Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 187

Publication Record

Connections

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.
1 Communities
2 Members
0 Resources
0 MeSH Terms
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.
0 Communities
1 Members
0 Resources
0 MeSH Terms
(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.
0 Communities
1 Members
0 Resources
0 MeSH Terms
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.
2 Communities
2 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 S, Tang N, Qin L, Emily CE, Guo Y, Knapp S, Beauchamp RD, Lee E, Wang J
(2016) Clin Cancer Res :
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 (CRC).
0 Communities
4 Members
0 Resources
0 MeSH Terms
Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics.
Haake SM, Li J, Bai Y, Kinose F, Fang B, Welsh EA, Zent R, Dhillon J, Pow-Sang JM, Chen YA, Koomen JM, Rathmell WK, Fishman M, Haura EB
(2016) Clin Cancer Res :
Show Abstract · Added August 8, 2016
Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes.
1 Communities
2 Members
0 Resources
0 MeSH Terms
A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.
Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL
(2017) Clin Cancer Res 23: 26-34
Show Abstract · Added April 6, 2017
PURPOSE - Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER(+)/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER(+) breast cancer refractory to endocrine therapy.
EXPERIMENTAL DESIGN - Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing.
RESULTS - Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER(+)/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER(+) breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. ©2016 AACR.
©2016 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
0 MeSH Terms
Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression.
Brooks SA, Khandani AH, Fielding JR, Lin W, Sills T, Lee Y, Arreola A, Milowsky MI, Wallen EM, Woods ME, Smith AB, Nielsen ME, Parker JS, Lalush DS, Rathmell WK
(2016) Clin Cancer Res 22: 2950-9
Show Abstract · Added August 8, 2016
Clear cell renal cell carcinoma (ccRCC) has recently been redefined as a highly heterogeneous disease. In addition to genetic heterogeneity, the tumor displays risk variability for developing metastatic disease, therefore underscoring the urgent need for tissue-based prognostic strategies applicable to the clinical setting. We have recently employed the novel PET/magnetic resonance (MR) image modality to enrich our understanding of how tumor heterogeneity can relate to gene expression and tumor biology to assist in defining individualized treatment plans.
0 Communities
1 Members
0 Resources
0 MeSH Terms
A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors.
Goff LW, Cohen RB, Berlin JD, de Braud FG, Lyshchik A, Noberasco C, Bertolini F, Carpentieri M, Stampino CG, Abbattista A, Wang E, Borghaei H
(2016) Clin Cancer Res 22: 2146-54
Show Abstract · Added May 7, 2016
Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors.
0 Communities
1 Members
0 Resources
0 MeSH Terms
InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma.
Ma Y, Tang N, Thompson RC, Mobley BC, Clark SW, Sarkaria JN, Wang J
(2016) Clin Cancer Res 22: 1767-76
MeSH Terms: Animals, Antineoplastic Agents, Cell Line, Tumor, Disease Models, Animal, Drug Resistance, Neoplasm, Glioblastoma, Humans, Insulin, Insulin-Like Growth Factor I, Mice, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Quinazolines, Receptor, Epidermal Growth Factor, Receptor, IGF Type 1, Receptor, Insulin, Signal Transduction, Tumor Burden, Xenograft Model Antitumor Assays
Show Abstract · Added April 18, 2017
PURPOSE - Aberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma.
EXPERIMENTAL DESIGN - We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy cotargeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R).
RESULTS - Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not express InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors.
CONCLUSIONS - Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma.
©2015 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
MeSH Terms