Partient Derived Tumor Xenographts

(1)

GIGA Journal Club

29/11/2013

PATIENT DERIVED TUMOR XENOGRAF

(PDTX)

Dr. TURTOI Andrei

Dr. BELLAHCENE Akeila

Yip Cassandre

(2)

Cancer models

• _{In Vitro cell culture :}

- Behavioral changes from

primary tumor

- Loss of complexity

- Loss of heterogeneity

- Selective pressure

• _{Injection in mice :}

- No microenvironment reproduction

- No interaction with immune cells

- Irreversible changes in genes

expression profiles

(3)

PDTX

Patient Derived Tumor Xenograf:

(4)

PDTX

Tumor mass isolation

Amplification Characterization Characterization freezing Fragmentation Isolation freezing

(5)

Anticancer drug response and expression of molecular markers in early-passage xenotransplanted colon carcinomas

Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice

Patent derived first generation xenograph of non-small cell lung cancer: promissing tool for predicting personalized chemotherapy

Growth of xenografted squamous cell carcinoma of the head and neck--possible correlation with patient survival

Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation

Short-term human prostate primary xenografts: an in vivo model of human prostate cancer vasculature and angiogenesis

Establishment and characterization of five new human renal tumor xenografts A reproducible brain tumour model established from human glioblastoma biopsies

Use of nude mouse xenografts as preclinical screens. Characterization of xenograft-derived melanoma cell lines

(6)

(7)

(8)

PDTX

Powerfull toll for studying tumor biology and therapeutic agent

• Mentainance of:

- Histological feature of primary tumor

- Gene expression profile

- Tumor microenvironment

- SNPs and copy number varients

• Orthotopic engraftment:

- Is a good reflexction of patient response to chemotherapy

- Respects a metastatic pattern very similar to original tumor

• Genetic changes generated by passages represent genomic rearrangement intrisic to tumor

progression

Is PDTX a valid model ?

(9)

Why PDTX

METASTASIS STUDIES

Drug Discovery

Pharmacodynamics

Drug combination

Patient personalised therapy

Tumor initiation and developement

Biomarker discovery

(10)

Preclinical drug screening

(11)

Investment

More than 400 cell lines and PDTX

More than 350 PDTX model

(12)

Investment

(13)

Center of Resource for Experimental Models of Cancer

(CReMEC) Consortium

Investment

Hospitals

Academic groups

Biotehnology companies

Pharmaceutical companies

(14)

Tumor grafts derived from women with breast

cancer authentically reflect tumor pathology, growth,

metastasis and desease outcomes

authentically

growth

(15)

Tumor graft bank generation

49 fresh cancer samples

42 patients

NOD/SCID mice

18 tumor graft lines growth

13 tumor graft lines maintenance

through serial transplantation

12 tumor graft lines

(16)

Maintenance of breast cancer

subtypes

Maintenance of breast cancer

subtypes

-/-/-+/+/+

(17)

Maintenance of breast cancer

subtypes

Maintenance of breast cancer

subtypes

(18)

Maintenance of breast cancer

subtypes

Maintenance of breast cancer

subtypes

ID Subject information Xenograft information HCI-001 Basal like Basal like

HCI-002 Basal like Basal like HCI-003 Luminal B Luminal B HCI-004 Basal like Basal like HCI-005 Luminal B Luminal B HCI-006 Luminal B Luminal B HCI-007 Luminal B Luminal B HCI-008 Basal like Luminal B HCI-009 HER2-like Luminal B HCI-010 Basal like Basal like HCI-011 Luminal B Luminal B HCI-012 Luminal B Luminal B

(19)

Validation of tumor graft

epithelial nature

Validation of tumor graft

epithelial nature

(20)

Lost of human stroma

in tumor grafts

Lost of human stroma

in tumor grafts

h-CD45 (patient)

h-CD45 (graft)

m-CD45 (graft)

(21)

Response of tumor grafts ER+

to the estrogen

Response of tumor grafts ER+

to the estrogen

(22)

Response of tumor grafts ER+

to the estrogen

Response of tumor grafts ER+

to the estrogen

(23)

Maintenance of matastatic

behaviour in tumor graft

Maintenance of matastatic

behaviour in tumor graft

CK

HE

(24)

Maintenance of metastatic

behaviour in tumor graft

Maintenance of metastatic

(25)

Improvement of tumor

engraftment with hMSC

Improvement of tumor

engraftment with hMSC

(26)

Maintenance of DNA copy

number variation

Maintenance of DNA copy

number variation

(27)

Prediction of disease outcome

(28)

Conclusion

-

_{Good maintenance of:}

 Breast cancer subtypes

 Epithelial nature

 Reponse of tumor ER+ to estrogen

 Metastatic behaviour

 DNA copy number variation

-

_{Improvement of tumor engraftment with hMSC}

-

_{Prediction of disease outcome}

- Low % of engraftment success

- Unpredictable success of engraftment

- Lost of human stroma

(29)

• _Coasty

• _{Latency period after engraftment}

• _{Technical challenge (special skills)}

• Imaging studies may be required

• _{Numerous transplantation site}

• _{Difficulties with hormone dependant}

cancers

• _{Loss of primary tumor stoma}

Risk benefit

ratio

Risk benefit

ratio

• _{Less coasty than XXXXX}

• _{High similarity with the patient}

primary tumor

• _{Respect of patient’s metastasis}

profile

• _{Reflex aggressively of the tumor}

• _{Xxxx patient specific treatment}

• _{Important model for cancer study}

(30)

• Over all conclusion

For sum up