Kris Wood

Positions:

Assistant Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Core Faculty in Innovation & Entrepreneurship

Duke Innovation & Entrepreneurship
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 2002

University of Kentucky at Lexington

Ph.D. 2007

Massachusetts Institute of Technology

Grants:

Pharmacology Industry Internships for Ph.D. Students

Administered By
Pharmacology & Cancer Biology
Awarded By
American Society for Pharmacology and Experimental Therapeutics
Role
Participating Faculty Member
Start Date
End Date

Medical Scientist Training Program

Administered By
School of Medicine
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Targeting the Hippo pathway in Ras-driven rhabdomyosarcoma

Administered By
Pediatrics, Hematology-Oncology
Awarded By
V Foundation for Cancer Research
Role
Collaborator
Start Date
End Date

Identification and validation of the PAX3-FOXO1 protein interactome

Administered By
Pediatrics, Hematology-Oncology
Role
Collaborator
Start Date
End Date

RalA signal transduction

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Publications:

Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models.

Extrinsic pathway agonists have failed repeatedly in the clinic for three core reasons: Inefficient ligand-induced receptor multimerization, poor pharmacokinetic properties, and tumor intrinsic resistance. Here, we address these factors by (i) using a highly potent death receptor agonist (DRA), (ii) developing an injectable depot for sustained DRA delivery, and (iii) leveraging a CRISPR-Cas9 knockout screen in DRA-resistant colorectal cancer (CRC) cells to identify functional drivers of resistance. Pharmacological blockade of XIAP and BCL-XL by targeted small-molecule drugs strongly enhanced the antitumor activity of DRA in CRC cell lines. Recombinant fusion of the DRA to a thermally responsive elastin-like polypeptide (ELP) creates a gel-like depot upon subcutaneous injection that abolishes tumors in DRA-sensitive Colo205 mouse xenografts. Combination of ELPdepot-DRA with BCL-XL and/or XIAP inhibitors led to tumor growth inhibition and extended survival in DRA-resistant patient-derived xenografts. This strategy provides a precision medicine approach to overcome similar challenges with other protein-based cancer therapies.
Authors
Manzari, MT; Anderson, GR; Lin, KH; Soderquist, RS; Çakir, M; Zhang, M; Moore, CE; Skelton, RN; Fèvre, M; Li, X; Bellucci, JJ; Wardell, SE; Costa, SA; Wood, KC; Chilkoti, A
MLA Citation
URI
https://scholars.duke.edu/individual/pub1411847
PMID
31517048
Source
pubmed
Published In
Science Advances
Volume
5
Published Date
Start Page
eaaw9162
DOI
10.1126/sciadv.aaw9162

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers.

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is aggressive and lethal. Although there is an urgent need for effective therapeutics in treating pancreatic cancer, none of the targeted therapies tested in clinical trials to date significantly improve its outcome. PORCN inhibitors show efficacy in preclinical models of Wnt-addicted cancers, including RNF43-mutant pancreatic cancers and have advanced to clinical trials. In this study, we aimed to develop drug combination strategies to further enhance the therapeutic efficacy of the PORCN inhibitor ETC-159. To identify additional druggable vulnerabilities in Wnt-driven pancreatic cancers, we performed an in vivo CRISPR loss-of-function screen. CTNNB1, KRAS, and MYC were reidentified as key oncogenic drivers. Notably, glucose metabolism pathway genes were important in vivo but less so in vitro. Knockout of multiple genes regulating PI3K/mTOR signaling impacted the growth of Wnt-driven pancreatic cancer cells in vivo. Importantly, multiple PI3K/mTOR pathway inhibitors in combination with ETC-159 synergistically suppressed the growth of multiple Wnt-addicted cancer cell lines in soft agar. Furthermore, the combination of the PORCN inhibitor ETC-159 and the pan-PI3K inhibitor GDC-0941 potently suppressed the in vivo growth of RNF43-mutant pancreatic cancer xenografts. This was largely due to enhanced suppressive effects on both cell proliferation and glucose metabolism. These findings demonstrate that dual PORCN and PI3K/mTOR inhibition is a potential strategy for treating Wnt-driven pancreatic cancers.
Authors
Zhong, Z; Sepramaniam, S; Chew, XH; Wood, K; Lee, MA; Madan, B; Virshup, DM
MLA Citation
Zhong, Zheng, et al. “PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers..” Oncogene, vol. 38, no. 40, Oct. 2019, pp. 6662–77. Pubmed, doi:10.1038/s41388-019-0908-1.
URI
https://scholars.duke.edu/individual/pub1404017
PMID
31391551
Source
pubmed
Published In
Oncogene
Volume
38
Published Date
Start Page
6662
End Page
6677
DOI
10.1038/s41388-019-0908-1

Label propagation defines signaling networks associated with recurrently mutated cancer genes.

Human tumors have distinct profiles of genomic alterations, and each of these alterations has the potential to cause unique changes to cellular homeostasis. Detailed analyses of these changes could reveal downstream effects of genomic alterations, contributing to our understanding of their roles in tumor development and progression. Across a range of tumor types, including bladder, lung, and endometrial carcinoma, we determined genes that are frequently altered in The Cancer Genome Atlas patient populations, then examined the effects of these alterations on signaling and regulatory pathways. To achieve this, we used a label propagation-based methodology to generate networks from gene expression signatures associated with defined mutations. Individual networks offered a large-scale view of signaling changes represented by gene signatures, which in turn reflected the scope of molecular events that are perturbed in the presence of a given genomic alteration. Comparing different networks to one another revealed common biological pathways impacted by distinct genomic alterations, highlighting the concept that tumors can dysregulate key pathways through multiple, seemingly unrelated mechanisms. Finally, altered genes inducing common changes to the signaling network were used to search for genomic markers of drug response, connecting shared perturbations to differential drug sensitivity.
Authors
Cakir, M; Mukherjee, S; Wood, KC
MLA Citation
Cakir, Merve, et al. “Label propagation defines signaling networks associated with recurrently mutated cancer genes..” Sci Rep, vol. 9, no. 1, June 2019. Pubmed, doi:10.1038/s41598-019-45603-3.
URI
https://scholars.duke.edu/individual/pub1395721
PMID
31253832
Source
pubmed
Published In
Scientific Reports
Volume
9
Published Date
Start Page
9401
DOI
10.1038/s41598-019-45603-3

Leveraging Synthetic Lethality to Target Convergent Therapeutic Resistance

Authors
MLA Citation
Wood, Kris C. “Leveraging Synthetic Lethality to Target Convergent Therapeutic Resistance.” Faseb Journal, vol. 31, FEDERATION AMER SOC EXP BIOL, 2017.
URI
https://scholars.duke.edu/individual/pub1274252
Source
wos
Published In
Faseb Journal
Volume
31
Published Date

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, Sandra, et al. “Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers..” Nat Commun, vol. 6, Sept. 2015. Pubmed, doi:10.1038/ncomms9305.
URI
https://scholars.duke.edu/individual/pub1091953
PMID
26392303
Source
pubmed
Published In
Nature Communications
Volume
6
Published Date
Start Page
8305
DOI
10.1038/ncomms9305