
Authors: Fink Lauren S. , Beatty Alexander , Devarajan Karthik , Peri Suraj , Peterson Jeffrey R.
Published: March 2024

Abstract
Triple-negative breast cancers (TNBC), negative for estrogen receptor, progesterone receptor, and ERBB2 amplification, are resistant to standard targeted therapies and exhibit a poor prognosis. Furthermore, they are highly heterogeneous with respect to genomic alterations, and common therapeutic targets are lacking though substantial evidence implicates dysregulated kinase signaling. Recently, six subtypes of TNBC were identified based on gene expression and were proposed to predict sensitivity to a variety of therapeutic agents including kinase inhibitors. To test this hypothesis, we screened a large collection of well-characterized, small molecule kinase inhibitors for growth inhibition in a panel of TNBC cell lines representing all six subtypes. Sensitivity to kinase inhibition correlated poorly with TNBC subtype. Instead, unsupervised clustering segregated TNBC cell lines according to clinically relevant features including dependence on epidermal growth factor signaling and mutation of the PTEN tumor suppressor. We further report the discovery of kinase inhibitors with selective toxicity to these groups. Overall, however, TNBC cell lines exhibited diverse sensitivity to kinase inhibition consistent with the lack of common driver mutations in this disease. Although our findings support specific kinase dependencies in subsets of TNBC, they are not associated with gene expression–based subtypes. Instead, we find that mutation status can be an effective predictor of sensitivity to inhibition of particular kinase pathways for subsets of TNBC. Mol Cancer Ther; 14(1); 298–306. ©2014 AACR.
Data from Selective Nuclear Export Inhibitor KPT-330 Enhances the Antitumor Activity of Gemcitabine in Human Pancreatic Cancer
Authors: Kazim Sabiha , Malafa Mokenge P. , Coppola Domenico , Husain Kazim , Zibadi Sherma , Kashyap Trinayan , Crochiere Marsha , Landesman Yosef , Rashal Tami , Sullivan Daniel M. , Mahipal Amit
Published: March 2024

Abstract
Pancreatic cancer is an aggressive and deadly malignancy responsible for the death of over 37,000 Americans each year. Gemcitabine-based therapy is the standard treatment for pancreatic cancer but has limited efficacy due to chemoresistance. In this study, we evaluated the in vitro and in vivo effects of gemcitabine combined with the selective nuclear export (CRM1) inhibitor KPT-330 on pancreatic cancer growth. Human pancreatic cancer MiaPaCa-2 and metastatic pancreatic cancer L3.6pl cell lines were treated with different concentrations of KPT-330 and gemcitabine alone or in combination, and anchorage–dependent/independent growth was recorded. In addition, L3.6pl cells with luciferase were injected orthotopically into the pancreas of athymic nude mice, which were treated with (i) vehicle (PBS 1 mL/kg i.p., 2/week and povidone/pluronic F68 1 mL/kg p.o., 3/week), (ii) KPT-330 (20 mg/kg p.o., 3/week), (iii) gemcitabine (100 mg/kg i.p., 2/week), or (iv) KPT-330 (10 mg/kg) + gemcitabine (50 mg/kg) for 4 weeks. KPT-330 and gemcitabine alone dose-dependently inhibited anchorage-dependent growth in vitro and tumor volume in vivo compared with vehicle treatment. However, the combination inhibited growth synergistically. In combination, KPT-330 and gemcitabine acted synergistically to enhance pancreatic cancer cell death greater than each single-agent therapy. Mechanistically, KPT-330 and gemcitabine promoted apoptosis, induced p27, depleted survivin, and inhibited accumulation of DNA repair proteins. Together, our data suggest that KPT-330 potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis. Mol Cancer Ther; 14(7); 1570–81. ©2015 AACR.
Data from Calpain-Mediated Integrin Deregulation as a Novel Mode of Action for the Anticancer Gallium Compound KP46
Authors: Jungwirth Ute , Gojo Johannes , Tuder Theresa , Walko Gernot , Holcmann Martin , Schöfl Thomas , Nowikovsky Karin , Wilfinger Nastasia , Schoonhoven Sushilla , Kowol Christian R. , Lemmens-Gruber Rosa , Heffeter Petra , Keppler Bernhard K. , Berger Walter
Published: March 2024

Abstract
On the basis of enhanced tumor accumulation and bone affinity, gallium compounds are under development as anticancer and antimetastatic agents. In this study, we analyzed molecular targets of one of the lead anticancer gallium complexes [KP46, Tris(8-quinolinolato)gallium(III)] focusing on colon and lung cancer. Within a few hours, KP46 treatment at low micromolar concentrations induced cell body contraction and loss of adhesion followed by prompt cell decomposition. This rapid KP46-induced cell death lacked classic apoptotic features and was insensitive toward a pan–caspase inhibitor. Surprisingly, however, it was accompanied by upregulation of proapoptotic Bcl-2 family members. Furthermore, a Bax- but not a p53-knockout HCT-116 subline exhibited significant KP46 resistance. Rapid KP46-induced detachment was accompanied by downregulation of focal adhesion proteins, including several integrin subunits. Loss of integrin-β1 and talin plasma membrane localization corresponded to reduced binding of RGD (Arg–Gly–Asp) peptides to KP46-treated cells. Accordingly, KP46-induced cell death and destabilization of integrins were enhanced by culture on collagen type I, a major integrin ligand. In contrast, KP46-mediated adhesion defects were partially rescued by Mg2+ ions, promoting integrin-mediated cell adhesion. Focal adhesion dynamics are regulated by calpains via cleavage of multiple cell adhesion molecules. Cotreatment with the cell-permeable calpain inhibitor PD150606 diminished KP46-mediated integrin destabilization and rapid cell death induction. KP46 treatment distinctly inhibited HCT-116 colon cancer xenograft in vivo by causing reduced integrin plasma membrane localization, tissue disintegration, and intense tumor necrosis. This study identifies integrin deregulation via a calpain-mediated mechanism as a novel mode of action for the anticancer gallium compound KP46. Mol Cancer Ther; 13(10); 2436–49. ©2014 AACR.
Data from Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies
Authors: Calpe Silvia , Wagner Koen , El Khattabi Mohamed , Rutten Lucy , Zimberlin Cheryl , Dolk Edward , Verrips C. Theo , Medema Jan Paul , Spits Hergen , Krishnadath Kausilia K.
Published: March 2024

Abstract
Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4+ malignancies. Mol Cancer Ther; 14(11); 2527–40. ©2015 AACR.
Data from Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors
Authors: Feneyrolles Clémence , Spenlinhauer Aurélia , Guiet Léa , Fauvel Bénédicte , Daydé-Cazals Bénédicte , Warnault Pierre , Chevé Gwénaël , Yasri Aziz
Published: March 2024

Abstract
Receptor tyrosine kinases (RTK) are transmembrane receptors that regulate signal transduction in cells. As a member of the TAM (Tyro-3, Axl, Mer) RTK subfamily, Axl regulates key processes such as cell growth, migration, aggregation, and apoptosis through several pathways. Its overexpression/overactivation has been underlined in several conditions, especially cancers, and in both chemotherapy and targeted therapy sensitivity loss. In this review, we propose to highlight the therapeutic implication of Axl, starting with the pathways it regulates, validating its interest as a therapeutic target, and defining the tools available to develop strategies for its inhibition. We especially focus on small molecule inhibitors, their structure, inhibition profile, and development stages. Mol Cancer Ther; 13(9); 2141–8. ©2014 AACR.
Data from A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies
Authors: Fan Xuejun , Brezski Randall J. , Deng Hui , Dhupkar Pooja M. , Shi Yun , Gonzalez Anneliese , Zhang Songlin , Rycyzyn Michael , Strohl William R. , Jordan Robert E. , Zhang Ningyan , An Zhiqiang
Published: March 2024

Abstract
Primary and acquired resistance to anticancer antibody immunotherapies presents significant clinical challenges. Here, we demonstrate that proteolytic inactivation of cancer-targeting antibodies is an unappreciated contributor to cancer immune evasion, and the finding presents novel opportunities for therapeutic intervention. A single peptide bond cleavage in the IgG1 hinge impairs cancer cell killing due to structural derangement of the Fc region. Hinge-cleaved trastuzumab gradually accumulated on the surfaces of HER2-expressing cancer cell lines in vitro, and was greatly accelerated when the cells were engineered to express the potent bacterial IgG-degrading proteinase (IdeS). Similar to cancer-related matrix metalloproteinases (MMP), IdeS exposes a hinge neoepitope that we have developed an antibody, mAb2095-2, to specifically target the epitope. In in vitro studies, mAb2095-2 restored the lost antibody-dependent cell-mediated cytotoxicity functionality of cell-bound single-cleaved trastuzumab (scIgG-T). In vivo, mAb2095-2 rescued the impaired Fc-dependent tumor-suppressive activity of scIgG-T in a xenograft tumor model and restored the recruitment of immune effector cells into the tumor microenvironment. More importantly, an Fc-engineered proteinase-resistant version of mAb2095-2 rescued trastuzumab antitumor efficacy in a mouse tumor model with human cancer cells secreting IdeS, whereas trastuzumab alone showed significantly reduced antitumor activity in the same model. Consistently, an Fc-engineered proteinase-resistant version of trastuzumab also greatly improved antitumor efficacy in the xenograft tumor model. Taken together, these findings point to a novel cancer therapeutic strategy to rescue proteolytic damage of antibody effector function by an Fc-engineered mAb against the hinge neoepitope and to overcome cancer evasion of antibody immunity. Mol Cancer Ther; 14(3); 681–91. ©2014 AACR.
Data from Identification of Kinase Inhibitor Targets in the Lung Cancer Microenvironment by Chemical and Phosphoproteomics
Authors: Gridling Manuela , Ficarro Scott B. , Breitwieser Florian P. , Song Lanxi , Parapatics Katja , Colinge Jacques , Haura Eric B. , Marto Jarrod A. , Superti-Furga Giulio , Bennett Keiryn L. , Rix Uwe
Published: March 2024

Abstract
A growing number of gene mutations, which are recognized as cancer drivers, can be successfully targeted with drugs. The redundant and dynamic nature of oncogenic signaling networks and complex interactions between cancer cells and the microenvironment, however, can cause drug resistance. While these challenges can be addressed by developing drug combinations or polypharmacology drugs, this benefits greatly from a detailed understanding of the proteome-wide target profiles. Using mass spectrometry-based chemical proteomics, we report the comprehensive characterization of the drug–protein interaction networks for the multikinase inhibitors dasatinib and sunitinib in primary lung cancer tissue specimens derived from patients. We observed in excess of 100 protein kinase targets plus various protein complexes involving, for instance, AMPK, TBK1 (sunitinib), and ILK (dasatinib). Importantly, comparison with lung cancer cell lines and mouse xenografts thereof showed that most targets were shared between cell lines and tissues. Several targets, however, were only present in tumor tissues. In xenografts, most of these proteins were of mouse origin suggesting that they originate from the tumor microenvironment. Furthermore, intersection with subsequent global phosphoproteomic analysis identified several activated signaling pathways. These included MAPK, immune, and integrin signaling, which were affected by these drugs in both cancer cells and the microenvironment. Thus, the combination of chemical and phosphoproteomics can generate a systems view of proteins, complexes, and signaling pathways that are simultaneously engaged by multitargeted drugs in cancer cells and the tumor microenvironment. This may allow for the design of novel anticancer therapies that concurrently target multiple tumor compartments. Mol Cancer Ther; 13(11); 2751–62. ©2014 AACR.
Data from Translational Exposure–Efficacy Modeling to Optimize the Dose and Schedule of Taxanes Combined with the Investigational Aurora A Kinase Inhibitor MLN8237 (Alisertib)
Authors: Huck Jessica J. , Zhang Mengkun , Mettetal Jerome , Chakravarty Arijit , Venkatakrishnan Karthik , Zhou Xiaofei , Kleinfield Rob , Hyer Marc L. , Kannan Karuppiah , Shinde Vaishali , Dorner Andy , Manfredi Mark G. , Shyu Wen Chyi , Ecsedy Jeffrey A.
Published: March 2024

Abstract
Aurora A kinase orchestrates multiple key activities, allowing cells to transit successfully into and through mitosis. MLN8237 (alisertib) is a selective Aurora A inhibitor that is being evaluated as an anticancer agent in multiple solid tumors and heme-lymphatic malignancies. The antitumor activity of MLN8237 when combined with docetaxel or paclitaxel was evaluated in in vivo models of triple-negative breast cancer grown in immunocompromised mice. Additive and synergistic antitumor activity occurred at multiple doses of MLN8237 and taxanes. Moreover, significant tumor growth delay relative to the single agents was achieved after discontinuing treatment; notably, durable complete responses were observed in some mice. The tumor growth inhibition data generated with multiple dose levels of MLN8237 and paclitaxel were used to generate an exposure–efficacy model. Exposures of MLN8237 and paclitaxel achieved in patients were mapped onto the model after correcting for mouse-to-human variation in plasma protein binding and maximum tolerated exposures. This allowed rank ordering of various combination doses of MLN8237 and paclitaxel to predict which pair would lead to the greatest antitumor activity in clinical studies. The model predicted that 60 and 80 mg/m2 of paclitaxel (every week) in patients lead to similar levels of efficacy, consistent with clinical observations in some cancer indications. The model also supported using the highest dose of MLN8237 that can be achieved, regardless of whether it is combined with 60 or 80 mg/m2 of paciltaxel. The modeling approaches applied in these studies can be used to guide dose-schedule optimization for combination therapies using other therapeutic agents. Mol Cancer Ther; 13(9); 2170–83. ©2014 AACR.