Modeling rectal cancer to advance neoadjuvant precision therapy.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Cetuximab
/ pharmacology
Fluorouracil
/ pharmacology
Heterografts
/ drug effects
Humans
Mice
Models, Biological
Mutation
Neoadjuvant Therapy
Organoids
/ drug effects
Precision Medicine
/ methods
Proto-Oncogene Proteins p21(ras)
/ genetics
Rectal Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
PDX model
chemoradiation
colorectal cancer
organoid
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
03
09
2019
revised:
11
11
2019
accepted:
20
12
2019
pubmed:
29
1
2020
medline:
7
4
2021
entrez:
29
1
2020
Statut:
ppublish
Résumé
Progress in rectal cancer therapy has been hindered by the lack of effective disease-specific preclinical models that account for the unique molecular profile and biology of rectal cancer. Thus, we developed complementary patient-derived xenograft (PDX) and subsequent in vitro tumor organoid (PDTO) platforms established from preneoadjuvant therapy rectal cancer specimens to advance personalized care for rectal cancer patients. Multiple endoscopic samples were obtained from 26 Stages 2 and 3 rectal cancer patients prior to receiving 5FU/RT and implanted subcutaneously into NSG mice to generate 15 subcutaneous PDXs. Second passaged xenografts demonstrated 100% correlation with the corresponding human cancer histology with maintained mutational profiles. Individual rectal cancer PDXs reproduced the 5FU/RT response observed in the corresponding human cancers. Similarly, rectal cancer PDTOs reproduced significant heterogeneity in cellular morphology and architecture. PDTO in vitro 5FU/RT treatment response replicated the clinical 5FU/RT neoadjuvant therapy pathologic response observed in the corresponding patient tumors (p < 0.05). The addition of cetuximab to the 5FU/RT regiment was significantly more sensitive in the rectal cancer PDX and PDTOs with wild-type KRAS compared to mutated KRAS (p < 0.05). Considering the close relationship between the patient's cancer and the corresponding PDX/PDTO, rectal cancer patient-derived research platforms represent powerful translational research resources as population-based tools for biomarker discovery and experimental therapy testing. In addition, our findings suggest that cetuximab may enhance RT effectiveness by improved patient selection based on mutational profile in addition to KRAS or by developing a protocol using PDTOs to identify sensitive patients.
Substances chimiques
KRAS protein, human
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Cetuximab
PQX0D8J21J
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1405-1418Subventions
Organisme : NCI NIH HHS
ID : R50 CA211529
Pays : United States
Organisme : VA
ID : I01 CX001880-01A1
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA138313
Pays : United States
Organisme : CSRD VA
ID : I01 CX001880
Pays : United States
Organisme : NIH HHS
ID : CA138313
Pays : United States
Informations de copyright
© 2020 UICC.
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