Name: development and maintenance of a preclinical patient derived tumor xenograft model for the investigation of novel anti-cancer therapies
Uploaded: 2016-09-30T13:00:00
Description: Watch this Scientific Journal Video about Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies at JoVE.com

This work was supported by grant 1R01CA152303-01.

윤리 정책 : 환자 유래 대장 선암 종양 표본이 콜로라도 여러 임상 시험 심사위원회 (08-0439)에 의해 승인 된 프로토콜에 따라 콜로라도 병원의 대학에서 환자 동의에서 얻었다. 모든 동물의 작업은 콜로라도 덴버 기관 동물 관리 및 사용위원회의 대학에 의해 승인 동물 프로토콜에 따라 수행 하였다 (IACUC, 프로토콜 # 51412 (06) 1E와 96813 (04) 1E). 1. 받기 및 환자 혈액을 준비 <ol><l...

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PDTX 신약 개발 플랫폼은 신규 화합물의 임상 활동을 예측 신뢰할 수없는 다른 전임상 모델의 단점을 개선 모델을 제공합니다. 중요한 것은,이 모델에서 종양이 생물학적으로 안정, 전이성 잠재력을 보유하고 세대 유사한 약물 반응성을 나타낸다. 이 모델에서, 환자 유래의 종양은 무 흉선 누드 마우스에 주사 계대하고,이어서 치료의 평가에 사용된다. 등 성공적인 PDTX 은행에 대한 몇 가지 중요한 ...

대장 암 (CRC)는 미국에서 암 사망에 크게 기여. 2015 년, 49,700 사망 1 CRC의 예상 132,700 새로운 사례가 있었다. 국소 질환 환자의 예후가 우수하지만, 고급 질환 환자는 신규 치료법의 개발이 중요한 우선 순위 결정, 불량한 결과를 갖는다. 치료 화학 요법이 질병에 배포 된 새로운 생물학적 제제의 기준에도 불구하고, 전체 생존 만 증분 증가하고있다. 따라서,이 질병에서 종양 성장을 촉진 관련된 드라이버 경로를 이해하는데 상당한 노력이 존재한다. 암 게놈 아틀라스 네트워크는 최근 다수의 주요 CRC의 이상 조절에 관여하고 포함하는 경로 확인했습니다 : WNT를, 포스 3- 키나제 (PI3K), RAS, 변형 성장 인자 β (TGF-β의)와 TP53 2. 함께 조사는 오티 설명과 함께CRC 성장을 강화할 그녀의 경로를 크게이 환자군 3-5 생존을 개선하기위한 새로운 치료법의 개발을 촉발 하였다. 종양 치료제 개발에 활용 전임상 모델은 이러한 신규 한 화합물의 임상 적 활성을 예측하는 과정이 필수적이었다. 다양한 전임상 모델은 신약 개발 과정에서 사용되어왔다. 전임상 트랜스 제닉 동물 모델 및 세포주 크게 때문에 인간 종양의 복잡도를 반영하기 위해 자신의 무능력을, 신규 종양 치료법의 임상 적 활성을 결정하는데 성공적이지 않은 불멸화 것을 고려하면, 환자 유래의 종양 이종 이식 (PDTX) 모델이 확립되었다. 이 모델의 가장 큰 장점은 종양 이질성은 그대로 유지하고 밀접하게 원래 환자 종양 6-9의 분자 특성과 clonality을 반영하는 것입니다. PDTX 모델은 생체 내에서 우수한을 제공전임상 플랫폼은 새로운 에이전트, 약물 내성 경로, 조합 전략, 암 줄기 세포 생물학 (10)을 공부한다. PDTX 공정의 일반적인 개요는도 1에 도시되어있다. 또한, 병원에서 시작 그 초과 종양 조직이 일부 연구에 사용될 수 있도록 환자 동의. 다음으로, 수술로 종양의 조각은 병리학 자에 의해 싫어할하고 연구 인력으로 운반 할 미디어에 넣어. 바로 그 후, 종양의 단면은 작은 조각으로 절단하고, 면역 결핍 마우스의 피하에 이식. 종양 성장 후에는 종양 (10)을 유지하기 위해 다른 세대의 마우스로 계대된다. 전형적으로, F3 생성 후에 종양은 신규 화합물 및 / 또는 조합 치료를 평가 치료 연구로 확장 될 수있다. 활용하여 차세대 서열 (엑솜 서열, RNA 서열과 SNP 어레이) 가능성 예측 바이오 마커 발견하다특정 치료에서 효과를 유도 할 수있다 환자의 선택에 도움 에디션. 1) 단일 에이전트로 또는 조합하여 새로운 치료법의 효능을 평가하고 2) 이전에 임상 시험에 대한 민감도 또는 저항의 예측 바이오 마커를 식별 : PDTX 모델을 사용하는 무엇보다 중요한 목표로합니다. 이 논문에서, 우리는 CRC PDTX 은행의 개시 및 유지 보수 방법론을 제공하고 신약 개발의 발견이 모델의 장점과 한계를 제공합니다. <img alt="그림 1" src="/files/ftp_upload/54393/54393fig1.jpg" /> CRC를 PDTX 모델 프로토콜의 그림 1. 개요. 환자 유래의 종양은 수술받은 즉시 피하 무 흉선 누드 마우스에 주입된다. 종양이 성장하면 그것은 다음 세대로 확장하고 결국 치료 연구에 확장됩니다. 치료 RESPONSE를을 평가하고 예측 바이오 마커는. 환자 선택에 도움을 수 식별 <a href="https://www.jove.com/files/ftp_upload/54393/54393fig1large.jpg" target="_blank">이 그림의 더 큰 버전을 보려면 여기를 클릭하십시오.</a>

<table border="0" cellpadding="0" cellspacing="0" width="915">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">RPMI or DMEM</td>
			<td style="width:81px;">Corning</td>
			<td style="width:119px;">10-040-CV</td>
			<td style="width:499px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Penicillin-Streptomycin</td>
			<td style="width:81px;">Corning</td>
			<td style="width:119px;">30-002-CI</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Non-essential Amino Acids</td>
			<td style="width:81px;">Corning</td>
			<td style="width:119px;">25-025-CI</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Fetal Bovine Serum</td>
			<td style="width:81px;">Corning</td>
			<td style="width:119px;">35-010-CV</td>
			<td>Thaw in -4 &#176;C, then activate for 30 minutes at 60 &#176;C water bath</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">CPT blood tube</td>
			<td style="width:81px;">BD vacutainer</td>
			<td style="width:119px;">362761</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Microcentrifuge tube</td>
			<td style="width:81px;">Surelock</td>
			<td style="width:119px;">A-7002</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Phospate-Buffered Saline</td>
			<td style="width:81px;">Corning</td>
			<td style="width:119px;">21-040-CV</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Cyrogenic vials</td>
			<td style="width:81px;">Cyroking</td>
			<td style="width:119px;">C0732901</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Plastic tumor cutting dish</td>
			<td style="width:81px;">Trueline</td>
			<td style="width:119px;">TR4001</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Scissors</td>
			<td style="width:81px;">Roboz</td>
			<td style="width:119px;">RS-5881</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Forceps</td>
			<td style="width:81px;">Roboz</td>
			<td style="width:119px;">RS-5135</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Matrigel (gelatinous protein mixture)</td>
			<td style="width:81px;">Corning</td>
			<td style="width:119px;">354234</td>
			<td>Store at -20 or -80 &#176;C, then thaw on ice, do not leave at room temperature</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">10% Formalin cups</td>
			<td style="width:81px;">Protocol</td>
			<td style="width:119px;">032-059</td>
			<td></td>
		</tr>
		<tr height="22">
			<td height="22" style="height:22px;width:216px;">Liquid Nitrogen Dewar Storage</td>
			<td style="width:81px;">Thermolyne</td>
			<td style="width:119px;">CY50900</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Portable liquid nitrogen dewar</td>
			<td style="width:81px;">Nalgene</td>
			<td style="width:119px;">4150-2000</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Dimethyl Sulfoxide</td>
			<td style="width:81px;">Fischer</td>
			<td style="width:119px;">67-68-5</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Freezing container: Mr Frosty</td>
			<td style="width:81px;">Nalgene</td>
			<td style="width:119px;">5100-0001</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Isopropyl Alcohol</td>
			<td style="width:81px;">Decon</td>
			<td style="width:119px;">64-17-5</td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:216px;">Trocars</td>
			<td style="width:81px;">Innovative Research of America</td>
			<td style="width:119px;">MP-182</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Anesthesia machine</td>
			<td style="width:81px;">Patterson Veterinary</td>
			<td style="width:119px;">none</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Anesthesia box</td>
			<td style="width:81px;">Patterson Veterinary</td>
			<td style="width:119px;">none</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Isoflurane</td>
			<td style="width:81px;">Vet one</td>
			<td style="width:119px;">1038005</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">F-Air Canister</td>
			<td style="width:81px;">Bickford Omnicon</td>
			<td style="width:119px;">80120</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Meloxicam</td>
			<td style="width:81px;">Vet one</td>
			<td style="width:119px;">5182-90C</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Calipers</td>
			<td style="width:81px;">Fowler</td>
			<td style="width:119px;">54-100-167</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Weight scale</td>
			<td style="width:81px;">Ohaus</td>
			<td style="width:119px;">Scout Pro SP601</td>
			<td></td>
		</tr>
	</tbody>
</table>

development and maintenance of a preclinical patient derived tumor xenograft model for the investigation of novel anti-cancer therapies

Patient derived tumor xenograft (PDTX) models provide a necessary platform in facilitating anti-cancer drug development prior to human trials. Human tumor pieces are injected subcutaneously into athymic nude mice (immunocompromised, T cell deficient) to create a bank of tumors and subsequently are passaged into different generations of mice in order to maintain these tumors from patients. Importantly, cellular heterogeneity of the original tumor is closely emulated in this model, which provides a more clinically relevant model for evaluation of drug efficacy studies (single agent and combination), biomarker analysis, resistant pathways and cancer stem cell biology. Some limitations of the PDTX model include the replacement of the human stroma with mouse stroma after the first generation in mice, inability to investigate treatment effects on metastasis due to the subcutaneous injections of the tumors, and the lack of evaluation of immunotherapies due to the use of immunocompromised mice. However, even with these limitations, the PDTX model provides a powerful preclinical platform in the drug discovery process.

CRC를 PDTX 모델과 TCGA에있는 일반적인 돌연변이의 유사점 우리는 CRC PDTX 은행에서 일반적으로 돌연변이 (KRAS, NRAS, BRAF, PIK3CA, APC, CTNNB1 및 TP53)의 비율은 CRC 환자 집단에서 볼 수있는 돌연변이 주파수를 대표했다 여부를 조사 하였다. 도 2A (TCGA) 및 B (CRC PDTX 뱅크)에 도시 된 바와 같이, ...

Watch this Scientific Journal Video about Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies at JoVE.com

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

피하 전임상 모델에서 환자 유래 종양을 활용하여 새로운 치료법, 예측 바이오 마커의 발견 및 약제 내성 경로의 효능을 연구 할 수있는 좋은 방법입니다. 이 모델은 신약 개발 과정에서 임상 시험에 앞서 많은 신규 항암 요법의 운명을 결정하는데 중요하다.

전임상 환자 유래 종양 소설 안티 - 암 치료의 조사를위한 이종 이식 모델의 개발 및 유지 보수

Patient derived tumor xenograft (PDTX) models provide a necessary platform in facilitating anti-cancer drug development prior to human trials. Human tumor ...

Research

JoVE Journal

Cancer Research

Labeling of Breast Cancer Patient-derived Xenografts with Traceable Reporters for Tumor Growth and Metastasis Studies

종양의 성장과 전이 연구 추적 가능한 기자와 유방암 환자 유래의 이종 이식의 라벨링

The use of preclinical models to study tumor biology and response to treatment is central to cancer research. Long-established human cell lines, and many ...

연구

암 연구학

A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies

전임상 치료의 양적 및 종 방향 평가를위한 동계 마우스 모델 전이성의 신장 세포 암

Renal cell carcinoma (RCC) affects &#62; 60,000 people in the United States annually, and ~ 30% of RCC patients have multiple metastases at the time of ...

Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma

인간의 맨 틀 세포 림프 종의이 종이 식 마우스 모델에서 종양 Engraftment

B lymphocytes are key players in immune cell circulation and they mainly home to and reside in lymphoid organs. While normal B cells only proliferate when ...

Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma

환자에서 파생 된 연 조직 육 종의 기본 문화 설립

Soft tissue sarcomas (STS) represent a spectrum of heterogeneous malignancies with a difficult diagnosis, classification, and management. To date, more ...

Digital Polymerase Chain Reaction Assay for the Genetic Variation in a Sporadic Familial Adenomatous Polyposis Patient Using the Chip-in-a-tube Format

튜브에 칩 형식을 사용 하 여 산발적 인 가족 용 대 환자에 있는 유전 변이 대 한 디지털 중 합 효소 연쇄 반응 분석 결과

The quantitative analysis of human genetic variation is crucial for understanding the molecular characteristics of serious medical conditions, such as ...

Investigation of Genetic Dependencies Using CRISPR-Cas9-based Competition Assays

CRISPR-Cas9-기반 경쟁 분석 실험을 사용 하 여 유전 종속성의 조사

Gene perturbation studies have been extensively used to investigate the role of individual genes in AML pathogenesis. For achieving complete gene ...

Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis

인간 비뇨기과 세포 암 및 대장암 종양 성장 및 자발적 전이를 위한 환자 유래 직교 이종이식 모델

Cancer patients have poor prognoses when lymph node (LN) involvement is present in both high-grade urothelial cell carcinoma (HG-UCC) of the bladder and ...

Patient-derived Heterogeneous Xenograft Model of Pancreatic Cancer Using Zebrafish Larvae as Hosts for Comparative Drug Assessment

비교 약물 평가를 위한 호스트로 Zebrafish 애벌레를 사용하여 췌장암의 환자 유래 이종 이종이식 모형

Patient-derived tumor xenograft (PDX) and cell-derived tumor xenograft (CDX) are important techniques for preclinical assessment, medication guidance and ...

A Melanoma Patient-Derived Xenograft Model

흑색종 환자 유래 이종이식 모델

Accumulating evidence suggests that molecular and biological properties differ in melanoma cells grown in traditional two-dimensional tissue culture ...

Establishment of Gastric Cancer Patient-derived Xenograft Models and Primary Cell Lines

위암 환자 유래 이종이식 모델 및 1차 세포주 구축

The use of preclinical models to advance our understanding of tumor biology and investigate the efficacy of therapeutic agents is key to cancer research. ...