Genetically Engineered Cancer Models, But Not Xenografts, Faithfully Predict Anticancer Drug Exposure in Melanoma Tumors

Combest, Austin J.; Roberts, Patrick; Dillon, Patrick M.; Sandison, Katie; Hanna, Suzan K.; Ross, Charlene; Habibi, Sohrab; Zamboni, Beth A.; Müller, Markus; Brunner, Martin; Sharpless, Norman E.; Zamboni, William C.

doi:10.1634/theoncologist.2012-0274

Cited by 33 publications

(37 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have shown that the PK of carboplatin in genetically engineered mouse models (GEMMs) of melanoma more closely resembles the tumor disposition of carboplatin seen in patient with cutaneous tumors when compared to other transplanted melanoma tumor models (Combest et al 2012). The combination of the results from the study by Combest et al (2012), and our current study suggest that flank tumor models may not be optimal to evaluate the tumor delivery and efficacy of CMAs. However, the comparison of the tumor delivery of CMAs and SMs in several types of tumors models and in patients with solid tumors needs to be performed to confirm these results.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

et al. 2014

Self Cite

View full text Add to dashboard Cite

The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0–last values than their CMA comparators and all SMs had greater tumor RDI-OT AUC0–6 h values than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems.

show abstract

Section: Discussionmentioning

confidence: 99%

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…33,34 Notwithstanding the above criticisms, GEMMs may have advantages over xenograft models in their cellular composition and/or sensitivity to therapeutic agents. 48 Specifically, GEMM tumors contain stromal and hematopoietic components not possible in a human tumor xenograft setting, and thus these tumors may respond more appropriately to small molecules, immunomodulatory, and/or biological agents that cross-react with mouse antigens. Nevertheless, for the various reasons outlined above, GEMMs will likely provide limited insight into oncogenesis and patient tumor heterogeneity.…”

Section: Traditional Models Have Not Predicted Clinical Successmentioning

confidence: 99%

Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

Williams

Anderson

Santaguida

et al. 2013

Laboratory Investigation

165

166

View full text Add to dashboard Cite

Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer.

show abstract

“…Genetically engineered mouse (GEM) models result in spontaneously growing tumors as opposed to induced; that is they begin growing from a small number of mutated cells and thus may more accurately represent the natural development of D. Ling et al tumors. In fact, preliminary studies seem to suggest they are more predictive of clinical outcomes than their xenograft counterparts [183]. Thus we wanted to grow both a spontaneous GEM mammary tumor and a 1 × 10 6 -cell induced mammary tumor in the same mouse.…”

Section: Conclusion and Prospectivesmentioning

confidence: 99%

Surface ligands in synthesis, modification, assembly and biomedical applications of nanoparticles

2014

View full text Add to dashboard Cite

Genetically Engineered Cancer Models, But Not Xenografts, Faithfully Predict Anticancer Drug Exposure in Melanoma Tumors

Cited by 33 publications

References 23 publications

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

Surface ligands in synthesis, modification, assembly and biomedical applications of nanoparticles

Contact Info

Product

Resources

About