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IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling.
Wang YA, Sun Y, Palmer JD, Solomides C, Huang LC, Shyr Y, Dicker AP, Lu B
(2017) Mol Cancer Res :
Show Abstract · Added April 18, 2017
Insulin-like growth factor binding protein 3 (IGFBP3) modulates cell growth through IGF-dependent and -independent mechanisms. Reports suggest that the serum levels of IGFBP3 are associated with various cancers and that IGFBP3 expression is significantly decreased in cisplatin (CDDP)-resistant lung cancer cells. Based on these findings, we investigated whether Igfbp3 deficiency accelerates mouse lung tumorigenesis and if expression of IGFBP3 enhances CDDP response by focusing on the IGF1 signaling cascade. To this end, an Igfbp3-null mouse model was generated in combination with KrasG12D to compare the tumor burden. Then, IGF-dependent signaling was assessed after expressing wild-type or a mutant IGFBP3 without IGF binding capacity in non-small cell lung cancer (NSCLC) cells. Finally, the treatment response to CDDP chemotherapy was evaluated under conditions of IGFBP3 overexpression. Igfbp3-null mice had increased lung tumor burden (>2-fold) and only half of human lung cancer cells survived after expression of IGFBP3, which corresponded to increased cleaved caspase 3 (10-fold), inactivation of IGF1 and MAPK signaling. In addition, overexpression of IGFBP3 increased susceptibility to CDDP treatment in lung cancer cells. These results, for the first time, demonstrate that IGFBP3 mediates lung cancer progression in a KrasG12D mouse model. Furthermore, overexpression IGFBP3 induced apoptosis and enhanced cisplatin response in vitro, and confirmed that the suppression is in part by blocking IGF1 signaling.
IMPLICATIONS - These findings reveal that IGFBP3 is effective in lung cancer cells with high IGF1 signaling activity and imply that relevant biomarkers are essential in selecting lung cancer patients for IGF1 targeted therapy.
Copyright ©2017, American Association for Cancer Research.
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A randomized phase II neoadjuvant study of cisplatin, paclitaxel with or without everolimus in patients with stage II/III triple-negative breast cancer (TNBC).
Jovanovic B, Mayer IA, Mayer EL, Abramson VG, Bardia A, Sanders M, Kuba MG, Estrada MV, Beeler JS, Shaver TM, Johnson KN, Sanchez V, Rosenbluth JM, Dillon PM, Forrero-Torres A, Chang JC, Meszoely I, Grau A, Lehmann BD, Shyr Y, Sheng Q, Chen SC, Arteaga CL, Pietenpol JA
(2017) Clin Cancer Res :
Show Abstract · Added April 9, 2017
PURPOSE - Due to inherent disease heterogeneity, targeted therapies have eluded TNBC, and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine if the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic anti-tumor effects in TNBC.
EXPERIMENTAL DESIGN - Stage II/III patients with TNBC were enrolled in a randomized phase II trial of preoperative weekly cisplatin, paclitaxel and daily everolimus or placebo for 12 weeks, until definitive surgery. Tumor specimens were obtained at baseline, cycle 1 and surgery. Primary endpoint was pathological complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome.
RESULTS - Between 2009 and 2013, 145 patients were accrued; 36% patients in the everolimus arm and 49% patients in the placebo arm achieved pCR; in each arm, 50% of patients achieved complete responses by imaging. Higher rates of neutropenia, mucositis and transaminase elevation were seen with everolimus. Clinical response to therapy and long-term outcome correlated with increased frequency of DNA damage response (DDR) gene mutations, Basal-like1 and Mesenchymal TNBC-subtypes, AR-negative status and high Ki67, but not with tumor infiltrating lymphocytes.
CONCLUSIONS - The paclitaxel/cisplatin combination was well tolerated and active, but addition of everolimus was associated with more adverse events without improvement in pCR or clinical response. However, discoveries made from correlative studies could lead to predictive TNBC biomarkers that may impact clinical decision-making and provide new avenues for mechanistic exploration that could lead to clinical utility.
Copyright ©2017, American Association for Cancer Research.
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Genetic manipulation of Helicobacter pylori virulence function by host carcinogenic phenotypes.
Suarez G, Romero-Gallo J, Sierra JC, Piazuelo MB, Krishna U, Gomez MA, Wilson KT, Peek RM
(2017) Cancer Res :
Show Abstract · Added February 18, 2017
Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is the cag type 4 secretion system (cagT4SS), which translocates an oncoprotein into host cells. A structural component of the cagT4SS is CagY, which become rapidly altered during in vivo adaptation in mice and rhesus monkeys, rendering the cagT4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the H. pylori cag+ strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. To understand how only a subset of infected individuals develop cancer, we used this model in conjunction with samples from patients with premalignant lesions to define the effects of a carcinogenic host environment on the virulence phenotype of H. pylori. H. pylori cagY sequence differences and cagT4SS function were directly related to the severity of inflammation in human gastric mucosa in either a synchronous or metachronous manner. Serial infections of Mongolian gerbils with H. pylori strain 7.13 identified an oscillating pattern of cagT4SS function. The development of dysplasia or cancer selected for attenuated virulence phenotypes, but robust cagT4SS function could be restored upon infection of new hosts. Changes in the genetic composition of cagY mirrored cagT4SS function, although the mechanisms of cagY alterations differed in human isolates (mutations) versus gerbil isolates (addition/deletion of motifs). These results indicate that host carcinogenic phenotypes modify cagT4SS function via altering cagY, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.
Copyright ©2017, American Association for Cancer Research.
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Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade.
Williams MM, Lee L, Hicks DJ, Joly MM, Elion D, Rahman B, McKernan C, Sanchez V, Balko JM, Stricker T, Estrada MV, Cook RS
(2017) Mol Cancer Res 15: 259-268
Show Abstract · Added April 6, 2017
An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα(+) tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα(+) breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured in situ using Mcl-1/Bim proximity ligation assays. Importantly, MCL1 gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of BCL2 or BCL2L1 and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing.Implications: Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. Mol Cancer Res; 15(3); 259-68. ©2016 AACR.
©2016 American Association for Cancer Research.
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Variants in WFS1 and other Mendelian deafness genes are associated with cisplatin-associated ototoxicity.
Wheeler HE, Gamazon ER, Frisina R, Perez-Cervantes C, El Charif O, Mapes B, Fossa SD, Feldman D, Hamilton R, Vaughn DJ, Beard C, Fung C, Kollmannsberger C, Kim J, Mushiroda T, Kubo M, Ardeshir-Rouhani-Fard S, Einhorn LH, Cox N, Dolan ME, Travis L
(2016) Clin Cancer Res :
Show Abstract · Added April 13, 2017
PURPOSE - Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).
EXPERIMENTAL DESIGN - We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.
RESULTS - One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P=1.4x10(-8)). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P=0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n=18,620 patients, Bonferroni adjusted P<0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P-values in the GWAS (P=0.048).
CONCLUSIONS - We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pre-therapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses.
Copyright ©2016, American Association for Cancer Research.
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(18)F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials.
Wang Y, Ayres KL, Goldman DA, Dickler MN, Bardia A, Mayer IA, Winer E, Fredrickson J, Arteaga CL, Baselga J, Manning HC, Mahmood U, Ulaner GA
(2016) Clin Cancer Res :
Show Abstract · Added April 6, 2017
Purpose: Evaluate (18)F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials.Experimental Design: In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as ≥90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed.Results: Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved ≥90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I.Conclusions: FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials. Clin Cancer Res; 1-8. ©2016 AACR.
©2016 American Association for Cancer Research.
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PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Anti-tumor Immunity and Anti-PD1 Responses.
Sai J, Owens P, Novitiskiy SV, Hawkins OE, Vilgelm AE, Yang J, Sobolik-Delmaire T, Lavender N, Johnson AC, McClain C, Ayers GD, Kelley MC, Sanders M, Mayer IA, Moses HL, Boothby M, Richmond A
(2016) Clin Cancer Res :
Show Abstract · Added January 4, 2017
PURPOSE - Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered anti-tumor immunity.
EXPERIMENTAL DESIGN - The effect of PI3K inhibition on tumor growth, metastasis, and anti-tumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or PI3Kγ null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30mg/kg, QD) or vehicle treated mice and PI3Kγ null versus PI3Kγ WT mice. Based on the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30mg/kg, QD) and anti-PD1 (100μg, twice weekly) was evaluated in PyMT tumor bearing mice.
RESULTS - Our findings show that PI3K activity facilitates tumor growth and surprisingly, restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by host genetic deletion of PI3Kγ. The anti-tumor effect of PI3Kγ loss in host, but not tumor, was partially reversed by CD8+T cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared to either agent alone.
CONCLUSIONS - PI3K inhibition slows tumor growth, enhances anti-tumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple negative breast cancer.
Copyright ©2016, American Association for Cancer Research.
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Novel hybrid phenotype revealed in Small Cell Lung Cancer by a transcription factor network model that can explain tumor heterogeneity.
Udyavar AR, Wooten DJ, Hoeksema MD, Bansal M, Califano A, Estrada L, Schnell S, Irish JM, Massion PP, Quaranta V
(2016) Cancer Res :
Show Abstract · Added December 10, 2016
Small cell lung cancer (SCLC) is a devastating disease due to its propensity for early invasion and refractory relapse after initial treatment response. Although these aggressive traits have been associated with phenotypic heterogeneity, our understanding of this association remains incomplete. To fill this knowledge gap, we inferred a set of 33 transcription factors (TF) associated with gene signatures of the known neuroendocrine/epithelial (NE) and non-neuroendocrine/mesenchymal-like (ML) SCLC phenotypes. The topology of this SCLC TF network was derived from prior knowledge and simulated using Boolean modeling. These simulations predicted that the network settles into attractors, or TF expression patterns, that correlate with NE or ML phenotypes, suggesting that TF network dynamics underlie the emergence of heterogeneous SCLC phenotypes. However, several cell lines and patient tumor specimens failed to correlate with either the NE or ML attractors. By flow cytometry, single cells within these cell lines simultaneously expressed surface markers of both NE and ML differentiation, confirming the existence of a "hybrid" phenotype. Upon exposure to standard-of-care cytotoxic drugs or epigenetic modifiers, NE and ML cell populations converged toward the hybrid state, suggesting possible escape from treatment. Our findings indicate that SCLC phenotypic heterogeneity can be specified dynamically by attractor states of a master regulatory TF network. Thus, SCLC heterogeneity may be best understood as states within an epigenetic landscape. Understanding phenotypic transitions within this landscape may provide insights to clinical applications.
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Eph Receptor Tyrosine Kinases in Tumor Immunity.
Shiuan E, Chen J
(2016) Cancer Res 76: 6452-6457
Show Abstract · Added March 29, 2017
The family of Eph receptor tyrosine kinases and their ephrin ligands regulate a diverse array of physiologic processes, such as axonal guidance, bone remodeling, and immune cell development and trafficking. Eph/ephrin interactions have also been implicated in various pathologic processes, including inflammation, cancer, and tumor angiogenesis. Because Eph receptors play prominent roles in both the immune system and cancer, they likely impact the tumor immune microenvironment, an area in which Eph receptors remain understudied. Here, we provide the first comprehensive review of Eph receptors in the context of tumor immunity. With the recent rise of cancer immunotherapies as promising therapeutic interventions, further elucidation of the roles of Eph receptors in the tumor immune microenvironment will be critical for understanding and developing novel targets against tumor immune evasion. Cancer Res; 76(22); 6452-7. ©2016 AACR.
©2016 American Association for Cancer Research.
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Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus.
Harlow ML, Maloney N, Roland J, Guillen Navarro MJ, Easton MK, Kitchen-Goosen SM, Boguslawski EA, Madaj ZB, Johnson BK, Bowman MJ, D'Incalci M, Winn ME, Turner L, Hostetter G, Galmarini CM, Aviles PM, Grohar PJ
(2016) Cancer Res 76: 6657-6668
Show Abstract · Added June 27, 2017
There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma. Cancer Res; 76(22); 6657-68. ©2016 AACR.
©2016 American Association for Cancer Research.
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