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C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3KInhibitors.
Croessmann S, Sheehan JH, Lee KM, Sliwoski G, He J, Nagy R, Riddle D, Mayer IA, Balko JM, Lanman R, Miller VA, Cantley LC, Meiler J, Arteaga CL
(2018) Clin Cancer Res 24: 1426-1435
Show Abstract · Added March 14, 2018
We describe herein a novel P447_L455 deletion in the C2 domain ofin a patient with an ERbreast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Althoughdeletions are relatively rare, a significant portion of deletions cluster within amino acids 446-460 of the C2 domain, suggesting these residues are critical for p110α function.A computational structural model ofin complex with the p85 regulatory subunit and MCF10A cells expressingandwere used to understand the phenotype of C2 domain deletions.Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Coimmunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared with wild-type p110α. The MCF10A cells expressingC2 deletions exhibited growth factor-independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All these changes were ablated by alpelisib treatment.C2 domain deletions ingenerate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors..
©2017 American Association for Cancer Research.
0 Communities
2 Members
0 Resources
0 MeSH Terms
The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations-The Lung Cancer Mutation Consortium (LCMC2).
Aisner DL, Sholl LM, Berry LD, Rossi MR, Chen H, Fujimoto J, Moreira AL, Ramalingam SS, Villaruz LC, Otterson GA, Haura E, Politi K, Glisson B, Cetnar J, Garon EB, Schiller J, Waqar SN, Sequist LV, Brahmer J, Shyr Y, Kugler K, Wistuba II, Johnson BE, Minna JD, Kris MG, Bunn PA, Kwiatkowski DJ, LCMC2 investigators
(2018) Clin Cancer Res 24: 1038-1047
Show Abstract · Added April 3, 2018
Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas.Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC.The use of targeted therapies in patients withorp.V600E mutations,, orrearrangements, oramplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in//, when compared with 75 never smokers with the same alterations. In addition, coexistingmutations were associated with shorter survival among patients with, oralterations.Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment..
©2017 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
0 MeSH Terms
T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling.
Josefsson SE, Huse K, Kolstad A, Beiske K, Pende D, Steen CB, Inderberg EM, Lingjærde OC, Østenstad B, Smeland EB, Levy R, Irish JM, Myklebust JH
(2018) Clin Cancer Res 24: 870-881
Show Abstract · Added December 15, 2017
T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets.Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry.TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored uponculture. The costimulatory receptor CD226 was downregulated in TIGITcompared with TIGITCD8 FL T cells, further skewing the balance toward immunosuppression.TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients..
©2017 American Association for Cancer Research.
1 Communities
1 Members
0 Resources
0 MeSH Terms
Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ERBreast Cancer.
Formisano L, Stauffer KM, Young CD, Bhola NE, Guerrero-Zotano AL, Jansen VM, Estrada MM, Hutchinson KE, Giltnane JM, Schwarz LJ, Lu Y, Balko JM, Deas O, Cairo S, Judde JG, Mayer IA, Sanders M, Dugger TC, Bianco R, Stricker T, Arteaga CL
(2017) Clin Cancer Res 23: 6138-6150
Show Abstract · Added March 14, 2018
amplification occurs in approximately 15% of estrogen receptor-positive (ER) human breast cancers. We investigated mechanisms by whichamplification confers antiestrogen resistance to ERbreast cancer.ERtumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER/-amplified breast cancer cells, and patient-derived xenografts (PDX) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by coimmunoprecipitation and proximity ligation, ER genomic activity by ChIP sequencing, and gene expression by RT-PCR.ER/-amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER/amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER/-amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER/amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.sThese data suggest the ERα pathway remains active in estrogen-deprived ER/-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists..
©2017 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
0 MeSH Terms
Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
Dolan ME, El Charif O, Wheeler HE, Gamazon ER, Ardeshir-Rouhani-Fard S, Monahan P, Feldman DR, Hamilton RJ, Vaughn DJ, Beard CJ, Fung C, Kim J, Fossa SD, Hertz DL, Mushiroda T, Kubo M, Einhorn LH, Cox NJ, Travis LB, Platinum Study Group
(2017) Clin Cancer Res 23: 5757-5768
Show Abstract · Added October 27, 2017
Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs).TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial.Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06;= 2 × 10), smoking (OR, 1.54;= 0.004), excess drinking (OR, 1.83;= 0.007), and hypertension (OR, 1.61;= 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56;= 2.6 × 10) and weight gain adjusted for years since treatment (OR per Δkg/m, 1.05;= 0.004). PrediXcan identified lower expressions ofandand higherexpression as associated with CisIPN (value for each < 5 × 10) with replication ofmeeting significance criteria (Fisher combined= 0.0089).CisIPN is associated with age, modifiable risk factors, and genetically determined expression level ofFurther study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN..
©2017 American Association for Cancer Research.
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1 Members
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0 MeSH Terms
A Randomized Phase II Neoadjuvant Study of Cisplatin, Paclitaxel With or Without Everolimus in Patients with Stage II/III Triple-Negative Breast Cancer (TNBC): Responses and Long-term Outcome Correlated with Increased Frequency of DNA Damage Response Gene Mutations, TNBC Subtype, AR Status, and Ki67.
Jovanović B, Mayer IA, Mayer EL, Abramson VG, Bardia A, Sanders ME, Kuba MG, Estrada MV, Beeler JS, Shaver TM, Johnson KC, Sanchez V, Rosenbluth JM, Dillon PM, Forero-Torres A, Chang JC, Meszoely IM, Grau AM, Lehmann BD, Shyr Y, Sheng Q, Chen SC, Arteaga CL, Pietenpol JA
(2017) Clin Cancer Res 23: 4035-4045
Show Abstract · Added April 9, 2017
Because of inherent disease heterogeneity, targeted therapies have eluded triple-negative breast cancer (TNBC), and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine whether the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic antitumor effects in TNBC.Patients with stage II/III 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 pathologic complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome.Between 2009 and 2013, 145 patients were accrued; 36% of patients in the everolimus arm and 49% of 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.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..
©2017 American Association for Cancer Research.
1 Communities
2 Members
0 Resources
0 MeSH Terms
Variants inand Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity.
Wheeler HE, Gamazon ER, Frisina RD, Perez-Cervantes C, El Charif O, Mapes B, Fossa SD, Feldman DR, Hamilton RJ, Vaughn DJ, Beard CJ, Fung C, Kollmannsberger C, Kim J, Mushiroda T, Kubo M, Ardeshir-Rouhani-Fard S, Einhorn LH, Cox NJ, Dolan ME, Travis LB
(2017) Clin Cancer Res 23: 3325-3333
Show Abstract · Added April 13, 2017
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).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.One SNP, rs62283056, in the first intron of Mendelian deafness gene(wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) formet genome-wide significance for association with CAO (= 1.4 × 10). 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 (= 0.035). The association between decreasedexpression and hearing loss was replicated in an independent BioVU cohort (= 18,620 patients, Bonferroni adjusted< 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 lowvalues in the GWAS (= 0.048).We show for the first time the role ofin CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses..
©2016 American Association for Cancer Research.
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1 Members
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0 MeSH Terms
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
(2017) Clin Cancer Res 23: 3053-3060
MeSH Terms: Adult, Aged, Biomarkers, Pharmacological, Breast Neoplasms, Cinnamates, Dose-Response Relationship, Drug, Estradiol, Estrogen Receptor alpha, Female, Humans, Indazoles, Middle Aged, Molecular Imaging, Molecular Targeted Therapy, Positron Emission Tomography Computed Tomography, Receptors, Estrogen, Tamoxifen
Show Abstract · Added April 6, 2017
EvaluateF-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.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.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.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..
©2016 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
17 MeSH Terms
PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses.
Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J, Sobolik T, Lavender N, Johnson AC, McClain C, Ayers GD, Kelley MC, Sanders M, Mayer IA, Moses HL, Boothby M, Richmond A
(2017) Clin Cancer Res 23: 3371-3384
Show Abstract · Added January 4, 2017
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 antitumor immunity.The effect of PI3K inhibition on tumor growth, metastasis, and antitumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or-null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor-infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30 mg/kg, every day) or vehicle-treated mice andversusmice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 μg, twice weekly) was evaluated in PyMT tumor-bearing mice.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 genetic deletion ofin the host. The antitumor effect ofloss in host, but not tumor, was partially reversed by CD8T-cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared with either agent alone.PI3K inhibition slows tumor growth, enhances antitumor 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..
©2016 American Association for Cancer Research.
2 Communities
3 Members
0 Resources
0 MeSH Terms
The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer.
Ma Y, Wang L, Neitzel LR, Loganathan SN, Tang N, Qin L, Crispi EE, Guo Y, Knapp S, Beauchamp RD, Lee E, Wang J
(2017) Clin Cancer Res 23: 2027-2037
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Mice, Mice, Nude, Nuclear Proteins, Real-Time Polymerase Chain Reaction, Transcription Factors, Xenograft Model Antitumor Assays
Show Abstract · Added November 19, 2016
The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer.Using a panel of molecularly defined colorectal cancer cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches.BET inhibitors as monotherapy moderately reduced colorectal cancer cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized colorectal cancer cells to BET inhibitors, leading to potent apoptosis and MYC downregulationandA combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous colorectal cancer xenografts.Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in colorectal cancer and propose an effective combination strategy for the treatment of colorectal cancer..
©2016 American Association for Cancer Research.
0 Communities
4 Members
0 Resources
17 MeSH Terms