Document text
Principal Investigator: Jesse Joshua Smith
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $580,684
Funding agency: National Cancer Institute
We propose to develop rectal cancer organoids (tumoroids) as
individualized models and to build a large rectal cancer tumoroid repository. Research on rectal cancers is
hampered by the paucity of models. Of the few existing in vivo models of rectal cancer, none place the tumors
in the rectal lumen, so the models fail to mimic the correct anatomic environment and local invasion. The
existing models also have not been observed to metastasize. Another problem is that we lack accurate means
to predict whether individual rectal cancer patients will respond to chemotherapy or radiation, both of which are
part of the current standard of care. We believe that both the paucity of models and the lack of predictive tools
can be addressed by patient-derived tumoroids. Tumoroids can be grown in 3-dimensional culture ex vivo or
implanted into mice, so they offer a flexible research platform. In preliminary results, we have derived tumoroid
lines from multiple patients' rectal cancers and found them to resemble the corresponding patient tumors. The
tumoroids, when implanted in mice endoluminally (i.e. in the rectum), formed locally invasive tumors capable of
metastasis. Moreover, we found tumoroids to have clinically relevant responses to chemotherapy and
radiation. Thus, drawing from these preliminary data, we hypothesize that rectal cancer tumoroids mirror the
traits of their original tumors, can be used to predict patients' response to therapy, and, when implanted
endoluminally into mice, can serve as an optimal model of rectal cancer.
We plan to develop 100 new tumoroids, which we expect to encompass much of the diversity of human rectal
adenocarcinoma. The tumoroids will be analyzed in ex vivo culture and in two mouse models: the endoluminal
implantation model and a conventional flank injection model. In these settings, we will test whether the
tumoroid accurately reflects its tumor of origin in terms of mutations, histology, and gene expression. We will
determine whether response of the tumoroids to patient-specific chemotherapy and radiation can predict the
corresponding patient's response. Of particular interest is whether individual human rectal cancers are more
accurately modeled by endoluminal implantation than by flank injection. Finally, to integrate our findings into a
comprehensive platform for broad use, we will develop a rectal cancer tumoroid biorepository seamlessly
integrated with online pathologic, genomic, and model-specific information. The online platform will be built
within our institution's cancer genomics portal, then integrated into the NCIP Hub. We have assembled a
collaborative team with expertise in colorectal surgical oncology, radiation oncology, and pathology; organoids;
mouse models; biostatistics; and bioinformatics. We anticipate that the proposed research will credential
tumoroids as accurate models for rectal cancer research and for predicting patient responses to therapy. The
large tumoroid biorepository is likely to stimulate research on new treatments for rectal cancer. The ultimate
result will be new treatment options and better treatment selection for patients affected by this deadly disease.
Terms: <2-dimensional><3-D><3-Dimensional><3D><Acceleration><Address><Adenocarcinoma of the Rectum><Affect><Anatomic Sites><Anatomic structures><Anatomy><Antioncogene Protein p53><Bio-Informatics><Bioinformatics><Biology><Biometrics><Biometry><Biostatistics><C-K-RAS><Cancer Patient><Cancers><Cell Culture Techniques><Cell Line><CellLine><Cellular Tumor Antigen P53><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinical><Collection><Colon and Rectal Surgery><Colorectal Surgery><Communities><Complex><Credentialing><Data><Development><Diagnosis><Disease><Disorder><Environment><Gene Expression><Genetic Alteration><Genetic Change><Genetic defect><Genitourinary><Genitourinary system><Genomics><Goals><Histology><Human><Implant><Incidence><Individual><Induction Therapy><Injections><Institution><Invaded><Investigation><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Life><Location><MSKCC><Malignant Neoplasms><Malignant Tumor><Memorial Sloan-Kettering Cancer Center><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Metastasis><Oncogene K-Ras><Oncoprotein p53><Operative Procedures><Operative Surgical Procedures><Organ><Organoids><P53><PDX model><Pathologic><Pathology><Patient Selection><Patient derived xenograft><Patients><Pelvic><Pelvic Region><Pelvis><Persons><Phosphoprotein P53><Phosphoprotein pp53><Physiologic><Physiological><Protein TP53><QOL><Quality of life><RASK2><Radiation><Radiation Oncology><Radiation therapy><Radiotherapeutics><Radiotherapy><Rectal Adenocarcinoma><Rectal Cancer><Rectal Carcinoma><Rectum><Research><Research Resources><Resources><Secondary Neoplasm><Secondary Tumor><Selection for Treatments><Strains Cell Lines><Surgical><Surgical Interventions><Surgical Oncology><Surgical Procedure><TP53><TP53 gene><TRP53><Testing><Transplantation><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Tissue><Urogenital><Urogenital System><anti-cancer research><biobank><biorepository><cBioPortal><cancer genomics><cancer metastasis><cancer research><cell culture><cell cultures><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><clinical relevance><clinically relevant><colon and rectum surgery><colon cancer cell line><colorectal cancer cell line><cultured cell line><depository><developmental><effective therapy><effective treatment><flexibility><flexible><genome mutation><global gene expression><global transcription profile><implantation><in vivo><in vivo Model><individual patient><individual response><individualized response><induction therapies><interest><malignancy><mouse model><murine model><neoplasm/cancer><oncogenomics><oncologic surgery><p53 Antigen><p53 Genes><p53 Tumor Suppressor><patient derived xenograft model><patient response><patient specific response><pilot test><pre-clinical><preclinical><predict responsiveness><predicting response><predictive tools><protein p53><radiation or chemotherapy><radiation treatment><repository><response><response to therapy><response to treatment><responsive patient><selection of treatment><standard care><standard of care><standard treatment><subcutaneous><subdermal><success><surgery><survival outcome><therapeutic response><therapy response><therapy selection><three dimensional><tool><trait><transcriptome><transplant><treatment response><treatment responsiveness><treatment selection><treatment with radiation><tumor><tumor cell metastasis><two-dimensional><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>