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:

Targeting the Hippo pathway in Ras-driven rhabdomyosarcoma

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

Identification and validation of the PAX3-FOXO1 protein interactome

Administered By
Pediatrics, Hematology-Oncology
Role
Principal Investigator
Start Date
End Date

RalA signal transduction

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

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

Administered By
Surgery
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Determining the Sub-Cellular Organelles that Link Lipid Signaling and Epigenetics

Administered By
Sarah Stedman Nutrition & Metabolism Center
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

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, Aug. 2019. Pubmed, doi:10.1038/s41388-019-0908-1.
URI
https://scholars.duke.edu/individual/pub1404017
PMID
31391551
Source
pubmed
Published In
Oncogene
Published Date
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

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, Kris C. “Suppressing oncogenic transcription with a little healthy competition..” Sci Transl Med, vol. 9, no. 374, Jan. 2017. Pubmed, doi:10.1126/scitranslmed.aal5000.
URI
https://scholars.duke.edu/individual/pub1169822
PMID
28123073
Source
pubmed
Published In
Sci Transl Med
Volume
9
Published Date
DOI
10.1126/scitranslmed.aal5000

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, Valerie A., et al. “Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation..” J Clin Invest, vol. 125, no. 1, Jan. 2015, pp. 194–207. Pubmed, doi:10.1172/JCI76012.
URI
https://scholars.duke.edu/individual/pub1051092
PMID
25437876
Source
pubmed
Published In
J Clin Invest
Volume
125
Published Date
Start Page
194
End Page
207
DOI
10.1172/JCI76012

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, Grace R., et al. “PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation..” Sci Transl Med, vol. 8, no. 369, Dec. 2016. Pubmed, doi:10.1126/scitranslmed.aae0348.
URI
https://scholars.duke.edu/individual/pub1162866
PMID
27974663
Source
pubmed
Published In
Sci Transl Med
Volume
8
Published Date
Start Page
369ra175
DOI
10.1126/scitranslmed.aae0348