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Wood, Kris Cameron

Positions:

Assistant Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Assistant Professor of Biomedical Engineering

Biomedical Engineering
Pratt School of Engineering

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 2002

B.S. — University of Kentucky at Lexington

Ph.D. 2007

Ph.D. — Massachusetts Institute of Technology

News:

Grants:

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2022

Selectively targeting apoptosis in PIK3CA mutant colorectal cancers

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 12, 2016
End Date
July 31, 2021

Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2017
End Date
June 30, 2021

Bioinformatics and Computational Biology Training Program

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2005
End Date
June 30, 2021

Genetics Training Grant

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 1979
End Date
June 30, 2020

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Pharmacological Sciences Training Program

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2020

Topological Methods for Morphology: Classifying Shape and Function via Dictionary Learning

Administered By
Statistical Science
AwardedBy
Columbia University
Role
Co-Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2020

Pharmacology Industry Internships for Ph.D. Students

Administered By
Pharmacology & Cancer Biology
AwardedBy
American Society for Pharmacology and Experimental Therapeutics
Role
Participating Faculty Member
Start Date
January 01, 2017
End Date
December 31, 2019

Targeting the Hippo pathway in Ras-driven rhabdomyosarcoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
V Foundation for Cancer Research
Role
Collaborator
Start Date
November 01, 2016
End Date
October 31, 2019

Targeting differential apoptosis regulation in triple negative breast cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
September 30, 2016
End Date
September 29, 2019

Unmasking targetable dependencies in cancer with intrinsic or acquired resistance to anti-cancer therapies

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2017
End Date
August 31, 2019

Exploring BCL-XL addiction in pancreatic ductal adenocarcinoma

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2016
End Date
March 31, 2019

RalA signal transduction

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
February 01, 2002
End Date
March 31, 2019

Exploiting collateral sensitivity to target kinase inhibitor-resistant lung cancers

Administered By
Pharmacology & Cancer Biology
AwardedBy
Burroughs Wellcome Fund
Role
Principal Investigator
Start Date
November 01, 2017
End Date
October 31, 2018

Integration of signaling and metabolic pathways in the regulation of EMT

Administered By
Pharmacology & Cancer Biology
AwardedBy
US-Israel Binational Science Foundation
Role
Principal Investigator
Start Date
October 01, 2016
End Date
September 30, 2018

Profiling Gene Interactions in the Human Kinome

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Science Foundation
Role
Principal Investigator
Start Date
September 01, 2015
End Date
August 31, 2018

Identification of synthetic lethal interactors in pancreatic cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
September 01, 2015
End Date
June 30, 2018

Targeting undruggable oncogenes through the epigenome

Administered By
Pharmacology & Cancer Biology
AwardedBy
Element Genomics, Inc.
Role
Principal Investigator
Start Date
June 09, 2017
End Date
June 08, 2018

Designing durable apoptosis-targeting therapies for acute myeloid leukemia

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2018

Defining new combination therapies for high-grade serous ovarian cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
Ovarian Cancer Research Fund, Inc.
Role
Principal Investigator
Start Date
February 01, 2015
End Date
January 31, 2018

Mapping the landscape of drug sensitizers in human cancers

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2015
End Date
September 30, 2017

Genomic and Computational Approaches for Development of Novel Anticancer Therapies

Administered By
Pharmacology & Cancer Biology
AwardedBy
Schlumberger Foundation
Role
Principal Investigator
Start Date
August 23, 2015
End Date
August 31, 2017

Systematic design of CDK4/6 inhibitor-based combination therapies

Administered By
Pharmacology & Cancer Biology
AwardedBy
G1 Therapeutics Inc.
Role
Principal Investigator
Start Date
April 01, 2015
End Date
October 28, 2016

A Platform for Real-time Drug Profiling of Patient-Derived Melanomas

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Sponsor
Start Date
August 01, 2014
End Date
July 31, 2016

Cancer Biology Training Grant

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Cancer Institute
Role
Mentor
Start Date
July 01, 1993
End Date
March 31, 2016

Systematic dissection of the breast cancer microenvironment using the MicroSCALE Toolkit

Administered By
Pharmacology & Cancer Biology
AwardedBy
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
December 01, 2013
End Date
November 30, 2015
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Publications:

A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.

Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.

Authors
Anderson, GR; Winter, PS; Lin, KH; Nussbaum, DP; Cakir, M; Stein, EM; Soderquist, RS; Crawford, L; Leeds, JC; Newcomb, R; Stepp, P; Yip, C; Wardell, SE; Tingley, JP; Ali, M; Xu, M; Ryan, M; McCall, SJ; McRee, AJ; Counter, CM; Der, CJ; Wood, KC
MLA Citation
Anderson, GR, Winter, PS, Lin, KH, Nussbaum, DP, Cakir, M, Stein, EM, Soderquist, RS, Crawford, L, Leeds, JC, Newcomb, R, Stepp, P, Yip, C, Wardell, SE, Tingley, JP, Ali, M, Xu, M, Ryan, M, McCall, SJ, McRee, AJ, Counter, CM, Der, CJ, and Wood, KC. "A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution." Cell reports 20.4 (July 2017): 999-1015.
PMID
28746882
Source
epmc
Published In
Cell Reports
Volume
20
Issue
4
Publish Date
2017
Start Page
999
End Page
1015
DOI
10.1016/j.celrep.2017.07.006

Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance.

KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. This difference is ascribed to common codon bias in HRAS, which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRASQ61 mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRASG12-driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS-driven resistance and provide a rationale for targeting translation to overcome resistance.

Authors
Ali, M; Kaltenbrun, E; Anderson, GR; Stephens, SJ; Arena, S; Bardelli, A; Counter, CM; Wood, KC
MLA Citation
Ali, M, Kaltenbrun, E, Anderson, GR, Stephens, SJ, Arena, S, Bardelli, A, Counter, CM, and Wood, KC. "Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance." Nature communications 8 (June 8, 2017): 15617-.
PMID
28593995
Source
epmc
Published In
Nature Communications
Volume
8
Publish Date
2017
Start Page
15617
DOI
10.1038/ncomms15617

Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection.

Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.

Authors
Price, AM; Dai, J; Bazot, Q; Patel, L; Nikitin, PA; Djavadian, R; Winter, PS; Salinas, CA; Barry, AP; Wood, KC; Johannsen, EC; Letai, A; Allday, MJ; Luftig, MA
MLA Citation
Price, AM, Dai, J, Bazot, Q, Patel, L, Nikitin, PA, Djavadian, R, Winter, PS, Salinas, CA, Barry, AP, Wood, KC, Johannsen, EC, Letai, A, Allday, MJ, and Luftig, MA. "Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection." eLife 6 (April 20, 2017).
Website
http://hdl.handle.net/10161/14611
PMID
28425914
Source
epmc
Published In
eLife
Volume
6
Publish Date
2017
DOI
10.7554/elife.22509

Suppressing oncogenic transcription with a little healthy competition.

Therapeutic strategies that stabilize wild-type MLL proteins have selective activity in MLL-rearranged leukemias.

Authors
Wood, KC
MLA Citation
Wood, KC. "Suppressing oncogenic transcription with a little healthy competition." Science translational medicine 9.374 (January 2017).
PMID
28123073
Source
epmc
Published In
Science Translational Medicine
Volume
9
Issue
374
Publish Date
2017
DOI
10.1126/scitranslmed.aal5000

An EXITS strategy for decreasing cancer risk in women.

Authors
Wood, KC
MLA Citation
Wood, KC. "An EXITS strategy for decreasing cancer risk in women." Science translational medicine 8.368 (December 2016): 368ec197-.
PMID
27928023
Source
epmc
Published In
Science Translational Medicine
Volume
8
Issue
368
Publish Date
2016
Start Page
368ec197
DOI
10.1126/scitranslmed.aal2806

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.

Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

Authors
Anderson, GR; Wardell, SE; Cakir, M; Crawford, L; Leeds, JC; Nussbaum, DP; Shankar, PS; Soderquist, RS; Stein, EM; Tingley, JP; Winter, PS; Zieser-Misenheimer, EK; Alley, HM; Yllanes, A; Haney, V; Blackwell, KL; McCall, SJ; McDonnell, DP; Wood, KC
MLA Citation
Anderson, GR, Wardell, SE, Cakir, M, Crawford, L, Leeds, JC, Nussbaum, DP, Shankar, PS, Soderquist, RS, Stein, EM, Tingley, JP, Winter, PS, Zieser-Misenheimer, EK, Alley, HM, Yllanes, A, Haney, V, Blackwell, KL, McCall, SJ, McDonnell, DP, and Wood, KC. "PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation." Science translational medicine 8.369 (December 2016): 369ra175-.
Website
http://hdl.handle.net/10161/13335
PMID
27974663
Source
epmc
Published In
Science Translational Medicine
Volume
8
Issue
369
Publish Date
2016
Start Page
369ra175
DOI
10.1126/scitranslmed.aae0348

Hacking T cells with synthetic circuits to program antitumor responses

Authors
Wood, KC
MLA Citation
Wood, KC. "Hacking T cells with synthetic circuits to program antitumor responses." Science Translational Medicine 8.362 (October 26, 2016): 362ec172-362ec172.
Source
crossref
Published In
Science Translational Medicine
Volume
8
Issue
362
Publish Date
2016
Start Page
362ec172
End Page
362ec172
DOI
10.1126/scitranslmed.aai9170

Mapping a path for precision cancer therapies

Authors
Wood, KC
MLA Citation
Wood, KC. "Mapping a path for precision cancer therapies." Science Translational Medicine 8.348 (July 20, 2016): 348ec115-348ec115.
Source
crossref
Published In
Science Translational Medicine
Volume
8
Issue
348
Publish Date
2016
Start Page
348ec115
End Page
348ec115
DOI
10.1126/scitranslmed.aah4512

Narrowing the focus: a toolkit to systematically connect oncogenic signaling pathways with cancer phenotypes.

Functional genomics approaches such as gain- and loss-of-function screening can efficiently reveal genes that control cancer cell growth, survival, signal transduction, and drug resistance, but distilling the results of large-scale screens into actionable therapeutic strategies is challenging given our incomplete understanding of the functions of many genes. Research over several decades, including the results of large-scale cancer sequencing projects, has made it clear that many oncogenic properties are controlled by a common set of core oncogenic signaling pathways. By directly screening this core set of pathways, rather than much larger numbers of individual genes, it may be possible to more directly and efficiently connect functional genomic screening results with therapeutic targets. Here, we describe the recent development of methods to directly screen oncogenic pathways in high-throughput. We summarize the results of studies that have used pathway-centric screening to map the pathways of resistance to targeted therapies in diverse cancer types, then conclude by expanding on potential future applications of this approach.

Authors
Singleton, KR; Wood, KC
MLA Citation
Singleton, KR, and Wood, KC. "Narrowing the focus: a toolkit to systematically connect oncogenic signaling pathways with cancer phenotypes." Genes & cancer 7.7-8 (July 2016): 218-228. (Review)
Website
http://hdl.handle.net/10161/13336
PMID
27738492
Source
epmc
Published In
Genes and Cancer
Volume
7
Issue
7-8
Publish Date
2016
Start Page
218
End Page
228

Targeting the cancer cells that just wont go away

Authors
Wood, KC
MLA Citation
Wood, KC. "Targeting the cancer cells that just wont go away." Science Translational Medicine 8.344 (June 22, 2016): 344ec101-344ec101.
Source
crossref
Published In
Science Translational Medicine
Volume
8
Issue
344
Publish Date
2016
Start Page
344ec101
End Page
344ec101
DOI
10.1126/scitranslmed.aag2112

Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.

ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.

Authors
Lin, KH; Winter, PS; Xie, A; Roth, C; Martz, CA; Stein, EM; Anderson, GR; Tingley, JP; Wood, KC
MLA Citation
Lin, KH, Winter, PS, Xie, A, Roth, C, Martz, CA, Stein, EM, Anderson, GR, Tingley, JP, and Wood, KC. "Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia." Scientific Reports 6 (June 10, 2016): 27696-.
PMID
27283158
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
27696
DOI
10.1038/srep27696

An Automated High-throughput Array Microscope for Cancer Cell Mechanics.

Changes in cellular mechanical properties correlate with the progression of metastatic cancer along the epithelial-to-mesenchymal transition (EMT). Few high-throughput methodologies exist that measure cell compliance, which can be used to understand the impact of genetic alterations or to screen the efficacy of chemotherapeutic agents. We have developed a novel array high-throughput microscope (AHTM) system that combines the convenience of the standard 96-well plate with the ability to image cultured cells and membrane-bound microbeads in twelve independently-focusing channels simultaneously, visiting all wells in eight steps. We use the AHTM and passive bead rheology techniques to determine the relative compliance of human pancreatic ductal epithelial (HPDE) cells, h-TERT transformed HPDE cells (HPNE), and four gain-of-function constructs related to EMT. The AHTM found HPNE, H-ras, Myr-AKT, and Bcl2 transfected cells more compliant relative to controls, consistent with parallel tests using atomic force microscopy and invasion assays, proving the AHTM capable of screening for changes in mechanical phenotype.

Authors
Cribb, JA; Osborne, LD; Beicker, K; Psioda, M; Chen, J; O'Brien, ET; Taylor Ii, RM; Vicci, L; Hsiao, JP-L; Shao, C; Falvo, M; Ibrahim, JG; Wood, KC; Blobe, GC; Superfine, R
MLA Citation
Cribb, JA, Osborne, LD, Beicker, K, Psioda, M, Chen, J, O'Brien, ET, Taylor Ii, RM, Vicci, L, Hsiao, JP-L, Shao, C, Falvo, M, Ibrahim, JG, Wood, KC, Blobe, GC, and Superfine, R. "An Automated High-throughput Array Microscope for Cancer Cell Mechanics." Scientific Reports 6 (June 6, 2016): 27371-.
PMID
27265611
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
27371
DOI
10.1038/srep27371

Collaborating tumor cells overcome multitargeted antiangiogenic therapies

Authors
Wood, KC
MLA Citation
Wood, KC. "Collaborating tumor cells overcome multitargeted antiangiogenic therapies." Science Translational Medicine 8.338 (May 11, 2016).
Source
scopus
Published In
Science Translational Medicine
Volume
8
Issue
338
Publish Date
2016

ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer.

Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination.

Authors
Park, S; Chang, C-Y; Safi, R; Liu, X; Baldi, R; Jasper, JS; Anderson, GR; Liu, T; Rathmell, JC; Dewhirst, MW; Wood, KC; Locasale, JW; McDonnell, DP
MLA Citation
Park, S, Chang, C-Y, Safi, R, Liu, X, Baldi, R, Jasper, JS, Anderson, GR, Liu, T, Rathmell, JC, Dewhirst, MW, Wood, KC, Locasale, JW, and McDonnell, DP. "ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer." Cell reports 15.2 (April 2016): 323-335.
PMID
27050525
Source
epmc
Published In
Cell Reports
Volume
15
Issue
2
Publish Date
2016
Start Page
323
End Page
335
DOI
10.1016/j.celrep.2016.03.026

Intercepting reversible drug tolerance to improve targeted therapy

Authors
Wood, KC
MLA Citation
Wood, KC. "Intercepting reversible drug tolerance to improve targeted therapy." Science Translational Medicine 8.332 (March 30, 2016): 332ec52-332ec52.
Source
crossref
Published In
Science Translational Medicine
Volume
8
Issue
332
Publish Date
2016
Start Page
332ec52
End Page
332ec52
DOI
10.1126/scitranslmed.aaf6467

Mapping the Pathways of Resistance to Targeted Therapies.

Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacologic approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients.

Authors
Wood, KC
MLA Citation
Wood, KC. "Mapping the Pathways of Resistance to Targeted Therapies." Cancer research 75.20 (October 2015): 4247-4251. (Review)
PMID
26392071
Source
epmc
Published In
Cancer Research
Volume
75
Issue
20
Publish Date
2015
Start Page
4247
End Page
4251
DOI
10.1158/0008-5472.can-15-1248

Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers.

Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.

Authors
Misale, S; Bozic, I; Tong, J; Peraza-Penton, A; Lallo, A; Baldi, F; Lin, KH; Truini, M; Trusolino, L; Bertotti, A; Di Nicolantonio, F; Nowak, MA; Zhang, L; Wood, KC; Bardelli, A
MLA Citation
Misale, S, Bozic, I, Tong, J, Peraza-Penton, A, Lallo, A, Baldi, F, Lin, KH, Truini, M, Trusolino, L, Bertotti, A, Di Nicolantonio, F, Nowak, MA, Zhang, L, Wood, KC, and Bardelli, A. "Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers." Nature communications 6 (September 22, 2015): 8305-.
PMID
26392303
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
8305
DOI
10.1038/ncomms9305

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.

Authors
Gerriets, VA; Kishton, RJ; Nichols, AG; Macintyre, AN; Inoue, M; Ilkayeva, O; Winter, PS; Liu, X; Priyadharshini, B; Slawinska, ME; Haeberli, L; Huck, C; Turka, LA; Wood, KC; Hale, LP; Smith, PA; Schneider, MA; MacIver, NJ; Locasale, JW; Newgard, CB; Shinohara, ML; Rathmell, JC
MLA Citation
Gerriets, VA, Kishton, RJ, Nichols, AG, Macintyre, AN, Inoue, M, Ilkayeva, O, Winter, PS, Liu, X, Priyadharshini, B, Slawinska, ME, Haeberli, L, Huck, C, Turka, LA, Wood, KC, Hale, LP, Smith, PA, Schneider, MA, MacIver, NJ, Locasale, JW, Newgard, CB, Shinohara, ML, and Rathmell, JC. "Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation." The Journal of clinical investigation 125.1 (January 2015): 194-207.
Website
http://hdl.handle.net/10161/10313
PMID
25437876
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
1
Publish Date
2015
Start Page
194
End Page
207
DOI
10.1172/jci76012

Systematic identification of signaling pathways with potential to confer anticancer drug resistance.

Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.

Authors
Martz, CA; Ottina, KA; Singleton, KR; Jasper, JS; Wardell, SE; Peraza-Penton, A; Anderson, GR; Winter, PS; Wang, T; Alley, HM; Kwong, LN; Cooper, ZA; Tetzlaff, M; Chen, P-L; Rathmell, JC; Flaherty, KT; Wargo, JA; McDonnell, DP; Sabatini, DM; Wood, KC
MLA Citation
Martz, CA, Ottina, KA, Singleton, KR, Jasper, JS, Wardell, SE, Peraza-Penton, A, Anderson, GR, Winter, PS, Wang, T, Alley, HM, Kwong, LN, Cooper, ZA, Tetzlaff, M, Chen, P-L, Rathmell, JC, Flaherty, KT, Wargo, JA, McDonnell, DP, Sabatini, DM, and Wood, KC. "Systematic identification of signaling pathways with potential to confer anticancer drug resistance." Science signaling 7.357 (December 23, 2014): ra121-.
PMID
25538079
Source
epmc
Published In
Science Signaling
Volume
7
Issue
357
Publish Date
2014
Start Page
ra121
DOI
10.1126/scisignal.aaa1877

RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis.

Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2(V617F) mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2(V617F) hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal-regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2(V617F) cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2)-associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2-like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co-occur with the JAK2(V617F) mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance.

Authors
Winter, PS; Sarosiek, KA; Lin, KH; Meggendorfer, M; Schnittger, S; Letai, A; Wood, KC
MLA Citation
Winter, PS, Sarosiek, KA, Lin, KH, Meggendorfer, M, Schnittger, S, Letai, A, and Wood, KC. "RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis." Science signaling 7.357 (December 23, 2014): ra122-.
PMID
25538080
Source
epmc
Published In
Science Signaling
Volume
7
Issue
357
Publish Date
2014
Start Page
ra122
DOI
10.1126/scisignal.2005301

Science Signaling Podcast: 23 December 2014

Authors
Wood, KC; VanHook, AM
MLA Citation
Wood, KC, and VanHook, AM. "Science Signaling Podcast: 23 December 2014." Science Signaling 7.357 (December 23, 2014): pc33-pc33.
Source
crossref
Published In
Science Signaling
Volume
7
Issue
357
Publish Date
2014
Start Page
pc33
End Page
pc33
DOI
10.1126/scisignal.aaa4213

Uncovering scaling laws to infer multidrug response of resistant microbes and cancer cells.

Drug resistance in bacterial infections and cancers constitutes a major threat to human health. Treatments often include several interacting drugs, but even potent therapies can become ineffective in resistant mutants. Here, we simplify the picture of drug resistance by identifying scaling laws that unify the multidrug responses of drug-sensitive and -resistant cells. On the basis of these scaling relationships, we are able to infer the two-drug response of resistant mutants in previously unsampled regions of dosage space in clinically relevant microbes such as E. coli, E. faecalis, S. aureus, and S. cerevisiae as well as human non-small-cell lung cancer, melanoma, and breast cancer stem cells. Importantly, we find that scaling relations also apply across evolutionarily close strains. Finally, scaling allows one to rapidly identify new drug combinations and predict potent dosage regimes for targeting resistant mutants without any prior mechanistic knowledge about the specific resistance mechanism.

Authors
Wood, KB; Wood, KC; Nishida, S; Cluzel, P
MLA Citation
Wood, KB, Wood, KC, Nishida, S, and Cluzel, P. "Uncovering scaling laws to infer multidrug response of resistant microbes and cancer cells." Cell reports 6.6 (March 6, 2014): 1073-1084.
PMID
24613352
Source
epmc
Published In
Cell Reports
Volume
6
Issue
6
Publish Date
2014
Start Page
1073
End Page
1084
DOI
10.1016/j.celrep.2014.02.007

MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma

Cell microarrays are a promising tool for performing large-scale functional genomic screening in mammalian cells at reasonable cost, but owing to technical limitations they have been restricted for use with a narrow range of cell lines and short-term assays. Here, we describe MicroSCALE (Microarrays of Spatially Confined Adhesive Lentiviral Features), a cell microarray-based platform that enables application of this technology to a wide range of cell types and longer-term assays. We used MicroSCALE to uncover kinases that when overexpressed partially desensitized B-RAFV600E-mutant melanoma cells to inhibitors of the mitogen-activated protein kinase kinase kinase (MAPKKK) RAF, the MAPKKs MEK1 and 2 (MEK1/2, mitogen-activated protein kinase kinase 1 and 2), mTOR (mammalian target of rapamycin), or PI3K (phosphatidylinositol 3-kinase). These screens indicated that cells treated with inhibitors acting through common mechanisms were affected by a similar profile of overexpressed proteins. In contrast, screens involving inhibitors acting through distinct mechanisms yielded unique profiles, a finding that has potential relevance for small-molecule target identification and combination drugging studies. Further, by integrating large-scale functional screening results with cancer cell line gene expression and pharmacological sensitivity data, we validated the nuclear factor kB pathway as a potential mediator of resistance to MAPK pathway inhibitors. The MicroSCALE platform described here may enable new classes of large-scale, resource-efficient screens that were not previously feasible, including those involving combinations of cell lines, perturbations, and assay outputs or those involving limited numbers of cells and limited or expensive reagents.

Authors
Wood, KC; Konieczkowski, DJ; Johannessen, CM; Boehm, JS; Tamayo, P; Botvinnik, OB; Mesirov, JP; Hahn, WC; Root, DE; Garraway, LA; Sabatini, DM
MLA Citation
Wood, KC, Konieczkowski, DJ, Johannessen, CM, Boehm, JS, Tamayo, P, Botvinnik, OB, Mesirov, JP, Hahn, WC, Root, DE, Garraway, LA, and Sabatini, DM. "MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma." Science Signaling 5.224 (2012).
PMID
22589389
Source
scival
Published In
Science Signaling
Volume
5
Issue
224
Publish Date
2012
DOI
10.1126/scisignal.2002612

Growth Signaling at the Nexus of Stem Cell Life and Death

Stress can activate tumor-suppressive mechanisms, causing the loss of adult stem cell function with age. In this issue of Cell Stem Cell and in Nature, Castilho et al. (2009) and Harrison et al. (2009) highlight the importance of mTOR signaling in stem cell exhaustion and mammalian aging, respectively. © 2009 Elsevier Inc. All rights reserved.

Authors
Wood, KC; Sabatini, DM
MLA Citation
Wood, KC, and Sabatini, DM. "Growth Signaling at the Nexus of Stem Cell Life and Death." Cell Stem Cell 5.3 (2009): 232-234.
PMID
19733530
Source
scival
Published In
Cell Stem Cell
Volume
5
Issue
3
Publish Date
2009
Start Page
232
End Page
234
DOI
10.1016/j.stem.2009.08.008

Tumor-targeted gene delivery using molecularly engineered hybrid polymers functionalized with a tumor-homing peptide

Before gene therapy can be used in clinical settings, safe and efficient DNA delivery systems must be developed to overcome a range of extra- and intracellular transport barriers. As a step toward the development of a modular, multifunctional gene delivery system to overcome these diverse barriers, we have developed a family of linear - dendritic "hybrid" polymers which contain functionalities for tissue targeting, minimization of nonspecific interactions, endosomal buffering, and DNA binding. Here, we demonstrate the rapid three-step, room-temperature, aqueous synthesis of hybrid polymers, as well as the functionalization of these polymers with a peptide targeting ligand that specifically binds to glucose-regulated protein-78 kDa (GRP-78), a clinically relevant tumor antigen identified in human cancer patients. These polymer systems can condense plasmid DNA into small nanoparticle structures (<210 nm) and transfect cells expressing GRP-78 with efficiencies that exceed that of branched polyethylenimine (bPEI), one of the best commercially available polymers for in vitro transfections. The synthetic approach described here may be useful for the rapid synthesis and optimization of polymer gene delivery systems bearing a range of diverse functional domains, and the specific GRP-78-targeted systems developed in this study may potentially have clinical applications in cancer gene therapy. © 2008 American Chemical Society.

Authors
Wood, KC; Azarin, SM; Arap, W; Pasqualini, R; Langer, R; Hammond, PT
MLA Citation
Wood, KC, Azarin, SM, Arap, W, Pasqualini, R, Langer, R, and Hammond, PT. "Tumor-targeted gene delivery using molecularly engineered hybrid polymers functionalized with a tumor-homing peptide." Bioconjugate Chemistry 19.2 (2008): 403-405.
PMID
18189340
Source
scival
Published In
Bioconjugate Chemistry
Volume
19
Issue
2
Publish Date
2008
Start Page
403
End Page
405
DOI
10.1021/bc700408r

Electroactive controlled release thin films

We present the fabrication of nanoscale electroactive thin films that can be engineered to undergo remotely controlled dissolution in the presence of a small applied voltage (+1.25 V) to release precise quantities of chemical agents. These films, which are assembled by using a nontoxic, FDA-approved, electroactive material known as Prussian Blue, are stable enough to release a fraction of their contents after the application of a voltage and then to restabilize upon its removal. As a result, it is possible to externally trigger agent release, exert control over the relative quantity of agents released from a film, and release multiple doses from one or more films in a single solution. These electroactive systems may be rapidly and conformally coated onto a wide range of substrates without regard to size, shape, or chemical composition, and as such they may find use in a host of new applications in drug delivery as well as the related fields of tissue engineering, medical diagnostics, and chemical detection. © 2008 by The National Academy of Sciences of the USA.

Authors
Wood, KC; Zacharia, NS; Schmidt, DJ; Wrightman, SN; Andaya, BJ; Hammond, PT
MLA Citation
Wood, KC, Zacharia, NS, Schmidt, DJ, Wrightman, SN, Andaya, BJ, and Hammond, PT. "Electroactive controlled release thin films." Proceedings of the National Academy of Sciences of the United States of America 105.7 (2008): 2280-2285.
PMID
18272499
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
105
Issue
7
Publish Date
2008
Start Page
2280
End Page
2285
DOI
10.1073/pnas.0706994105

Controlling interlayer diffusion to achieve sustained, multiagent delivery from layer-by-layer thin films

We present the fabrication of conformal, hydrolytically degradable thin films capable of administering sustained, multiagent release profiles. Films are constructed one molecular layer at a time by using the layer-by-layer, directed-deposition technique; the subsequent hydrolytic surface erosion of these systems results in the release of incorporated materials in a sequence that reflects their relative positions in the film. The position of each species is determined by its ability to diffuse throughout the film architecture, and, as such, the major focus of this work is to define strategies that physically block interlayer diffusion during assembly to create multicomponent, stratified films. By using a series of radiolabeled polyelectrolytes as experimental probes, we show that covalently crosslinked barriers can effectively block interlayer diffusion, leading to compartmentalized structures, although even very large numbers of ionically crosslinked (degradable or nondegradable) barrier layers cannot block interlayer diffusion. By using these principles, we designed degradable films capable of extended release as well as both parallel and serial multiagent release. The ability to fabricate multicomponent thin films with nanoscale resolution may lead to a host of new materials and applications. © 2006 by The National Academy of Sciences of the USA.

Authors
Wood, KC; Chuang, HF; Batten, RD; Lynn, DM; Hammond, PT
MLA Citation
Wood, KC, Chuang, HF, Batten, RD, Lynn, DM, and Hammond, PT. "Controlling interlayer diffusion to achieve sustained, multiagent delivery from layer-by-layer thin films." Proceedings of the National Academy of Sciences of the United States of America 103.27 (2006): 10207-10212.
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
103
Issue
27
Publish Date
2006
Start Page
10207
End Page
10212
DOI
10.1073/pnas.0602884103

Tunable drug release from hydrolytically degradable layer-by-layer thin films

The development of new thin film fabrication techniques that allow for precise control of degradation and drug release properties could represent an important advance in the fields of drug delivery and biomedicine. Polyelectrolyte layer-by-layer (LBL) thin films can be assembled with nanometer scale control over spatial architecture and morphology, yet very little work has focused on the deconstruction of these ordered thin films for controlled release applications. In this study, hydrolytically degradable LBL thin films are constructed by alternately depositing a degradable poly(β-amino ester) (polymer 1) and a series of model therapeutic polysaccharides (heparin, low molecular weight heparin, and chondroitin sulfate). These films exhibit pH-dependent, pseudo-first-order degradation and release behavior. The highly versatile and tunable properties of these materials make them exciting candidates for the controlled release of a wide spectrum of therapeutics.

Authors
Wood, KC; Boedicker, JQ; Lynn, DM; Hammond, PT
MLA Citation
Wood, KC, Boedicker, JQ, Lynn, DM, and Hammond, PT. "Tunable drug release from hydrolytically degradable layer-by-layer thin films." Langmuir 21.4 (2005): 1603-1609.
Source
scival
Published In
Langmuir
Volume
21
Issue
4
Publish Date
2005
Start Page
1603
End Page
1609
DOI
10.1021/la0476480

A family of hierarchically self-assembling linear-dendritic hybrid polymers for highly efficient targeted gene delivery

(Figure Presented) Modular materials composed of concentric functional "shells" with independently tuneable properties are prepared from the self-assembly of DNA and linear-dendritic hybrid polymers (see scheme; PAMAM = poly(amidoamine), PEG = poly(ethylene glycol)). These ligand-targeted systems demonstrate serum stability, low toxicity, and transfection efficiencies that exceed those of the most efficient commercially available polymer poly(ethylenimine). © 2005 Wiley-VCH Verlag GmbH & Co. KGaA.

Authors
Wood, KC; Little, SR; Langer, R; Hammond, PT
MLA Citation
Wood, KC, Little, SR, Langer, R, and Hammond, PT. "A family of hierarchically self-assembling linear-dendritic hybrid polymers for highly efficient targeted gene delivery." Angewandte Chemie - International Edition 44.41 (2005): 6704-6708.
PMID
16173106
Source
scival
Published In
Angewandte Chemie International Edition
Volume
44
Issue
41
Publish Date
2005
Start Page
6704
End Page
6708
DOI
10.1002/anie.200502152

Degradation of chlorinated organics by membrane-immobilized nanosized metals

The use of electronegative metals, such as Fe, has been extensively studied for the treatment of ground-water containing toxic chlorinated organics. Much of the recent work has been focused on the use of nanoscale particles with diameters from 2 to 100 nm. This work examines the use of bimetallic (Fe/Ni) nanoscale particles immobilized in a cellulose acetate domain for the destruction of trichloroethylene (TCE). The organic/inorganic hybrid film is synthesized using phase inversion with sodium borohydride reduction. The resulting nanoparticles have an average diameter of 24 nm. Using a small quantity of membrane-immobilized metal (31 mg total, Fe-Ni = 4:1), it was possible to achieve over a 75% reduction in TCE levels in 4.25 h, with ethane as the only observable product. For shorter reaction times (<2 h), traces of cis- and trans-DCE could be extracted from the baseline of the MS chromatogram. For longer reaction times, products of coupling reactions (butane and hexane) were observed. This corresponds to a surface-area-normalized pseudo-first-order rate constant, k SA, for the immobilized system of 3.7 × 10 -2 L m -2 h -1. Analysis of the aqueous phase for metal content showed minimal leaching of the metals into the surrounding solution during treatment. Because various combinations of membranes containing immobilized metal nanoparticles can be achieved using the synthesis techniques presented, a more versatile platform for the application of zero-valent treatment is possible. © 2004 American Institute of Chemical Engineers Environ Prog.

Authors
Meyer, DE; Wood, K; Bachas, LG; Bhattacharyya, D
MLA Citation
Meyer, DE, Wood, K, Bachas, LG, and Bhattacharyya, D. "Degradation of chlorinated organics by membrane-immobilized nanosized metals." Environmental Progress 23.3 (2004): 232-242.
Source
scival
Published In
Environmental Progress
Volume
23
Issue
3
Publish Date
2004
Start Page
232
End Page
242
DOI
10.1002/ep.10031
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