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许茹冰·短视频运营精准获客

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许茹冰·短视频运营精准获客

can explain why the study of GEA and treatment options have lagged behind the progress

in other cancer research. “Heterogeneity among the cells of an individual tumor can

wreak havoc with efficacy predictions made from animal experiments that typically

examine at most a handful of tumor models” (Kamb ). While a single driver

mutation or simple pattern of mutations leading to cancer development can help identify

an appropriate treatment option, the inherent heterogeneity of gastro-esophageal

adenocarcinoma, as Alexander Kamb has characterized it, has “wreaked havoc” on

efforts to identify an effective treatment. That is to say that simply targeting the driver

mutation can be sufficient in less heterogenous cancers, but the complexity of the

mutational profile in GEA demonstrates why this is not sufficient for this specific cancer

type. “Chemotherapy has, in fact, transitioned to the age of ‘targeted therapy’”(DeVita

and Chu ). In place of more cytotoxic chemotherapy drugs, owing to our ability to

sequence and analyze tumor tissue, therapies that are specific to a given mutation in one’s

cancer have become part of a standard screening protocol. In fact, clinical trials

involving recurrent mutations of a specific genetic signature work well in a mouse model.

In his review of cancer models, Kamb goes so far as to say that “the single most

important determinants of success is the degree to which the cell models match the

genetic traits of the real malignancy to be treated in the clinic” (Kamb ). While

Kamb’s assessment was correct and advances in clinical response were impressive for the

exemplified cancers (HER/neu breast cancer and BCR/ABL chronic myelogenous

leukemia), clinical response in gastro-esophageal adenocarcinoma had yet to see the same

benefit.

Indeed, many clinical trials were conducted with preliminary drug response data

such as the EXPAND trial, REAL trial, RILOMET- trial, and were discontinued

prematurely because patient responses to the drugs did not recapitulate the expected

outcome from the original model and improvement was not observed (Nagaraja, Kikuchi,

and Bass ). The failure of these GEA-specific clinical trials after successful

outcomes using pre-clinical models calls into question the quality of the pre-clinical

model and its predictive value. Multiple negative clinical trial results using gene

amplification/mutation information alone pointed to the need to find more accurate

predictive factors to match an effective therapeutic to a responsive patient or patient

population. These circumstances gave rise to the possibility of developing a personalized

medicine pipeline for patients who do not respond to standard of care or at least a model

within which to study the drug/tumor interaction.

Specific goals of the present review

Many gastro-esophageal adenocarcinoma patients will not respond to first line

therapy, many may develop therapeutic resistance, or will show disease recurrence.

Furthermore, as noted earlier, even though a great deal of research and drug screening has

been conducted in this field, these efforts have historically failed to produce effective

actionable therapeutics for patients. The goal of this literature review is to evaluate the

potential promise of the organoid model and assess what it brings to in vitro drug

screening in gastro-esophageal adenocarcinoma research. The following discussion will

serve as an overview and evaluation of the work that has been conducted to date, and

present a critical consideration about how this new model system can contribute to our

understanding of GEA and to our treatment of patients. The review will outline what the

literature suggests as the potential benefits of this burgeoning model system in addressing

the pitfalls of the past, its clinical relevance, and the potential shortcomings of organoids

for the sake of in vitro drug screening. Finally, work currently being carried out by

myself and our research team and how that research is meant to advance the utility of

organoids and the organoid model in GEA research, specifically from bench-to-bedside

will be discussed. Some of the ongoing work in the field, and how it may resolve some

of the lingering questions and limitations of the model, will be addressed briefly.

PUBLISHED STUDIES

At their most basic level, “organoids” are simplified in vitro mini-organs (mini

guts in the case of gastro-esophageal adenocarcinoma research). They are structures that

consist of multiple cells interacting with one another and creating organoids which share