Kaposi's sarcoma herpesvirus (KSHV) is the etiologic agent for primary effusion lymphoma (PEL), a nonHodgkin type lymphoma manifesting as an effusion malignancy in the affected individual. Although KSHV has been recognized as a tumor virus for over a decade, the pathways for its tumorigenic conversion are incompletely understood, which has greatly hampered the development of efficient therapies for KSHV-induced malignancies like PEL and Kaposi's sarcoma. There are no current therapies effective against the aggressive, KSHV-induced PEL. Here we demonstrate that activation of the p53 pathway using murine double minute 2 (MDM2) inhibitor Nutlin-3a conveyed specific and highly potent activation of PEL cell killing. Our results demonstrated that the KSHV latency-associated nuclear antigen (LANA) bound to both p53 and MDM2 and that the MDM2 inhibitor Nutlin-3a disrupted the p53-MDM2-LANA complex and selectively induced massive apoptosis in PEL cells. Together with our results indicating that KSHV-infection activated DNA damage signaling, these findings contribute to the specificity of the cytotoxic effects of Nutlin-3a in KSHV-infected cells. Moreover, we showed that Nutlin-3a had striking antitumor activity in vivo in a mouse xenograft model. Our results therefore present new options for exploiting reactivation of p53 as what we believe to be a novel and highly selective treatment modality for this virally induced lymphoma.

Manipulation of the activity of the p53 tumor suppressor pathway has demonstrated potential benefit in preclinical mouse tumor models and has entered human clinical trials. We describe here an improved, extensive small-molecule chemical compound library screen for p53 pathway activation in a human cancer cell line devised to identify hits with potent antitumor activity. We uncover six novel small-molecule lead compounds, which activate p53 and repress the growth of human cancer cells. Two tested compounds suppress in vivo tumor growth in an orthotopic mouse model of human B-cell lymphoma. All compounds interact with DNA, and two activate p53 pathway in a DNA damage signaling-dependent manner. A further screen of a drug library of approved drugs for medicinal uses and analysis of gene-expression signatures of the novel compounds revealed similarities to known DNA intercalating and topoisomerase interfering agents and unexpected connectivities to known drugs without previously demonstrated anticancer activities. These included several neuroleptics, glycosides, antihistamines and adrenoreceptor antagonists. This unbiased screen pinpoints interference with the DNA topology as the predominant mean of pharmacological activation of the p53 pathway and identifies potential novel antitumor agents.

Each normal organ and pathological condition contains organ- or disease-specific molecular tags on its vasculature that constitute a vascular 'zip code' system. Tissue-selective tumour metastasis may also depend on vascular addresses. We have used phage display peptide libraries to map disease-specific differences in the vasculature. By using this technology, we have isolated several peptides which are targeted specifically to tumour blood vessels, lymphatic vessels and/or tumour cells. Some of the tumour-homing peptides recognize common angiogenesis markers and are capable of binding to several types of tumour, whereas other peptides recognize tumour-type-specific differences. We have also shown that the vasculature of a pre-malignant lesion differs from that of a full-blown tumour and also from the vasculature of the corresponding normal organ. Our peptides have revealed molecules that act as novel biomarkers of this vascular heterogeneity. Interestingly, some of our homing peptides are able to penetrate the target cells. This internalization differs from that of the Tat, penetratins and other related peptides in that our peptides enter the cell in a cell-type-specific manner. These peptides appear to be able to concentrate in the target tissue, making them particularly efficient delivery vectors for the targeting of drugs, other therapeutic moieties and imaging agents.

Malignant gliomas are associated with high mortality due to infiltrative growth, recurrence and malignant progression. Even with the most efficient therapy combinations, median survival of the glioblastoma multiforme (grade IV) patients is less than 15 months. Therefore, new treatment approaches are urgently needed. We describe here identification of a novel homing peptide that recognizes tumor vessels and invasive tumor satellites in glioblastomas. We demonstrate successful brain tumor imaging using radiolabeled peptide in whole-body SPECT/CT-imaging. Peptide-targeted delivery of chemotherapeutics prolonged the lifespan of mice bearing invasive brain tumors and significantly reduced the number of tumor satellites compared to the free drug. Moreover, we identified mammary-derived growth inhibitor (MDGI/H-FABP/FABP3), as the interacting partner for our peptide on brain tumor tissue. MDGI was expressed in human brain tumor specimens in a grade-dependent manner and its expression positively correlated with the histological grade of the tumor suggesting MDGI as a novel marker for malignant gliomas.