Innovative Minds in Prostate Cancer Today IMPaCT Conference Congressionally Directed Medical Research Program of the U.S. Department of Defense Dr. Martin H. Hager presentation New treatment strategies Angiogenesis, Invasion, Metastasis Martin H. Hager Targeted Therapy Cancer Angiogenesis Metastasis

2. Dr. Martin H. Hager – Instructor in Surgery
Harvard Medical School

3. The metastatic cascade

4. Tumor cell invasion mechanisms
MAT
EMT

5. Mesenchymal cell movement

6. Tumor cell invasion mechanisms
MAT
EMT

7. Amoeboid cell movement

8. Identification of significant focal copy number alterations
Beroukhim et al. Nat. 463, 18 Feb 2010

9. DIAPH3 loss is associated with metastatic prostate cancer
Breast
Carcinoma
Prostate
Carcinoma
Hepatocellular
CarcinomaChr13

10. DIAPH3 loss is associated with metastatic prostate cancer

11. DIAPH3log2copy
numberunits
-0.5
0.1
0
-0.1
-0.2
-0.3
-0.4
n=181 n=37
Primary
Site
Met
DIAPH3log2copynumberunits
-0.5
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
Gleason Score
6 87 9
n=53 n=12n=102 n=12 n=36
Met
DIAPH3 loss is associated with metastatic prostate cancer

12. An unidentified region of HD matches the DIAPH3 gene locus

13. An unidentified region of HD matches the DIAPH3 gene locus

14. DRF3 forms a complex with EGFR

15. DRF3 regulates EGFR trafficking

16. DRF3 regulates EGFR signaling

17. DRF3 regulates proliferation and epithelial morphogenesis

18. Loss of DRF3 cooperates with RAS to promote cell invasion

19. Loss of DRF3 cooperates with RAS to promote cell invasion

20. HMEC HRASV12 Control shRNA HMEC HRASV12 DRF3 shRNA
Loss of DRF3 cooperates with RAS to promote cell invasion

21. Loss of DRF3 promotes an amoeboid phenotype

22. Loss of DRF3 promotes invasion and metastasis

23. Supported by:
In collaboration with:
Michael J. Eck, M.D., Ph.D.
David S. Pellman, M.D.
James E. Bradner, M.D.
Richard O. Hynes, Ph.D.
Henry H. Higgs, Ph.D.
Joan S. Brugge, Ph.D.
Jose M. Silva, Ph.D.
William C. Hahn, M.D., Ph.D.
Sizhen Gao, M.D.
Ghassan Mouneimne, Ph.D.
Robert A. Weinberg, Ph.D.
Gregory Hannon, Ph.D.
Ilona N. Holcomb, Ph.D.
William B. Isaacs, Ph.D.
Wennuan Liu, Ph.D.
Acknowledgements:
Michael R. Freeman, Ph.D.
the Freeman lab
Please see poster P24-39 tomorrow, 4:00-5:30 PM
(P24 - Genetics and Molecular Biology II)