Abstract
New approaches to optimization of cancer drug development in the laboratory and the clinic will be required to fully achieve the goal of individualized, precision cancer therapy. Improved preclinical models that more closely reflect the now recognized genomic complexity of human cancers are needed. Here we describe a collaborative research project that integrates core resources of The Jackson Laboratory Basic Science Cancer Center with genomics and clinical research facilities at the UC Davis Comprehensive Cancer Center to establish a clinically and genomically annotated patient-derived xenograft (PDX) platform designed to enhance new drug development and strategies for targeted therapies. Advanced stage non-small-cell lung cancer (NSCLC) was selected for initial studies because of emergence of a number of "druggable" molecular targets, and recent recognition of substantial inter- and intrapatient tumor heterogeneity. Additionally, clonal evolution after targeted therapy interventions make this tumor type ideal for investigation of this platform. Using the immunodeficient NOD scid gamma mouse, > 200 NSCLC tumor biopsies have been xenotransplanted. During the annotation process, patient tumors and subsequent PDXs are compared at multiple levels, including histomorphology, clinically applicable molecular biomarkers, global gene expression patterns, gene copy number variations, and DNA/chromosomal alterations. NSCLC PDXs are grouped into panels of interest according to oncogene subtype and/or histologic subtype. Multiregimen drug testing, paired with next-generation sequencing before and after therapy and timed tumor pharmacodynamics enables determination of efficacy, signaling pathway alterations, and mechanisms of sensitivity-resistance in individual models. This approach should facilitate derivation of new therapeutic strategies and the transition to individualized therapy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 165-172 |
| Number of pages | 8 |
| Journal | Clinical Lung Cancer |
| Volume | 16 |
| Issue number | 3 |
| DOIs | |
| State | Published - May 1 2015 |
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Keywords
- Clinical trials
- Lung cancer
- Mouse model
- Patient derived xenograft
ASJC Scopus subject areas
- Cancer Research
- Oncology
- Pulmonary and Respiratory Medicine
Cite this
Bridging tumor genomics to patient outcomes through an integrated patient-derived xenograft platform. / Gandara, David R; Mack, Philip; Bult, Carol; Li, Tianhong; Lara, Primo N; Riess, Jonathan; Astrow, Stephanie H.; Gandour-Edwards, Regina F; Cooke, David T; Yoneda, Ken Y; Moore, Elizabeth H; Pan, Chong-Xian; Burich, Rebekah A.; David, Elizabeth; Keck, James G.; Airhart, Susan; Goodwin, Neal; deVere White, Ralph W; Liu, Edison T.
In: Clinical Lung Cancer, Vol. 16, No. 3, 01.05.2015, p. 165-172.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Bridging tumor genomics to patient outcomes through an integrated patient-derived xenograft platform
AU - Gandara, David R
AU - Mack, Philip
AU - Bult, Carol
AU - Li, Tianhong
AU - Lara, Primo N
AU - Riess, Jonathan
AU - Astrow, Stephanie H.
AU - Gandour-Edwards, Regina F
AU - Cooke, David T
AU - Yoneda, Ken Y
AU - Moore, Elizabeth H
AU - Pan, Chong-Xian
AU - Burich, Rebekah A.
AU - David, Elizabeth
AU - Keck, James G.
AU - Airhart, Susan
AU - Goodwin, Neal
AU - deVere White, Ralph W
AU - Liu, Edison T.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - New approaches to optimization of cancer drug development in the laboratory and the clinic will be required to fully achieve the goal of individualized, precision cancer therapy. Improved preclinical models that more closely reflect the now recognized genomic complexity of human cancers are needed. Here we describe a collaborative research project that integrates core resources of The Jackson Laboratory Basic Science Cancer Center with genomics and clinical research facilities at the UC Davis Comprehensive Cancer Center to establish a clinically and genomically annotated patient-derived xenograft (PDX) platform designed to enhance new drug development and strategies for targeted therapies. Advanced stage non-small-cell lung cancer (NSCLC) was selected for initial studies because of emergence of a number of "druggable" molecular targets, and recent recognition of substantial inter- and intrapatient tumor heterogeneity. Additionally, clonal evolution after targeted therapy interventions make this tumor type ideal for investigation of this platform. Using the immunodeficient NOD scid gamma mouse, > 200 NSCLC tumor biopsies have been xenotransplanted. During the annotation process, patient tumors and subsequent PDXs are compared at multiple levels, including histomorphology, clinically applicable molecular biomarkers, global gene expression patterns, gene copy number variations, and DNA/chromosomal alterations. NSCLC PDXs are grouped into panels of interest according to oncogene subtype and/or histologic subtype. Multiregimen drug testing, paired with next-generation sequencing before and after therapy and timed tumor pharmacodynamics enables determination of efficacy, signaling pathway alterations, and mechanisms of sensitivity-resistance in individual models. This approach should facilitate derivation of new therapeutic strategies and the transition to individualized therapy.
AB - New approaches to optimization of cancer drug development in the laboratory and the clinic will be required to fully achieve the goal of individualized, precision cancer therapy. Improved preclinical models that more closely reflect the now recognized genomic complexity of human cancers are needed. Here we describe a collaborative research project that integrates core resources of The Jackson Laboratory Basic Science Cancer Center with genomics and clinical research facilities at the UC Davis Comprehensive Cancer Center to establish a clinically and genomically annotated patient-derived xenograft (PDX) platform designed to enhance new drug development and strategies for targeted therapies. Advanced stage non-small-cell lung cancer (NSCLC) was selected for initial studies because of emergence of a number of "druggable" molecular targets, and recent recognition of substantial inter- and intrapatient tumor heterogeneity. Additionally, clonal evolution after targeted therapy interventions make this tumor type ideal for investigation of this platform. Using the immunodeficient NOD scid gamma mouse, > 200 NSCLC tumor biopsies have been xenotransplanted. During the annotation process, patient tumors and subsequent PDXs are compared at multiple levels, including histomorphology, clinically applicable molecular biomarkers, global gene expression patterns, gene copy number variations, and DNA/chromosomal alterations. NSCLC PDXs are grouped into panels of interest according to oncogene subtype and/or histologic subtype. Multiregimen drug testing, paired with next-generation sequencing before and after therapy and timed tumor pharmacodynamics enables determination of efficacy, signaling pathway alterations, and mechanisms of sensitivity-resistance in individual models. This approach should facilitate derivation of new therapeutic strategies and the transition to individualized therapy.
KW - Clinical trials
KW - Lung cancer
KW - Mouse model
KW - Patient derived xenograft
UR - http://www.scopus.com/inward/record.url?scp=84928697142&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928697142&partnerID=8YFLogxK
U2 - 10.1016/j.cllc.2015.03.001
DO - 10.1016/j.cllc.2015.03.001
M3 - Article
C2 - 25838158
AN - SCOPUS:84928697142
VL - 16
SP - 165
EP - 172
JO - Clinical Lung Cancer
JF - Clinical Lung Cancer
SN - 1525-7304
IS - 3
ER -