Kris Wood

Positions:

Associate Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Associate Professor of Cell Biology

Cell 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

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
Awarded By
St. Baldrick's Foundation
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:

Endogenous and imposed determinants of apoptotic vulnerabilities in cancer

The intrinsic apoptosis pathway is controlled by the BCL-2 family of proteins. Although the prosurvival members of this family can help cancer cells evade apoptosis, they may also produce apoptotic vulnerabilities that can potentially be exploited therapeutically. Apoptotic vulnerabilities can be driven by endogenous factors, including altered genetics, signaling, metabolism, structure, and lineage or differentiation state, as well as imposed factors, the most prominent being exposure to anticancer agents. The recent development of BH3 mimetics that inhibit prosurvival BCL-2 family proteins has allowed these apoptotic vulnerabilities to be targeted with demonstrable clinical success. Here, we review the key concepts that are vital for understanding, uncovering, and exploiting apoptotic vulnerabilities in cancer for the potential improvement of patient outcomes.
Authors
Sarosiek, KA; Wood, KC
MLA Citation
Sarosiek, K. A., and K. C. Wood. “Endogenous and imposed determinants of apoptotic vulnerabilities in cancer.” Trends in Cancer, Jan. 2022. Scopus, doi:10.1016/j.trecan.2022.10.004.
URI
https://scholars.duke.edu/individual/pub1555335
Source
scopus
Published In
Trends in Cancer
Published Date
DOI
10.1016/j.trecan.2022.10.004

A high throughput proliferation and cytotoxicity assay for co-cultured isogenic cell lines.

PTEN is a well-known tumor suppressor that is inactivated or suppressed at a high frequency in cancer. We sought an assay to screen compounds for ones that differentially inhibited proliferation or induced cytotoxicity in PTEN mutated cancer cells. We employed the isogenic pair of cell lines MCF10-A breast cell line (wild type, WT) and the same cell line with PTEN knocked out (KO) by CRISPR. We sought an assay where these PTEN WT and KO isogenic cell lines were co-cultured in the same well for compound testing. The KO cell line, but not the WT, was tagged with the red fluorescent protein mKate2. We employed a real time microscopic imaging instrument to identify cell populations in co-culture based on red fluorescence to obtain a cell count for each cell line. To acquire cytotoxicity data for each population, the dye CellTox Green was added to the media. To assess the assay, we determined the concentration response of paclitaxel. In order to assess the potential for screening, we performed mock screening in 384-well plate format. Thus, we developed a high throughput co-culture cell cytotoxicity and proliferation assay method that could be employed for any pair of cell lines to identify selective compounds.
Authors
Ahmad, S; Wood, KC; Scott, JE
MLA Citation
Ahmad, Syed, et al. “A high throughput proliferation and cytotoxicity assay for co-cultured isogenic cell lines.Methodsx, vol. 9, 2022, p. 101927. Pubmed, doi:10.1016/j.mex.2022.101927.
URI
https://scholars.duke.edu/individual/pub1557614
PMID
36438856
Source
pubmed
Published In
Methodsx
Volume
9
Published Date
Start Page
101927
DOI
10.1016/j.mex.2022.101927

Challenges and Emerging Opportunities for Targeting mTOR in Cancer.

The mechanistic target of rapamycin (mTOR) plays a key role in normal and malignant cell growth. However, pharmacologic targeting of mTOR in cancer has shown little clinical benefit, in spite of aberrant hyperactivation of mTOR in most solid tumors. Here, we discuss possible reasons for the reduced clinical efficacy of mTOR inhibition and highlight lessons learned from recent combination clinical trials and approved indications of mTOR inhibitors in cancer. We also discuss how the emerging systems level understanding of mTOR signaling in cancer can be exploited for the clinical development of novel multimodal precision targeted therapies and immunotherapies aimed at achieving tumor remission.
Authors
Wood, KC; Gutkind, JS
MLA Citation
Wood, Kris C., and J. Silvio Gutkind. “Challenges and Emerging Opportunities for Targeting mTOR in Cancer.Cancer Research, vol. 82, no. 21, Nov. 2022, pp. 3884–87. Epmc, doi:10.1158/0008-5472.can-22-0602.
URI
https://scholars.duke.edu/individual/pub1555271
PMID
36321262
Source
epmc
Published In
Cancer Research
Volume
82
Published Date
Start Page
3884
End Page
3887
DOI
10.1158/0008-5472.can-22-0602

Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-mutant Pancreatic Cancer.

Mutational loss of CDKN2A (encoding p16INK4A) tumor suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, anti-apoptotic signaling, and MYC expression. Based on these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell cycle regulatory proteins centered on CDK2 activation, PI3K-AKT-mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small molecule inhibitor-based approaches. Additionally, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to PDAC patients.
Authors
Goodwin, CM; Waters, AM; Klomp, JE; Javaid, S; Bryant, KL; Stalnecker, CA; Drizyte-Miller, K; Papke, B; Yang, R; Amparo, AM; Ozkan-Dagliyan, I; Baldelli, E; Calvert, V; Pierobon, M; Sorrentino, JA; Beelen, AP; Bublitz, N; Lüthen, M; Wood, KC; Petricoin, EF; Sers, C; McRee, AJ; Cox, AD; Der, CJ
MLA Citation
Goodwin, Craig M., et al. “Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-mutant Pancreatic Cancer.Cancer Research, Nov. 2022, p. CAN-22-0391. Epmc, doi:10.1158/0008-5472.can-22-0391.
URI
https://scholars.duke.edu/individual/pub1556514
PMID
36346366
Source
epmc
Published In
Cancer Research
Published Date
Start Page
CAN-22-0391
DOI
10.1158/0008-5472.can-22-0391

Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies.

Intrahepatic cholangiocarcinoma (ICC) remains a deadly malignancy lacking systemic therapies for advanced disease. Recent advancements include selective FGFR1-3 inhibitors for the 15% of ICC patients harboring fusions, although survival is limited by poor response and resistance. Herein we report generation of a patient-derived FGFR2 fusion-positive ICC model system consisting of a cell line, organoid, and xenograft, which have undergone complete histologic, genomic, and phenotypic characterization, including testing standard-of-care systemic therapies. Using these FGFR2 fusion-positive ICC models, we conducted an unbiased high-throughput small molecule screen to prioritize combination strategies with FGFR inhibition, from which HDAC inhibition together with pemigatinib was validated in vitro and in vivo as a synergistic therapy for ICC. Additionally, we demonstrate broad utility of the FGFR/HDAC combination for other FGFR fusion-positive solid tumors. These data are directly translatable and justify early phase trials to establish dosing, safety, and therapeutic efficacy of this synergistic combination.
Authors
Lidsky, ME; Wang, Z; Lu, M; Liu, A; Hsu, SD; McCall, SJ; Sheng, Z; Granek, JA; Owzar, K; Anderson, KS; Wood, KC
MLA Citation
Lidsky, Michael E., et al. “Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies.Npj Precis Oncol, vol. 6, no. 1, Oct. 2022, p. 75. Pubmed, doi:10.1038/s41698-022-00320-5.
URI
https://scholars.duke.edu/individual/pub1554318
PMID
36274097
Source
pubmed
Published In
Npj Precis Oncol
Volume
6
Published Date
Start Page
75
DOI
10.1038/s41698-022-00320-5