Publications by authors named "Amanda J Redig"

44 Publications

A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers.

Cancer Cell 2020 05 2;37(5):705-719.e6. Epub 2020 Apr 2.

Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatments are lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein HOXC10, largely due to unappreciated defects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograft and PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replication complex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppress pre-RC proteins in cycling cells, triggering stalled replication, DNA damage, and death. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset of NSCLCs with a targetable epigenetic vulnerability.
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http://dx.doi.org/10.1016/j.ccell.2020.03.004DOI Listing
May 2020

Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib.

JAMA Oncol 2018 11;4(11):1527-1534

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood.

Objective: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.

Design, Setting, And Participants: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.

Main Outcomes And Measures: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.

Results: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).

Conclusions And Relevance: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
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http://dx.doi.org/10.1001/jamaoncol.2018.2969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240476PMC
November 2018

Amplification of Wild-type Imparts Resistance to Crizotinib in Exon 14 Mutant Non-Small Cell Lung Cancer.

Clin Cancer Res 2018 12 2;24(23):5963-5976. Epub 2018 Aug 2.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Purpose: MET inhibitors can be effective therapies in patients with exon 14 (ex14) mutant non-small cell lung cancer (NSCLC). However, long-term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild-type (WT) as a molecular mechanism behind crizotinib resistance in three cases of ex14-mutant NSCLC and propose a combination therapy to target it.

Experimental Design: The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant ex14-mutant patient tumor with massive focal amplification of WT . To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy and using viability and apoptotic assays.

Results: amplification is a recurrent genetic event in crizotinib-resistant ex14-mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition.

Conclusions: Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by amplification in ex14-mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279568PMC
December 2018

Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation.

Radiother Oncol 2018 03 3;126(3):511-518. Epub 2018 Feb 3.

Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, USA.

Background: Pemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases.

Materials/methods: We identified 149 patients with adenocarcinoma of the lung and newly diagnosed brain metastases without a targetable mutation receiving stereotactic radiation. Kaplan-Meier plots and Cox regression were employed to assess whether use of pemetrexed was associated with intracranial disease control and radiation necrosis.

Results: Among the entire cohort, 105 patients received pemetrexed while 44 did not. Among patients who were chemotherapy-naïve, use of pemetrexed (n = 43) versus alternative regimens after stereotactic radiation (n = 24) was associated with a reduced likelihood of developing new brain metastases (HR 0.42, 95% CI 0.22-0.79, p = 0.006) and a reduced need for salvage brain-directed radiation therapy (HR 0.36, 95% CI 0.18-0.73, p = 0.005). Pemetrexed use was associated with increased radiographic necrosis. (HR 2.70, 95% CI 1.09-6.70, p = 0.03).

Conclusions: Patients receiving pemetrexed after brain-directed stereotactic radiation appear to benefit from improved intracranial disease control at the possible expense of radiation-related radiographic necrosis. Whether symptomatic radiation injury occurs more frequently in patients receiving pemetrexed requires further study.
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http://dx.doi.org/10.1016/j.radonc.2018.01.005DOI Listing
March 2018

Raising the bar: the future of EGFR inhibition in non-small lung cancer.

Authors:
Amanda J Redig

Transl Lung Cancer Res 2017 Dec;6(Suppl 1):S58-S61

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

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http://dx.doi.org/10.21037/tlcr.2017.10.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750143PMC
December 2017

Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study.

Neuro Oncol 2017 Oct;19(11):1511-1521

Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts; Department of Biostatistics, Harvard T. H. Chan School of Public Health, and Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Background: Brain metastases are associated with significant morbidity and mortality. Population-level data describing the incidence and prognosis of patients with brain metastases are lacking. The aim of this study was to characterize the incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy using recently released data from the Surveillance, Epidemiology, and End Results (SEER) program.

Methods: We identified 1302166 patients with diagnoses of nonhematologic malignancies originating outside of the CNS between 2010 and 2013 and described the incidence proportion and survival of patients with brain metastases.

Results: We identified 26430 patients with brain metastases at diagnosis of cancer. Patients with small cell and non-small cell lung cancer displayed the highest rates of identified brain metastases at diagnosis; among patients presenting with metastatic disease, patients with melanoma (28.2%), lung adenocarcinoma (26.8%), non-small cell lung cancer not otherwise specified/other lung cancer (25.6%), small cell lung cancer (23.5%), squamous cell carcinoma of the lung (15.9%), bronchioloalveolar carcinoma (15.5%), and renal cancer (10.8%) had an incidence proportion of identified brain metastases of >10%. Patients with brain metastases secondary to prostate cancer, bronchioloalveolar carcinoma, and breast cancer displayed the longest median survival (12.0, 10.0, and 10.0 months, respectively).

Conclusions: In this study we provide generalizable estimates of the incidence and prognosis for patients with brain metastases at diagnosis of a systemic malignancy. These data may allow for appropriate utilization of brain-directed imaging as screening for subpopulations with cancer and have implications for clinical trial design and counseling of patients regarding prognosis.
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http://dx.doi.org/10.1093/neuonc/nox077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737512PMC
October 2017

Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.

Nat Commun 2017 04 7;8:14922. Epub 2017 Apr 7.

Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02144, USA.

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.
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http://dx.doi.org/10.1038/ncomms14922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385585PMC
April 2017

Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.

Cancer Res 2017 05 31;77(10):2712-2721. Epub 2017 Mar 31.

Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.

Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-3404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596996PMC
May 2017

KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer.

Elife 2017 02 1;6. Epub 2017 Feb 1.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.

Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of , a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.
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http://dx.doi.org/10.7554/eLife.18970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305212PMC
February 2017

Targeting BET bromodomain proteins in solid tumors.

Oncotarget 2016 08;7(33):53997-54009

Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

There is increasing interest in inhibitors targeting BET (bromodomain and extra-terminal) proteins because of the association between this family of proteins and cancer progression. BET inhibitors were initially shown to have efficacy in hematologic malignancies; however, a number of studies have now shown that BET inhibitors can also block progression of non-hematologic malignancies. In this Review, we summarize the efficacy of BET inhibitors in select solid tumors; evaluate the role of BET proteins in mediating resistance to current targeted therapies; and consider potential toxicities of BET inhibitors. We also evaluate recently characterized mechanisms of resistance to BET inhibitors; summarize ongoing clinical trials with these inhibitors; and discuss potential future roles of BET inhibitors in patients with solid tumors.
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http://dx.doi.org/10.18632/oncotarget.9804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288238PMC
August 2016

A Prospective Evaluation of Circulating Tumor Cells and Cell-Free DNA in EGFR-Mutant Non-Small Cell Lung Cancer Patients Treated with Erlotinib on a Phase II Trial.

Clin Cancer Res 2016 Dec 8;22(24):6010-6020. Epub 2016 Jun 8.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Genotype-directed therapy is the standard of care for advanced non-small cell lung cancer (NSCLC), but obtaining tumor tissue for genotyping remains a challenge. Circulating tumor cell (CTC) or cell-free DNA (cfDNA) analysis may allow for noninvasive evaluation. This prospective trial evaluated CTCs and cfDNA in EGFR-mutant NSCLC patients treated with erlotinib until progression.

Experimental Design: EGFR-mutant NSCLC patients were enrolled in a phase II trial of erlotinib. Blood was collected at baseline, every 2 months on study, and at disease progression. Plasma genotyping was performed by droplet digital PCR for EGFR19del, L858R, and T790M. CTCs were isolated by CellSave, enumerated, and analyzed by immunofluorescence for CD45 and pan-cytokeratin and EGFR and MET FISH were also performed. Rebiopsy was performed at disease progression.

Results: Sixty patients were enrolled; 44 patients discontinued therapy for disease progression. Rebiopsy occurred in 35 of 44 patients (80%), with paired CTC/cfDNA analysis in 41 of 44 samples at baseline and 36 of 44 samples at progression. T790M was identified in 23 of 35 (66%) tissue biopsies and 9 of 39 (23%) cfDNA samples. CTC analysis at progression identified MET amplification in 3 samples in which tissue analysis could not be performed. cfDNA analysis identified T790M in 2 samples in which rebiopsy was not possible. At diagnosis, high levels of cfDNA but not high levels of CTCs correlated with progression-free survival.

Conclusions: cfDNA and CTCs are complementary, noninvasive assays for evaluation of acquired resistance to first-line EGFR TKIs and may expand the number of patients in whom actionable genetic information can be obtained at acquired resistance. Serial cfDNA monitoring may offer greater clinical utility than serial monitoring of CTCs. Clin Cancer Res; 22(24); 6010-20. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0909DOI Listing
December 2016

No Target Left Behind: Improving Therapeutic Options for ERBB2-Mutant Non-Small Cell Lung Cancer.

J Thorac Oncol 2016 06;11(6):784-6

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Harvard Medical School, Harvard University, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2016.04.009DOI Listing
June 2016

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.

Nat Commun 2016 Feb 17;7:10501. Epub 2016 Feb 17.

Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
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http://dx.doi.org/10.1038/ncomms10501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757784PMC
February 2016

Clinical and Molecular Characteristics of NF1-Mutant Lung Cancer.

Clin Cancer Res 2016 07 9;22(13):3148-56. Epub 2016 Feb 9.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: NF1 is a tumor suppressor that negatively regulates Ras signaling. NF1 mutations occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of NF1 mutant lung cancers with comparison to tumors with KRAS mutations.

Experimental Design: Between July 2013 and October 2014, 591 non-small cell lung cancer (NSCLC) tumors underwent targeted next-generation sequencing in a 275 gene panel that evaluates gene mutations and genomic rearrangements. NF1 and KRAS cohorts were identified, with subsequent clinical and genomic analysis.

Results: Among 591 patients, 60 had NF1 mutations (10%) and 141 (24%) had KRAS mutations. 15 NF1 mutations (25%) occurred with other oncogenic mutations [BRAF (2); ERBB2 (2); KRAS (9); HRAS (1); NRAS (1)]. There were 72 unique NF1 variants. NF1 tumor pathology was diverse, including both adenocarcinoma (36, 60%) and squamous cell carcinoma (10, 17%). In contrast, KRAS mutations occurred predominantly in adenocarcinoma (136, 96%). Both mutations were common in former/current smokers. Among NF1 tumors without concurrent oncogenic alterations, TP53 mutations/2-copy deletions occurred more often (33, 65%) than with KRAS mutation (46, 35%; P < 0.001). No difference between cohorts was seen with other tumor suppressors.

Conclusions: NF1 mutations define a unique population of NSCLC. NF1 and KRAS mutations present in similar patient populations, but NF1 mutations occur more often with other oncogenic alterations and TP53 mutations. Therapeutic strategies targeting KRAS activation, including inhibitors of MAP kinase signaling, may warrant investigation in NF1 mutant tumors. Tumor-suppressor inactivation patterns may help further define novel treatment strategies. Clin Cancer Res; 22(13); 3148-56. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129179PMC
July 2016

Basket trials and the evolution of clinical trial design in an era of genomic medicine.

J Clin Oncol 2015 Mar 9;33(9):975-7. Epub 2015 Feb 9.

Dana-Farber Cancer Institute, Harvard Medical School, and Brigham and Women's Hospital, Boston, MA

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http://dx.doi.org/10.1200/JCO.2014.59.8433DOI Listing
March 2015

Pathogenesis and clinical implications of HIV-related anemia in 2013.

Hematology Am Soc Hematol Educ Program 2013 ;2013:377-81

1Department of Medicine, and.

Anemia is a common feature of HIV-related disease and has been uniformly demonstrated to be an independent predictor of morbidity and mortality. Although anemia often responds to combination antiretroviral therapy, many patients remain anemic despite therapy and such persistent anemia continues to negatively affect prognosis regardless of drug response. Anemia is also a common feature of normal aging. We postulate that the pathophysiology of anemia in HIV, especially that which persists in the face of combination antiretroviral therapy, is a reflection of underlying proinflammatory pathways that are also thought to contribute to anemia in the elderly, as well as other age-related chronic diseases such as cardiovascular disease and chronic obstructive pulmonary disease. This suggests that HIV induces inflammatory pathways that are associated with a pattern of accelerated aging and that anemia is a biomarker of these processes. A better understanding of the pathophysiology of HIV-related anemia may provide important entry points for improving the chronic manifestations of HIV-related disease.
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http://dx.doi.org/10.1182/asheducation-2013.1.377DOI Listing
July 2014

Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression.

Biochem J 2012 Jan;441(2):541-52

Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

PDAC (pancreatic ductal adenocarcinoma) is among the most deadly of human malignances. A hallmark of the disease is a pronounced collagen-rich fibrotic extracellular matrix known as the desmoplastic reaction. Intriguingly, it is precisely these areas of fibrosis in which human PDAC tumours demonstrate increased expression of a key collagenase, MT1-MMP [membrane-type 1 MMP (matrix metalloproteinase); also known as MMP-14]. Furthermore, a cytokine known to mediate fibrosis in vivo, TGF-β1 (transforming growth factor-β1), is up-regulated in human PDAC tumours and can promote MT1-MMP expression. In the present review, we examine the regulation of PDAC progression through the interplay between type I collagen (the most common extracellular matrix present in human PDAC tumours), MT1-MMP and TGF-β1. Specifically, we examine the way in which signalling events through these pathways mediates invasion, regulates microRNAs and contributes to chemoresistance.
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http://dx.doi.org/10.1042/BJ20111240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215985PMC
January 2012

A piece of my mind. The patient's patients.

Authors:
Amanda J Redig

JAMA 2011 Jul;306(3):247-8

Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1001/jama.2011.934DOI Listing
July 2011

Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors.

Clin Cancer Res 2011 Jul 17;17(13):4378-88. Epub 2011 Mar 17.

Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University Medical School and Jesse Brown VA Medical Center, Chicago, Illinois, USA.

Purpose: To determine whether mTORC2 and rapamycin-insensitive (RI)-mTORC1 complexes are present in acute myeloid leukemia (AML) cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors.

Experimental Design: Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell-proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor-colony formation.

Results: mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. RI-mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027 blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro.

Conclusions: Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-2285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131493PMC
July 2011

The monsters of medicine: Political violence and the physician.

Authors:
Amanda J Redig

Pharos Alpha Omega Alpha Honor Med Soc 2011 ;74(1):16-22

Department of Medicine, Brigham and Women's Hospital, Boston, USA.

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March 2011

Regulation of mammalian target of rapamycin and mitogen activated protein kinase pathways by BCR-ABL.

Leuk Lymphoma 2011 Feb;52 Suppl 1:45-53

Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University Medical School and Jesse Brown VA Medical Center, Chicago, IL, USA.

A large body of evidence has established that BCR-ABL regulates engagement and activation of mammalian target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling cascades. mTOR-mediated signals, as well as signals transduced by ERK, JNK, and p38 MAPK, are important components of the aberrant signaling induced by BCR-ABL. Such deregulation of mTOR or MAPK pathways contributes to BCR-ABL leukemogenesis, and their targeting with selective inhibitors provides an approach to enhance antileukemic responses and/or overcome leukemic cell resistance in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review explores recent advances in our understanding of mTOR and MAPK signaling in BCR-ABL-expressing leukemias and discusses the potential therapeutic targeting of these pathways in CML and Ph+ ALL.
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http://dx.doi.org/10.3109/10428194.2010.546919DOI Listing
February 2011

Incorporating fertility preservation into the care of young oncology patients.

Cancer 2011 Jan;117(1):4-10

Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

As the number of cancer survivors continues to increase, oncologists are faced with the challenge of providing cancer therapy to patients who may 1 day want to have children. Yet, gonadotoxic cancer treatments can compromise future fertility, either temporarily or permanently. There are established means of preserving fertility before cancer treatment; specifically, sperm cryopreservation for men and in vitro fertilization and embryo cryopreservation for women. Several innovative techniques are being actively investigated, including oocyte and ovarian follicle cryopreservation, ovarian tissue transplantation, and in vitro follicle maturation, which may expand the number of fertility preservation choices for young cancer patients. Fertility preservation may also require some modification of cancer therapy; thus, patients' wishes regarding future fertility and available fertility preservation alternatives should be discussed before initiation of therapy. This commentary provides an overview of the range of fertility preservation options currently available and under development, using case-based discussions to illustrate ways in which fertility preservation can be incorporated into oncology care. Cases involving breast cancer, testicular cancer, and rectal cancer are described to illustrate fertility issues experienced by male and female patients, as well as to provide examples of strategies for modifying surgical, medical, and radiation therapy to spare fertility. Current guidelines in oncology and reproductive medicine are also reviewed to underscore the importance of communicating fertility preservation options to young patients with cancer.
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http://dx.doi.org/10.1002/cncr.25398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057679PMC
January 2011

Metabolic syndrome after hormone-modifying therapy: risks associated with antineoplastic therapy.

Oncology (Williston Park) 2010 Aug;24(9):839-44

Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

The incidence of metabolic syndrome is rapidly increasing. Metabolic syndrome is associated with elevated morbidity and mortality secondary to cardiovascular disease, insulin resistance, and hepatic dysfunction. A body of evidence has already implicated metabolic syndrome as a cancer risk factor; emerging evidence now suggests that cancer survivors themselves may be at risk for developing metabolic syndrome as a result of their anti-cancer therapy. Treatment of both breast cancer and prostate cancer often involves hormone-modifying agents that have been linked to features of metabolic syndrome. Androgen suppression in men with prostate cancer is associated with dyslipidemia, increasing risk of cardiovascular disease, and insulin resistance. Anti-estrogen therapy in women with breast cancer can affect lipid profiles, cardiovascular risk, and liver function. Similar findings have been noted in men with testicular cancer treated with chemotherapy. In addition, several emerging therapies, including mammalian target of rapamycin (mTOR) inhibitors and targeted kinase inhibitors, are increasingly associated with some features of metabolic syndrome. As the number of cancer survivors continues to grow, consideration of these factors and of the risk of metabolic syndrome will become increasingly important when choosing between therapy options and managing long-term follow-up.
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August 2010

Rho-ROCK-myosin signaling mediates membrane type 1 matrix metalloproteinase-induced cellular aggregation of keratinocytes.

J Biol Chem 2010 Sep 6;285(36):28363-72. Epub 2010 Jul 6.

Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.

Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP14), which is associated with extracellular matrix (ECM) breakdown in squamous cell carcinoma (SCC), promotes tumor formation and epithelial-mesenchymal transition. However, in this report we demonstrate that MT1-MMP, by cleaving the underlying ECM, causes cellular aggregation of keratinocytes and SCC cells. Treatment with an MMP inhibitor abrogated MT1-MMP-induced phenotypic changes, but decreasing E-cadherin expression did not affect MT1-MMP-induced cellular aggregation. As ROCK1/2 can regulate cell-cell and cell-ECM interaction, we examined its role in mediating MT1-MMP-induced phenotypic changes. Blocking ROCK1/2 expression or activity abrogated the cellular aggregation resulting from MT1-MMP expression. Additionally, blocking Rho and non-muscle myosin attenuated MT1-MMP-induced phenotypic changes. Moreover, SCC cells expressing only the catalytically active MT1-MMP protein demonstrated increased cellular aggregation and increased myosin II activity in vivo when injected subcutaneously into nude mice. Together, these results demonstrate that expression of MT1-MMP may be anti-tumorigenic in keratinocytes by promoting cellular aggregation.
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http://dx.doi.org/10.1074/jbc.M110.146019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934700PMC
September 2010
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