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Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment.

ABSTRACT: Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.

SUBMITTER: Hung KE

PROVIDER: S-EPMC2824379 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment.

Hung Kenneth E KE Maricevich Marco A MA Richard Larissa Georgeon LG Chen Wei Y WY Richardson Michael P MP Kunin Alexandra A Bronson Roderick T RT Mahmood Umar U Kucherlapati Raju R

Proceedings of the National Academy of Sciences of the United States of America 20100104 4

Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates t ...[more]

PMID: 20080688

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Project description:Pituitary neuroendocrine tumors (PitNETs) are the most common pituitary tumors and the second most common brain tumors. Although the vast majority (>90%) are benign, a small percentage (<2%) are aggressive. These aggressive PitNETs (AgPitNETs) are defined by the presence of radiological invasion, a high rate of cell proliferation, resistance to conventional treatments, and/or a high propensity for recurrence. Lastly, there are the rare pituitary carcinomas, also known as metastatic PitNETs (MetPitNETs), which account for only 0.2% of cases and are defined by the presence of craniospinal or distant metastases. At present, there are no definitive factors that allow us to predict with certainty the aggressive behavior of PitNETs, making the therapeutic management of AgPitNETs a real challenge. Surgery is considered the first-line treatment for AgPitNETs and MetPitNETs. Radiation therapy can be effective in controlling tumor growth and regulating hormone hypersecretion. Currently, there are no approved non-endocrine medical therapies for the management of AgPitNETs/MetPitNETs, mainly due to the lack of randomized controlled clinical trials. As a result, many of the medical therapies used are off-label drugs, and several are under investigation. Temozolomide (TMZ) is now recognized as the primary medical treatment following the failure of standard therapy (medical treatment, surgery, and radiotherapy) in AgPitNETs/MetPitNETs due to its ability to improve overall and progression-free survival rates in responding patients over 5 years. Other therapeutic options include pituitary-targeted therapies (dopamine agonists and somatostatin analogs), hormonal antisecretory drugs, non-hormonal targeted therapies, radionuclide treatments, and immunotherapy. However, the number of patients who have undergone these treatments is limited, and the results obtained to date have been inconsistent. As a result, it is imperative to expand the cohort of patients undergoing treatment to better determine the therapeutic efficacy and safety of these drugs for individuals with AgPitNETs/MetPitNETs.

Project description:Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed.Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach.The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous).This simulation study demonstrates that the PD effect predicted from in vitro growth inhibition assays does not accord well with the PD effect of the anti-malarials observed within the patient. This simulation-based PK-PD modelling approach should not be considered as a replacement to conducting clinical trials but instead as a decision tool to improve the design of a clinical trial during drug development.

Dataset Information

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment.

Publications

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment.

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