MISSION

human p53 knock-in (Hupki) mouse that is tolerant to human p53. Efficacay of the MVAp53 vaccine was
tested in the Hupki mouse. The rationale behind the study was that the intracellular concentration of
non-mutated p53 is normally very low, and cells expressing wild type p53 at low levels escape autoimmune
attack by an enhanced immune response to over-expressed mutant p53. For this purposes p53-specific
cytotoxic T-cells that are able to lyse p53-overexpressing tumors can be generated from the peripheral
blood of cancer patients. The PI explored potential of an MVAp53 vaccine for patients with malignancy
and identified appropriate laboratory links of p53-specific immunity. Based on this evidence the PI was
able to show that stimulation with MVAp53 resulting in p53-specific immunity can overcome the tolerance
to p53.
FAMRI Supported Publications
Mojica P, Smith D, Ellenhorn JDI. Adjuvant radiation therapy is associated with improved survival for gallbladder
carcinoma with regional metastatic disease. J Surg Oncol 2007;96:8-13.
Mojica-Manosa P, Smith D, Ellenhorn JDI. Adjuvant radiation therapy is associated with improved survival
in Merkel cell carcinoma of the skin. Am J Clin Oncol 2007;25:1043-1047.
Podnos YD, Smith D, Wagman LD, Ellenhorn JDI. Radioactive iodine offers survival improvement in
patients with follicular carcinoma of the thyroid. Surgery 2005;138:1072-1077.
Podnos YD, Smith DD, Wagman LD, Ellenhorn JDI. Survival in patients with papillary thyroid cancer is
not affected by the use of radioactive isotope. J Surg Oncol 2007;96:3-7.
Podnos YD, Tsai NC, Smith D, Ellenhorn JDI. Factors affecting survival in patients with anal melanoma.
Am Surg 2006;72:917-920.
Podnos YD, Smith D, Wagman LD, Ellenhorn JDI. The implication of lymph node metastasis on survival
in patients with well-differentiated thyroid cancer. Am Surg 2005;71:731-734.
Roberts M, Maghami E, Kandeel F, Yamauchi D, Ellenhorn HL, Ellenhorn JDI. The role of positron
emission tomography scanning in patients with radioactive iodine scan-negative, recurrent differentiated
thyroid cancer. Am Surg 2007;73:1052-1056.
Song GY, Gibson G, Haq W, Huang ECC, Srivasta T, Hollstein M, Daftarian P, Wang Z, Diamond D,
Ellenhorn JDI. An MVA vaccine overcomes tolerance to human p53 in mice and humans. Cancer
Immunol Immunother 2007;56:1193-1205.
ONCOGENIC ROLE OF RHBDF1 IN BREAST CANCER
Luyuan Li, PhD: University of Pittsburgh; CIA 2005
The rhomboid family of genes carries out a wide range of important functions in a variety of organisms,
but little is known about the function of the human rhomboid family-1 gene (RHBDF1). The studies have
shown that the RHBDF1 gene expression level is significantly elevated in clinical specimens of invasive
ductal carcinoma of the breast, and the protein is readily detectable in human breast cancer or head and
neck cancer cell lines. The RHBDF1 gene was silenced with short interfering RNA (siRNA) results in
breast cancer cell-line MDA-MB-435 cells and head and neck squamous cell cancer cell-line 1483 cells.
The treatment caused apoptosis to the former and autophagy to the latter. The treatment also led to
down-modulation of activated AKT and extracellular signal-regulated kinases. Diminished strength of these
critical growth signals may be the key attributes of the induction of apoptosis or autophagy. Furthermore,
the RHBDF1 gene in established MDA-MB-435 or 1483 xenograft tumors have been silenced by using
intravenously administered histidine-lysine polymer nanoparticle-encapsulated siRNA. The treatment
resulted in marked inhibition of tumor growth in both cases. The findings indicate that RHBDF1 has a
pivotal role in sustaining growth signals in epithelial cancer cells, and thus may serve as a therapeutic target
for treating epithelial cancers.
THE ROLE OF WT1 IN THE PATHOGENESIS OF BREAST CANCER
David M. Loeb MD, PhD; The Johns Hopkins University; YCSA 2002
The hypothesis of the project is that Wilms’ tumor protein (WT1), a transcription factor aberrantly
expressed in breast cancer. His aims were to identify new WT1 target genes important for proliferation and
cell death, to determine the effect of expressing WT1 in mammary epithelial cells, and to utilize a breast
tumor bank to correlate WT1 expression with expression of putative target genes and with clinical outcome.
Results have demonstrated that different forms of WT1 have distinct effects on mammary epithelial
cells, and one form promotes changes typically seen in cancer cells. Dr. Loeb and colleagues have also
identified a number of new potential WT1 target genes, including ribosomal protein S6 kinase, vascularendothelial
growth factor, and the cell survival-promoting gene, Bfl-1. Ongoing work will determine which
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